Atezolizumab Intravenous

Urothelial Carcinoma

Atezolizumab is used as a single agent for the treatment of locally advanced or metastatic urothelial carcinoma in adult patients with high programmed-death ligand-1 (PD-L1) expression (defined as PD-L1 staining in tumor-infiltrating immune cells covering at least 5% of the tumor area) who are not candidates for cisplatin-containing therapy;^[1][13] an FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy in patients who are not candidates for cisplatin-containing therapy.^[1]

Atezolizumab also is used as a single agent for the treatment of locally advanced or metastatic urothelial carcinoma in adult patients who are not candidates for platinum-containing chemotherapy regardless of PD-L1 expression.^[1]

The accelerated approval of atezolizumab for these indications is based on objective response rate and duration of response.^[1][13] Continued approval for these indications may be contingent on verification and description of clinical benefit of atezolizumab in confirmatory studies.^[1]

The current indications for atezolizumab in the treatment of locally advanced or metastatic urothelial carcinoma are based principally on the results of a single cohort (cohort 1) from an open-label, multicenter, noncomparative, 2-cohort, phase 2 study (IMvigor210).^[1][13] Cohort 1 consisted of 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy.^[1][13] The primary measure of efficacy was objective response rate as assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors (RECIST).^[1][13] Patients received atezolizumab 1200 mg administered as an IV infusion every 3 weeks until disease progression or unacceptable toxicity occurred.^[1][13] Patients with a history of autoimmune disease; those with active or corticosteroid-dependent brain metastases; those who had received a live, attenuated vaccine within 28 days prior to enrollment; and those who had received systemic immunostimulatory agents within 6 weeks or immunosuppressive agents within 2 weeks prior to enrollment were excluded from the study.^[1]

In the cisplatin-ineligible cohort (cohort 1), the median age of patients was 73 years; 91% were Caucasian, 81% were male, 80% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 66% had visceral metastases, 35% had non-bladder urothelial carcinoma, and 20% had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting.^[1][13] Most patients (73%) had low expression of PD-L1 (defined as PD-L1 staining in tumor-infiltrating immune cells covering less than 5% of the tumor area) as detected by an immunohistochemistry assay (Ventana PD-L1 [SP142]).^[1][13] Approximately 27% of patients had high expression of PD-L1 (defined as PD-L1 staining in tumor-infiltrating immune cells covering 5% or more of the tumor area).^[1] The median age of patients with high expression of PD-L1 was 67 years; 88% were Caucasian, 81% were male, 72% had a baseline ECOG performance status of 0 or 1, 56% had visceral metastases, 28% had non-bladder urothelial carcinoma, and 31% had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting.^[1] Reasons for cisplatin ineligibility included baseline renal impairment (creatinine clearance 30-59 mL/minute), poor performance status (ECOG performance status of 2), hearing loss (25-decibel or more loss at 2 contiguous frequencies), or baseline grade 2-4 peripheral neuropathy in 70, 20, 14, or 6%, respectively, of patients in the entire cohort and in 66, 28, 16, or 9%, respectively, of those in the subset with high PD-L1 expression.^[1] The objective response rate for patients in the cisplatin-ineligible cohort of this study was 23.5%; complete response was achieved in 6.7% of patients in this cohort.^[1] Among patients who had disease progression following therapy in the neoadjuvant or adjuvant setting, the objective response rate was 33%.^[1] Objective response rates in patients with high or low levels of PD-L1 expression were 28.1 or 21.8%, respectively; complete response was achieved in 6.3 or 6.9% of patients, respectively.^[1] At a median follow-up of 14.4 months, the median duration of response had not been reached.^[1]

Decreased survival with atezolizumab monotherapy compared with platinum-based therapy has been reported in an ongoing clinical trial (IMvigor130) in patients with previously untreated metastatic urothelial carcinoma with low PD-L1 expression; atezolizumab monotherapy is not currently FDA-labeled for use in such patients.^[1][14] In this trial, patients with previously untreated metastatic urothelial carcinoma who were eligible for platinum-containing therapy were randomized to receive atezolizumab monotherapy, atezolizumab in combination with platinum-based therapy (cisplatin or carboplatin in combination with gemcitabine), or platinum-based therapy alone.^[1] A preliminary data analysis showed decreased survival of patients with low PD-L1 expression who were receiving atezolizumab monotherapy compared with those receiving platinum-based therapy.^[1][14] Therefore, at the request of the independent data monitoring committee, enrollment in the atezolizumab monotherapy group was halted for patients with low expression of PD-L1 (defined as PD-L1 staining in tumor-infiltrating immune cells covering less than 5% of the tumor area) as detected by an immunohistochemistry assay (Ventana PD-L1 [SP142]).^[1][14] At a median follow-up of 11.8 months, median progression-free or overall survival in the intent-to-treat population was 8.2 or 16 months, respectively, in patients receiving atezolizumab plus platinum-based chemotherapy, and 6.3 or 13.4 months, respectively, in patients receiving placebo plus platinum-based chemotherapy.^[28] No difference in median overall survival was observed in patients receiving single-agent atezolizumab compared with those receiving placebo plus platinum-based chemotherapy.^[28]

Regulatory History

Atezolizumab received FDA approval for use in patients with locally advanced or metastatic urothelial carcinoma who progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy in 2016 under the principles and procedures of FDA's accelerated review process that allows approval based on analysis of surrogate markers of response rather than clinical end points (e.g., prolongation of overall survival).^{[4][15][18][29]} Approval for this indication was based principally on the results of a cohort of patients previously treated with platinum-containing therapy in the IMvigor210 study.^[18] As a condition of the accelerated approval process, the manufacturer of atezolizumab was required to submit data from a phase 3 study (IMvigor211) to confirm overall survival benefit of the drug in patients with platinum-refractory locally advanced or metastatic urothelial carcinoma.^[18] In the IMvigor211 study, patients were randomized (stratified by PD-L1 expression, chemotherapy, presence of liver metastases, and prognostic factors) to receive atezolizumab 1200 mg or investigator's choice of chemotherapy IV every 3 weeks.^[30] The primary end point of overall survival in the IMvigor211 study was not met in patients with platinum-refractory metastatic urothelial carcinoma with high expression of PD-L1; therefore, the manufacturer voluntarily withdrew use of atezolizumab for the treatment of platinum-refractory locally advanced or metastatic urothelial carcinoma from labeling in recognition of the principles of the accelerated approval program.^[1][18][30] The manufacturer states that patients currently receiving atezolizumab for the treatment of metastatic urothelial carcinoma previously treated with platinum-containing chemotherapy should consult their clinician about whether to continue atezolizumab therapy or consider other treatment options.^[18]

Non-small Cell Lung Cancer

Monotherapy for Previously Untreated Metastatic Non-small Cell Lung Cancer

Atezolizumab is used as monotherapy for the initial treatment of metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression and without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic aberrations.^[1][19] High PD-L1 expression is defined as PD-L1 staining of at least 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering at least 10% of the tumor area; an FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy.^[1][19]

The current indication for atezolizumab for previously untreated metastatic NSCLC in adult patients with high PD-L1 expression and without EGFR or ALK genomic aberrations is based principally on the results of a randomized, open-label, phase 3 study (IMpower110).^[1][19] In this study, 572 adults with metastatic NSCLC with squamous or nonsquamous histology who had previously untreated metastatic disease were randomized (stratified by sex, ECOG status, histology, and PD-L1 expression) in a 1:1 ratio to receive atezolizumab 1200 mg every 3 weeks or investigator's choice of platinum-based chemotherapy.^[1][19] Patients with non-squamous NSCLC were randomized to an investigator's choice of platinum-based chemotherapy received either cisplatin (75 mg/m²) in combination with pemetrexed (500 mg/m²) or carboplatin (dose required to obtain an AUC of 6 mg/mL per minute) in combination with pemetrexed (500 mg/m²); chemotherapy was administered on day 1 of each 21-day cycle for up to 4 or 6 cycles, followed by pemetrexed (500 mg/m²) as a single agent until disease progression or unacceptable toxicity occurred.^[1][19] Patients with squamous NSCLC randomized to an investigator's choice of platinum-based therapy received cisplatin (75 mg/m²) on day 1 in combination with gemcitabine (1250 mg/m²) on days 1 and 8 of each 21-day cycle or carboplatin (dose required to obtain an AUC of 5 mg/mL per minute) on day 1 in combination with gemcitabine (1000 mg/m²) on days 1 and 8 of each 21-day cycle for up to 4 or 6 cycles.^[1][19] Treatment was continued for the specified duration or until disease progression or unacceptable toxicity occurred; however, clinically stable patients with disease progression could continue treatment if they were considered to be deriving clinical benefit.^[1][19] In this study, the primary measure of efficacy was overall survival in a cohort of patients with wild-type EGFR and ALK expression.^[1]

In the cohort of 205 patients with wild-type EGFR and ALK and high PD-L1 expression, the median age was 65 years; 70% were male, 82% were White, and 17% were Asian.^[1] All patients had a baseline ECOG performance status of 0 or 1, 88% were current or former smokers, and 76% had non-squamous disease histology.^[1][19] The study excluded patients with a history of autoimmune disease; those with active or untreated CNS metastases; those who had received a live, attenuated vaccine within 28 days prior to randomization; and those who had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization.^[1][19]

In the cohort of patients with wild-type EGFR and ALK and high PD-L1 expression, median overall survival was prolonged in those receiving atezolizumab compared with those receiving platinum-based chemotherapy (20.2 versus 13.1 months; hazard ratio: 0.59).^[1][19] Median investigator-assessed progression-free survival in this cohort of patients was also prolonged in those receiving atezolizumab compared with those receiving platinum-based chemotherapy (8.1 versus 5 months; hazard ratio: 0.63).^[1][19] Investigator-assessed overall response rates were 38 or 29% in patients receiving atezolizumab or platinum-based chemotherapy, respectively.^[1][19]

At the time of the interim analysis, no difference in median overall survival was observed in patients with high or intermediate PD-L1 expression (PD-L1 staining of at least 1%, but less than 50%, of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering at least 1%, but less than 10%, of the tumor area) receiving atezolizumab or platinum-based chemotherapy (18.2 versus 14.9 months).^[1][19]

Combination Therapy for Previously Untreated Metastatic Nonsquamous Non-small Cell Lung Cancer

Combination with Bevacizumab, Paclitaxel, and Carboplatin

Atezolizumab is used in combination with bevacizumab, carboplatin, and paclitaxel for the initial treatment of metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations.^[1][16]

The current indication for atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel for the initial treatment of metastatic nonsquamous NSCLC is based principally on the results of a randomized, open-label, phase 3 study (IMpower150).^[1][16] In this study, 1202 adults with metastatic NSCLC with nonsquamous histology who had not received prior chemotherapy for metastatic disease were randomized (stratified by sex, presence of liver metastases, and PD-L1 expression) in a 1:1:1 ratio to receive 4 or 6 cycles of therapy with atezolizumab in combination with carboplatin and paclitaxel (atezolizumab-carboplatin-paclitaxel); atezolizumab in combination with bevacizumab, carboplatin, and paclitaxel (atezolizumab-bevacizumab-carboplatin-paclitaxel); or bevacizumab, carboplatin, and paclitaxel alone (bevacizumab-carboplatin-paclitaxel).^[1][16] Following the initial 4 or 6 cycles of therapy, carboplatin and paclitaxel were discontinued and patients continued receiving atezolizumab and/or bevacizumab as initially assigned until disease progression or unacceptable toxicity occurred;^[1][16] however, atezolizumab-treated patients with disease progression could continue receiving treatment if they were considered to be deriving clinical benefit.^[16] The treatment regimens were administered in 3-week cycles at the following dosages: atezolizumab 1200 mg every 3 weeks, bevacizumab 15 mg/kg every 3 weeks, carboplatin at the dose required to obtain an area under the concentration-time curve (AUC) of 6 mg/mL per minute every 3 weeks, and paclitaxel 200 mg/m² (175 mg/m² in patients of Asian ancestry) every 3 weeks.^[1][16] The primary measures of efficacy were overall survival in patients with wild-type EGFR and ALK expression (wild-type population) and progression-free survival as assessed by investigators according to RECIST in the wild-type population and in the subset of the wild-type population with high expression of an effector T-cell (Teff) gene signature.^[1][16]

The median age of patients receiving atezolizumab-bevacizumab-carboplatin-paclitaxel or bevacizumab-carboplatin-paclitaxel in the IMpower150 study was 63 years; within these 2 treatment groups, 82% of patients were Caucasian, 80% were current or prior smokers, 60% were male, 49% had negative PD-L1 expression (defined as PD-L1 expression on less than 1% of tumor cells and tumor-infiltrating immune cells, as detected by the Ventana PD-L1 [SP142] immunohistochemistry assay), 39% had high Teff gene-signature expression (defined as a score of -1.91 or greater based on PD-L1, CXCL9, and interferon gamma mRNA expression in tumor tissue, as detected by a clinical trial assay), 14% had liver metastases at baseline, 13% were of Asian ancestry, and 10% were Hispanic.^[1][16] All patients had a baseline ECOG performance status of 0 or 1.^[1][16] The study excluded patients with a history of autoimmune disease; those with active or untreated CNS metastases; those who had received a live, attenuated vaccine within 28 days prior to randomization; those who had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization; and those with tumor infiltration into the thoracic great vessels or cavitation of pulmonary lesions.^[1][16] Neoadjuvant or adjuvant chemotherapy must have been completed at least 6 months before randomization into the IMpower150 study.^[16]

In the subset of patients with wild-type EGFR and ALK expression, median progression-free survival was prolonged in those receiving atezolizumab-bevacizumab-carboplatin-paclitaxel compared with those receiving bevacizumab-carboplatin-paclitaxel (8.5 versus 7 months; hazard ratio: 0.71).^[1] At a median follow-up of approximately 20 months, median overall survival also was prolonged in those receiving atezolizumab-bevacizumab-carboplatin-paclitaxel compared with those receiving bevacizumab-carboplatin-paclitaxel (19.2 versus 14.7 months; hazard ratio: 0.78).^[1][16] However, neither progression-free survival (6.7 or 7 months, respectively; hazard ratio: 0.94) nor overall survival (19.4 or 14.7 months, respectively; hazard ratio: 0.84) was prolonged in those receiving atezolizumab-carboplatin-paclitaxel compared with those receiving bevacizumab-carboplatin-paclitaxel.^[1] In patients with wild-type EGFR and ALK expression, the objective response rate was 55% in those receiving atezolizumab-bevacizumab-carboplatin-paclitaxel, 43% in those receiving atezolizumab-carboplatin-paclitaxel, and 42% in those receiving bevacizumab-carboplatin-paclitaxel; complete responses were achieved in 4, 3, or 1% of patients receiving these respective treatments.^[1] The median duration of response was 10.8 months in patients receiving atezolizumab-bevacizumab-carboplatin-paclitaxel, 9.5 months in those receiving atezolizumab-carboplatin-paclitaxel, and 6.5 months in those receiving bevacizumab-carboplatin-paclitaxel.^[1] In patients with wild-type EGFR and ALK expression, subset analyses indicated a progression-free survival benefit for atezolizumab-bevacizumab-carboplatin-paclitaxel compared with bevacizumab-carboplatin-paclitaxel regardless of level of PD-L1 or Teff gene-signature expression and across subgroups based on sex, age, ECOG performance status, smoking status, presence of liver metastases, and KRAS mutation status.^[16]

In the subset of patients with wild-type EGFR and ALK expression and high Teff gene-signature expression, median progression-free survival was prolonged in patients receiving atezolizumab-bevacizumab-carboplatin-paclitaxel compared with those receiving bevacizumab-carboplatin-paclitaxel; however, progression-free survival was not prolonged in patients receiving atezolizumab-carboplatin-paclitaxel compared with those receiving bevacizumab-carboplatin-paclitaxel.^[1]

In an exploratory analysis, efficacy in patients receiving atezolizumab-bevacizumab-carboplatin-paclitaxel appeared to be similar in those who tested positive for anti-atezolizumab antibodies by week 4 compared with those who did not develop anti-atezolizumab antibodies by week 4.^[1] (See Immunogenicity under Cautions.)

Combination with Albumin-bound Paclitaxel and Carboplatin

Atezolizumab is used in combination with albumin-bound paclitaxel and carboplatin for the initial treatment of metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations.^[1][20]

The current indication for atezolizumab in combination with albumin-bound paclitaxel and carboplatin for the initial treatment of metastatic nonsquamous NSCLC is based principally on the results of a randomized, open-label, phase 3 study (IMpower130).^[1][20] In this study, 724 adults with stage IV metastatic NSCLC with nonsquamous histology who had not received prior chemotherapy for metastatic disease were randomized (stratified by sex, presence of liver metastases, and PD-L1 expression as detected by Ventana PD-L1 [SP142] immunochemistry assay) in a 2:1 ratio to receive atezolizumab (1200 mg) and carboplatin (dose required to obtain an AUC of 6 mg/mL per minute) on day 1 and albumin-bound paclitaxel 100 mg/m² on days 1, 8, and 15 of each 21-day cycle for up to 4 or 6 cycles, followed by atezolizumab (1200 mg) once every 3 weeks until disease progression or unacceptable toxicity occurred or carboplatin in combination with albumin-bound paclitaxel at the same dosage, followed by best supportive care or pemetrexed.^[1][20] Patients who received prior therapy with an EGFR or ALK kinase inhibitor, if appropriate, were eligible for enrollment.^[1] The primary measures of efficacy were overall survival and investigator-assessed progression-free survival according to RECIST in the subgroup of patients with wild-type EGFR and ALK.^[1][20]

In the subgroup of 681 patients with wild-type EGFR and ALK, the median age of patients was 64 years; 90% were current or prior smokers, 52% had negative PD-L1 expression (defined as PD-L1 expression on less than 1% of tumor cells and tumor-infiltrating immune cells), 59% were male, 90% were White, 5% were Hispanic, 4% were Black, and 2% were of Asian ancestry.^[1][20] Baseline ECOG performance status was 0 or 1 in 99% of patients.^[1][20] The study excluded patients with a history of autoimmune disease; those with active or untreated CNS metastases; those who had received a live, attenuated vaccine within 28 days prior to randomization; and those who had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization.^[1][20] In this subgroup of patients, median progression-free survival was prolonged in those receiving atezolizumab with carboplatin and albumin-bound paclitaxel compared with those receiving carboplatin and albumin-bound paclitaxel (7.2 versus 6.5 months; hazard ratio: 0.75).^[1][20] Median overall survival also was prolonged in those receiving atezolizumab combined with carboplatin and albumin-bound paclitaxel compared with those receiving carboplatin and albumin-bound paclitaxel (18.6 versus 13.9 months; hazard ratio: 0.80).^[1][20] In patients with wild-type EGFR and ALK, the objective response rate was 46% in those receiving atezolizumab combined with carboplatin and albumin-bound paclitaxel and 32% in those receiving carboplatin and albumin-bound paclitaxel; complete responses were achieved in 5 or 1% of patients receiving these respective treatments.^[1] The median duration of response was 10.8 months in patients receiving atezolizumab combined with carboplatin and albumin-bound paclitaxel and 7.8 months in patients receiving carboplatin and albumin-bound paclitaxel.^[1] In a subgroup analysis based on age, sex, ECOG performance status, smoking status, presence of liver metastases, and PD-L1 expression, clinical benefit (i.e., progression-free and overall survival) associated with atezolizumab plus chemotherapy compared with chemotherapy alone was consistent across subgroups in IMpower130; however, atezolizumab was not associated with an overall survival benefit in patients with liver metastases or those with EGFR or ALK genomic aberrations.^[20]

Monotherapy for Previously Treated Metastatic Non-small Cell Lung Cancer

Atezolizumab is used as a single agent for the treatment of metastatic NSCLC that has progressed during or following platinum-based chemotherapy.^[1] Patients with EGFR- or ALK-positive tumors also should have documented disease progression during or following an FDA-labeled anti-EGFR or anti-ALK therapy prior to initiating therapy with atezolizumab.^[1]

The current indication for atezolizumab in the treatment of previously treated NSCLC is based principally on the results of a randomized, open-label phase 3 study (OAK), with supporting data from a similarly designed phase 2 study (POPLAR), in patients with locally advanced or metastatic NSCLC that had progressed during or following platinum-based chemotherapy.^[1][11][12] Patients in these studies were randomized (stratified by level of PD-L1 expression in tumor-infiltrating immune cells, number of prior chemotherapy regimens, and histology) in a 1:1 ratio to receive either atezolizumab (1200 mg IV every 3 weeks) or docetaxel (75 mg/m² IV every 3 weeks).^[1][11][12] Treatment was continued until disease progression or unacceptable toxicity occurred; however, atezolizumab-treated patients with disease progression could continue receiving treatment if they were considered to be deriving clinical benefit.^[1][11][12] The studies excluded patients with a history of autoimmune disease; those with symptomatic or corticosteroid-dependent brain metastases; and those who received systemic immunosuppressive agents within 2 weeks prior to enrollment.^[1][15] In both studies, the primary measure of efficacy was overall survival.^[1][11][12]

In the OAK study, the primary efficacy population consisted of the initial 850 patients randomized in the study.^[1] In the primary efficacy population, the median age of patients was 64 years;^[1][12] 94% had metastatic disease, 74% had nonsquamous histology, 70% were Caucasian, 67% were former smokers, 61% were male, 55% had positive PD-L1 expression, 47% were 65 years of age or older, 21% were of Asian ancestry, 15% were current smokers, 10% had EGFR mutation-positive disease, 7% had KRAS mutation-positive disease, and less than 1% had ALK-positive disease.^[1][12] All patients had a baseline ECOG performance status of 0 or 1.^[1][12] Most patients (75%) had received one prior platinum-based chemotherapy regimen.^[1] In the primary efficacy population, patients receiving atezolizumab had longer median overall survival (13.8 versus 9.6 months; hazard ratio: 0.74) compared with patients receiving docetaxel; however, progression-free survival appeared to be shorter in patients receiving atezolizumab compared with those receiving docetaxel (2.8 versus 4 months).^[1] At the time of analysis, no difference in objective response rates was observed between patients receiving atezolizumab and those receiving docetaxel (14 and 13%, respectively); however, median response duration was prolonged in patients receiving atezolizumab compared with those receiving docetaxel (16.3 versus 6.2 months).^[1] Effects of atezolizumab on overall survival in the total patient population were comparable to those observed in the primary efficacy population.^[1] In the primary efficacy population, a planned subgroup analysis indicated that the risk of death was decreased with atezolizumab compared with docetaxel regardless of PD-L1 expression; however, survival benefit for atezolizumab compared with docetaxel was more pronounced in patients with high levels of PD-L1 expression (defined as PD-L1 expression on 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells) as detected by an immunohistochemistry assay (Ventana PD-L1 [SP142]) (hazard ratio: 0.41) compared with those with lower levels of PD-L1 expression (hazard ratio: 0.82).^[1][12] In an exploratory analysis, efficacy appeared to be reduced in patients who tested positive for anti-atezolizumab antibodies by week 4 compared with those who did not develop anti-atezolizumab antibodies by week 4.^[1] (See Immunogenicity under Cautions.)

In the POPLAR study, the median age of patients was 62 years.^[11][15] All patients enrolled in the study had a baseline ECOG performance status of 0 or 1, 66% had nonsquamous histology, 7% had EGFR mutation-positive disease, and 1% had ALK-positive disease.^[11][15] Approximately 67% had received one prior platinum-based chemotherapy regimen.^[15] After a median follow-up of 22 months, patients receiving atezolizumab had longer median overall survival (12.6 versus 9.7 months) compared with patients receiving docetaxel.^[11][15] Although objective response rates were similar between both treatment groups, patients receiving atezolizumab had a longer median duration of response (18.6 versus 7.2 months) compared with those receiving docetaxel.^[15] A subgroup analysis also indicated that increasing levels of PD-L1 expression were associated with an overall survival benefit for atezolizumab compared with docetaxel.^[11] Overall survival benefit for atezolizumab compared with docetaxel also was apparent regardless of histology and prior tobacco use.^[11]

Breast Cancer

Atezolizumab is used in combination with albumin-bound paclitaxel for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer in adult patients with PD-L1 expression (defined as PD-L1 staining in tumor-infiltrating immune cells of any intensity covering at least 1% of the tumor area); an FDA-approved diagnostic test is required to confirm the presence of PD-L1 expression prior to initiation of therapy.^[1][21][22] Atezolizumab is not indicated for use in combination with conventional paclitaxel for treating triple-negative breast cancer.^[1] (See Treatment-related Mortality under Cautions.)

The accelerated approval of atezolizumab for this indication is based on progression-free survival.^[1] Continued approval for this indication may be contingent on verification and description of clinical benefit of atezolizumab in confirmatory studies.^[1]

The current indication for use of atezolizumab in combination with albumin-bound paclitaxel in the treatment of unresectable locally advanced or metastatic triple-negative breast cancer in adults with PD-L1 expression is based principally on the results of a phase 3, double-blind, placebo-controlled study (IMpassion130).^[1][21][22] In this study, 902 patients with locally advanced or metastatic triple-negative breast cancer who had not received prior chemotherapy for metastatic disease were randomized (stratified by presence of liver metastases, prior taxane treatment, and PD-L1 expression) in a 1:1 ratio to receive atezolizumab 840 mg IV or placebo on days 1 and 15 in combination with albumin-bound paclitaxel 100 mg/m² IV on days 1, 8, and 15 of each 28-day cycle.^[1][21][22] Treatment was continued until radiographic disease progression per RECIST v1.1 or until unacceptable toxicity occurred.^[1][21][22] The primary measures of efficacy were investigator-assessed progression-free survival per RECIST v1.1 and overall survival in the intent-to-treat population and the subset of patients with PD-L1 expression on at least 1% of tumor-infiltrating immune cells, as detected by the Ventana PD-L1 (SP142) immunohistochemistry assay.^[1][21][22]

The median age of patients in the IMpassion130 study was 55 years and 99.6% of patients were women; 68% of patients were White, 18% were of Asian ancestry, 7% were Black or African American, 4% were American Indian or Alaskan Native, baseline ECOG performance status was 0 or 1 in 99% of patients, 41% of patients had PD-L1 expression on at least 1% of tumor-infiltrating immune cells, and liver and brain metastases were present in 27 and 7% of patients, respectively.^[1][21][22] The study excluded patients with a history of autoimmune disease; those with untreated or corticosteroid-dependent CNS metastases; those who had received a live, attenuated vaccine within 28 days prior to randomization; and those who had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization.^[1][21][22]

In the subset of patients with PD-L1 expression on at least 1% of tumor-infiltrating immune cells, median progression-free survival was prolonged in those receiving atezolizumab combined with albumin-bound paclitaxel compared with those receiving placebo and albumin-bound paclitaxel (7.4 versus 4.8 months; hazard ratio: 0.60).^[1][21] Median overall survival also was prolonged in those receiving atezolizumab combined with albumin-bound paclitaxel compared with those receiving placebo and albumin-bound paclitaxel (25.4 versus 17.9 months; hazard ratio: 0.67).^[1][21] The objective response rate was 53% in those receiving atezolizumab combined with albumin-bound paclitaxel and 33% in those receiving placebo and albumin-bound paclitaxel; complete responses were achieved in 9 and <1% of patients receiving these respective treatments.^[1] The median duration of response was 9.2 months in atezolizumab-treated patients and 6.2 months in those randomized to the placebo arm.^[1]

In the subset of patients in the IMpassion130 study with negative PD-L1 expression, no difference in median overall survival was observed between patients receiving atezolizumab in combination with albumin-bound paclitaxel compared with those receiving placebo in combination with albumin-bound paclitaxel (19.7 and 19.6 months, respectively; hazard ratio: 0.97).^[21]

Atezolizumab did not confer a survival benefit when used in combination with conventional paclitaxel in a clinical trial (IMpassion131) in patients with unresectable locally advanced or metastatic triple-negative breast cancer who had not received prior chemotherapy for metastatic disease.^[1] Atezolizumab is not indicated for use in combination with conventional paclitaxel in such patients.^[1] In this randomized, double-blind, placebo-controlled trial, patients with previously untreated, unresectable locally advanced or metastatic triple-negative breast cancer were randomized (stratified by presence of liver metastases, prior taxane treatment, and PD-L1 expression) to receive either atezolizumab 840 mg or placebo on days 1 and 15 in combination with conventional paclitaxel 90 mg/m² on days 1, 8, and 15 of each 28-day cycle.^[1] Treatment was continued until radiographic disease progression or unacceptable toxicity occurred.^[1] The primary measure of efficacy was investigator-assessed progression-free survival according to RECIST v1.1 in patients with PD-L1 expression (defined as PD-L1 expression on at least 1% of tumor-infiltrating immune cells, as detected by the Ventana PD-L1 [SP142] immunohistochemistry assay).^[1] In the subset of patients with PD-L1 expression, no difference in median progression-free survival was observed between patients receiving atezolizumab in combination with conventional paclitaxel and those receiving placebo in combination with conventional paclitaxel (6 versus 5.7 months; hazard ratio: 0.82 with a 95% confidence interval of 0.6-1.12).^[1] Median overall survival in the subset of patients with PD-L1 expression was 22.1 months in patients receiving atezolizumab and conventional paclitaxel and 28.3 months in patients receiving placebo and conventional paclitaxel.^[1]

Small Cell Lung Cancer

Atezolizumab is used in combination with carboplatin and etoposide for the initial treatment of extensive-stage small cell lung cancer (SCLC).^[1][23] Atezolizumab has been designated an orphan drug by FDA for the treatment of this cancer.^[17]

The current indication for use of atezolizumab in combination with carboplatin and etoposide for the initial treatment of extensive-stage SCLC is based principally on the results of a phase 3, double-blind, placebo-controlled study (IMpower133).^[1][23] In this study, 403 patients with extensive-stage SCLC were randomized (stratified by sex, ECOG status, and presence of brain metastases) in a 1:1 ratio to receive atezolizumab 1200 mg on day 1 in combination with carboplatin (dose required to obtain an AUC of 5 mg/mL per minute) on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 4 cycles, followed by atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity occurred, or placebo in combination with carboplatin and etoposide at the same dosages for up to 4 cycles, followed by placebo once every 3 weeks until disease progression or unacceptable toxicity occurred.^[1][23] The primary measures of efficacy were overall and progression-free survival as assessed by investigators according to RECIST v1.1.^[1][23]

The median age of patients in IMpower133 was 64 years; 97% were current or previous smokers, 65% were male, 80% were White, 17% were of Asian ancestry, 4% were Hispanic, and 1% were Black.^[1][23] All patients had a baseline ECOG performance status of 0 or 1 and 9% of patients had a history of brain metastases.^[1][23] The study excluded patients with a history of autoimmune disease; those with active or untreated CNS metastases; those who had received a live, attenuated vaccine within 4 weeks prior to randomization; and those who had received systemic immunosuppressive agents within 1 week prior to randomization.^[1][23]

At a median follow-up of 13.9 months, median overall survival was prolonged in patients receiving atezolizumab combined with carboplatin and etoposide compared with those receiving placebo, carboplatin, and etoposide (12.3 versus 10.3 months; hazard ratio: 0.70).^[1][23] Median progression-free survival also was longer in patients receiving atezolizumab combined with carboplatin and etoposide compared with those receiving placebo, carboplatin, and etoposide (5.2 versus 4.3 months; hazard ratio: 0.77).^[1][23] Clinical benefit (e.g., overall and progression-free survival) associated with the addition of atezolizumab to chemotherapy was consistent across relevant subgroups.^[23] The objective response rate was 60% in those receiving atezolizumab combined with carboplatin and etoposide and 64% in those receiving placebo, carboplatin, and etoposide; complete responses were achieved in 2 and 1% of patients receiving these respective treatments.^[1][23] The median duration of response was 4.2 months in patients receiving atezolizumab combined with carboplatin and etoposide and 3.9 months in those receiving placebo, carboplatin, and etoposide.^[1][23]

Hepatocellular Carcinoma

Atezolizumab is used in combination with bevacizumab for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.^[1][24] Atezolizumab has been designated an orphan drug by FDA for the treatment of this cancer.^[17]

The current indication for use of atezolizumab in combination with bevacizumab for the treatment of patients with previously untreated unresectable or metastatic HCC is primarily based on the results of a phase 3, open-label study (IMbrave150).^[1][24] In this study, 501 patients with unresectable locally advanced or metastatic HCC who had not received prior systemic therapy were randomized in a 2:1 ratio to receive atezolizumab 1200 mg in combination with bevacizumab 15 mg/kg, administered on the same day, once every 3 weeks, or sorafenib 400 mg orally twice daily; therapy was continued until disease progression or unacceptable toxicity occurred.^[1][24] The primary measures of efficacy were overall survival and progression-free survival as assessed by an independent review facility (IRF) according to RECIST v1.1; IRF-assessed overall response rate was also assessed using RECIST v1.1 and hepatocellular carcinoma-specific modified RECIST (mRECIST) criteria. ^[1][24]

The median age of patients in the IMbrave150 study was 65 years; 83% of patients were male, 57% of patients were of Asian ancestry, 40% were from Asia (excluding Japan), and 35% were White. ^[1][24] At baseline, macrovascular invasion and/or extrahepatic spread were present in approximately 75% of patients and AFP serum glycoprotein concentrations were at least 400 ng/mL in 37% of patients.^[1] All patients enrolled in the study had an ECOG performance status of 0 or 1 at baseline.^[1][24] The majority (82%) of patients had BCLC stage C disease at baseline, while 16 or 3% had stage B or A disease, respectively.^[1][24] Hepatitis B, hepatitis C, or nonviral liver disease were risk factors for HCC in 48, 22, or 31% of patients, respectively.^[1][24] The study excluded patients with a history of variceal bleeding within 6 months before treatment, and those with untreated or incompletely treated bleeding varices, high risk of bleeding, history of hepatic encephalopathy, Child-Pugh class B or C cirrhosis, or moderate or severe ascites. ^[1][24] Patients with a history of autoimmune disease; those with untreated or corticosteroid-dependent CNS metastases; those who had received a live, attenuated vaccine within 4 weeks prior to randomization; and those who had received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive agents within 2 weeks prior to randomization also were excluded from the study.^[1][24]

At a median follow-up of 8.6 months, median overall survival was prolonged in patients receiving atezolizumab in combination with bevacizumab compared with those receiving sorafenib (71 versus 61%; hazard ratio: 0.58).^[1][24] Median progression-free survival also was prolonged in patients receiving atezolizumab-bevacizumab compared with those receiving sorafenib (6.8 versus 4.3 months; hazard ratio: 0.59).^[1][24] The overall response rate (according to RECIST v1.1) was 28% in patients receiving atezolizumab-bevacizumab and 12% in patients receiving sorafenib; complete responses were achieved in 7% of those treated with atezolizumab-bevacizumab and in none of the patients receiving sorafenib.^[1][24] The overall response rate (according to mRECIST) was 33% in patients receiving atezolizumab-bevacizumab and 13% in patients receiving sorafenib; complete responses were achieved in 11 and 1.8% of patients receiving these respective treatments.^[1] Median duration of response was not reached at the time of analysis in patients receiving atezolizumab-bevacizumab, but was 6.3 months in patients treated with sorafenib.^[1]

An exploratory analysis indicated reduced efficacy (e.g., overall survival) in patients receiving atezolizumab-bevacizumab who developed anti-atezolizumab antibodies by week 6 of therapy compared with those who did not develop anti-atezolizumab antibodies by week 6; no difference in overall survival was observed in patients who developed anti-atezolizumab antibodies and those treated with sorafenib.^[1][24] (See Immunogenicity under Cautions.)

Melanoma

Atezolizumab is used in combination with cobimetinib and vemurafenib for the treatment of unresectable or metastatic melanoma harboring BRAF V600 mutation.^[1][25] Atezolizumab has been designated an orphan drug by FDA for the treatment of this cancer.^[17]

The current indication for use of atezolizumab in combination with cobimetinib and vemurafenib for the treatment of patients with unresectable or metastatic melanoma harboring BRAF V600 mutation is based principally on the results of a phase 3, double-blind, placebo-controlled study (IMspire150).^[1][25] In this study, 514 patients with previously untreated BRAF mutation-positive unresectable or metastatic melanoma were randomized (stratified by geographical location and baseline lactate dehydrogenase) in a 1:1 ratio to receive atezolizumab or placebo combined with cobimetinib and vemurafenib.^[1][25] Atezolizumab was initiated after patients received one 28-day cycle of cobimetinib 60 mg orally once daily on days 1-21 and vemurafenib 960 mg orally twice daily on days 1-21, followed by vemurafenib 720 mg orally twice daily on days 22-28; for subsequent cycles, patients received atezolizumab 840 mg administered by IV infusion over 60 minutes on days 1 and 15, cobimetinib 60 mg orally once daily on days 1-21, and vemurafenib 720 mg orally twice daily on days 1-28 of a 28-day cycle.^[1][25] Patients randomized to placebo received cobimetinib 60 mg orally once daily on days 1-21 and vemurafenib 960 mg twice daily on days 1-28 of each 28-day cycle.^[1][25] The primary measure of efficacy was investigator-assessed progression-free survival according to RECIST v1.1.^[1][25]

The median age of patients in the IMspire150 study was 54 years; 58% were male, 95% were White, 33% had elevated lactate dehydrogenase, 94% had metastatic disease, 60% had stage IV disease, 14% had received prior adjuvant systemic therapy, and 3% had received prior treatment for brain metastases.^[1][25] At baseline, 56% of patients had fewer than 3 metastatic sites and 30% had liver metastases.^[1] Most (74%) patients had BRAF V600E mutation, 11% had BRAF V600K mutation, and 1% had BRAF V600D or V600R mutation.^[1][25] All patients had an ECOG performance status of 0 or 1 (77 or 23%, respectively).^[1][25] The study excluded patients with a history of autoimmune disease; those with active or untreated CNS metastases; those who had received a live, attenuated vaccine within 28 days prior to randomization; and those who had received systemic immunostimulatory agents within 4 weeks or immunosuppressive agents within 2 weeks prior to randomization.^[1][25]

At a median follow-up of 18.9 months, median progression-free survival was prolonged in patients receiving atezolizumab-cobimetinib-vemurafenib compared with those receiving placebo-cobimetinib-vemurafenib (15.1 versus 10.6 months; hazard ratio: 0.78).^[1][25] The overall response rate was 66% in patients receiving atezolizumab-cobimetinib-vemurafenib and 65% in those receiving placebo-cobimetinib-vemurafenib; complete responses were achieved in 16 and 18% of patients receiving these respective treatments.^[1][25] The median duration of response was 20.4 months in patients treated with atezolizumab-cobimetinib-vemurafenib and 12.5 months in patients treated with placebo-cobimetinib-vemurafenib.^[1][25] Overall survival data were not mature at the time of analysis; however, median overall survival was 28.8 months in patients receiving atezolizumab-cobimetinib-vemurafenib and 25.1 months in patients receiving placebo-cobimetinib-vemurafenib at the time of the interim analysis.^[1][25]

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.^[1]Liver function tests.^[1]Thyroid function.^[1]

Biomarker TestingSelect patients for treatment with atezolizumab based on the presence of biomarkers.^[1] (See Table 1.)

Patient Monitoring

Immune-mediated effects during and following therapy.^[1]Manifestations of pneumonitis.^[1]Signs and symptoms of hepatitis (e.g., liver function tests) during therapy.^[1]Signs and symptoms of colitis (e.g., diarrhea, abdominal pain, lower GI bleeding).^[1]Thyroid function periodically during therapy.^[1] Monitor for thyroiditis.^[1]Signs and symptoms of adrenal insufficiency.^[1]Signs and symptoms of diabetes mellitus (e.g., hyperglycemia).^[1]Signs and symptoms of hypophysitis (e.g., headache, photophobia, visual field changes, hypopituitarism).^[1]Signs and symptoms of dermatologic effects.^[1]Signs and symptoms of infusion-related reactions.^[1]

Other General Considerations

Consider potential benefits and risks of anti-PD-1 monoclonal antibody therapy administered either before or after allogeneic stem cell transplantation.^[1] Closely monitor for early manifestations of stem cell transplantation-related complications and manage promptly if they occur.^[1]

Administration

Atezolizumab is administered by IV infusion.^[1] The initial dose of atezolizumab should be administered as an IV infusion over 60 minutes; if the first infusion is tolerated, subsequent doses may be administered by IV infusion over 30 minutes.^[1] The drug should not be administered by rapid IV injection, such as IV push or bolus.^[1]

Unopened vials of atezolizumab injection concentrate should be protected from light, stored at 2-8°C, and should not be frozen or shaken.^[1]

Atezolizumab injection concentrate must be diluted prior to administration.^[1] The appropriate vial size should be selected based on the dose required.^[1] Prior to dilution and administration, atezolizumab injection concentrate should be inspected visually for particulate matter and discoloration.^[1] The undiluted solution should be colorless to slightly yellow; the solution should not be used if it is cloudy or discolored or if particulate matter is present.^[1] Atezolizumab is diluted by adding the required volume of atezolizumab injection concentrate (containing 60 mg/mL) to a polyvinyl chloride (PVC), polyethylene, or polyolefin infusion bag containing 0.9% sodium chloride injection.^[1] No other diluent should be used.^[1] The final concentration of the diluted atezolizumab solution should be 3.2-16.8 mg/mL.^[1] The diluted solution should be mixed by gentle inversion and should not be shaken.^[1] The manufacturer recommends immediate administration of diluted solutions of the drug.^[1] If immediate administration is not possible, the diluted solution of the drug should be stored at room temperature for up to 6 hours from the time of preparation (including infusion time) or 2-8°C for up to 24 hours from time of preparation; diluted solutions of the drug should not be frozen.^[1]

Atezolizumab should not be administered simultaneously through the same IV line with any other drug.^[1] Use of a low-protein-binding 0.2- to 0.22-mcm inline filter is optional.^[1] Atezolizumab injection concentrate contains no preservatives and is intended for single use only; any partially used vials should be discarded.^[1]

Dosage

Urothelial Carcinoma

For the treatment of locally advanced or metastatic urothelial carcinoma in patients with high programmed-death ligand-1 (PD-L1) expression (defined as PD-L1 staining in tumor-infiltrating immune cells covering at least 5% of the tumor area) who are not candidates for cisplatin-containing therapy, and in those who are not candidates for platinum-containing chemotherapy regardless of PD-L1 expression, the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Non-small Cell Lung Cancer

For the initial treatment of metastatic NSCLC with high PD-L1 expression and without EGFR or ALK genomic aberrations, the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

For the initial treatment of metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations, atezolizumab is used in combination with bevacizumab, carboplatin, and paclitaxel, or in combination with albumin-bound paclitaxel and carboplatin.^[1] The manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1] Administer atezolizumab prior to concomitant chemotherapy or bevacizumab when scheduled on the same day.^[1]

In the IMpower150 study, carboplatin and paclitaxel were administered for a maximum of 4-6 cycles; therapy with atezolizumab and bevacizumab was continued until disease progression or unacceptable toxicity occurred.^[1][16]

In the IMpower130 study, albumin-bound paclitaxel and carboplatin were administered for a maximum of 4-6 cycles; therapy with atezolizumab was continued until disease progression or unacceptable toxicity occurred.^[1][20]

For the treatment of metastatic NSCLC that has progressed during or following platinum-based chemotherapy, the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Breast Cancer

For the treatment of locally advanced or metastatic triple-negative breast cancer (in combination with albumin-bound paclitaxel) in patients with PD-L1 expression (defined as PD-L1 staining in tumor-infiltrating immune cells of any intensity covering at least 1% of the tumor area), the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1]

Albumin-bound paclitaxel 100 mg/m² is administered on days 1, 8, and 15 of each 28-day cycle; conventional paclitaxel should not be substituted for albumin-bound paclitaxel.^[1] Administer atezolizumab prior to albumin-bound paclitaxel when scheduled on the same day.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

If toxicity occurs, atezolizumab and albumin-bound paclitaxel may be discontinued independently of each other.^[1]

Atezolizumab is not indicated for use in combination with conventional paclitaxel for the treatment of triple-negative breast cancer.^[1] (See Treatment-related Mortality under Cautions.)

Small Cell Lung Cancer

For the treatment of adult patients with previously untreated, extensive-stage small cell lung cancer (in combination with carboplatin and etoposide), the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1] Administer atezolizumab prior to carboplatin and etoposide when scheduled on the same day.^[1]

In the principal efficacy study, carboplatin and etoposide were administered for up to 4 cycles, and atezolizumab therapy was continued until disease progression or unacceptable toxicity occurred.^[1][23]

Hepatocellular Carcinoma

For the treatment of unresectable or metastatic hepatocellular carcinoma (in combination with bevacizumab) in patients who have not received prior systemic therapy, the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1]

Administer atezolizumab prior to bevacizumab when scheduled on the same day.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Melanoma

For the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma (in combination cobimetinib and vemurafenib), the manufacturer recommends one of the following dosages for atezolizumab in adults: 840 mg as an IV infusion every 2 weeks, 1200 mg as an IV infusion every 3 weeks, or 1680 mg as an IV infusion every 4 weeks.^[1]

Atezolizumab should be initiated after patients receive one 28-day cycle of cobimetinib 60 mg orally once daily on days 1-21 and vemurafenib 960 mg orally twice daily on days 1-21, followed by vemurafenib 720 mg orally twice daily on days 22-28; for subsequent cycles, patients should receive atezolizumab in combination with cobimetinib 60 mg orally once daily on days 1-21 and vemurafenib 720 mg orally twice daily on days 1-28 of a 28-day cycle.^[1] Continue therapy until disease progression or unacceptable toxicity occurs.^[1]

Therapy Interruption for Toxicity

If adverse effects occur, temporary or permanent discontinuance of atezolizumab may be required based on the toxicity and severity of the reaction; the manufacturer does not recommend dosage reductions for managing toxicity.^[1]

In general, temporarily interrupt atezolizumab therapy if severe (grade 3) immune-mediated adverse effects occur.^[1]

Permanently discontinue atezolizumab therapy in patients experiencing grade 4 immune-mediated adverse effects, recurrent grade 3 immune-mediated adverse effects requiring systemic immunosuppressive therapy, and in patients unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1]

Immune-mediated Pulmonary Effects

If grade 2 immune-mediated pneumonitis occurs, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.^[1] Atezolizumab should be permanently discontinued if immune-mediated pneumonitis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Immune-mediated Pulmonary Effects under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, atezolizumab therapy should be permanently discontinued.^[1]

Immune-mediated Hepatic Effects

For patients without tumor involvement of the liver experiencing immune-mediated hepatitis characterized by serum ALT or AST elevations exceeding 3 times but not more than 8 times the upper limit of normal (ULN), or total bilirubin concentrations exceeding 1.5 times but not more than 3 times the ULN, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.^[1] Atezolizumab should be permanently discontinued if immune-mediated hepatitis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Immune-mediated Hepatic Effects under Cautions.)

For patients without tumor involvement of the liver experiencing immune-mediated hepatitis characterized by ALT or AST elevations exceeding 8 times the ULN, or total bilirubin concentrations exceeding 3 times the ULN, atezolizumab therapy should be permanently discontinued.^[1]

For patients with liver involvement and baseline ALT or AST concentrations exceeding the ULN but not more than 3 times the ULN who develop immune-mediated hepatitis characterized by ALT or AST elevations exceeding 5 times but not more than 10 times the ULN, or in those with baseline ALT or AST concentrations exceeding 3 times the ULN but not more than 5 times the ULN who develop immune-mediated hepatitis characterized by ALT or AST elevations exceeding 8 times the ULN but not more than 10 times the ULN, atezolizumab therapy should be interrupted until immune-mediated hepatitis resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.^[1] Atezolizumab should be permanently discontinued if immune-mediated hepatitis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Immune-mediated Hepatic Effects under Cautions.)

For patients with liver involvement who develop immune-mediated hepatitis characterized by ALT or AST elevations exceeding 10 times the ULN or total bilirubin increases exceeding 3 times the ULN, atezolizumab therapy should be permanently discontinued.^[1]

For patients with liver involvement and baseline AST and ALT less than or equal to the ULN who develop immune-mediated hepatitis characterized by serum ALT or AST elevations exceeding 3 times but not more than 8 times the upper limit of normal ULN, or total bilirubin concentrations exceeding 1.5 times but not more than 3 times the ULN, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.^[1][31] Atezolizumab should be permanently discontinued if immune-mediated hepatitis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1][31]

For patients with liver involvement and baseline AST and ALT less than or equal to the ULN who develop immune-mediated hepatitis characterized by ALT or AST elevations exceeding 8 times the ULN, or total bilirubin concentrations exceeding 3 times the ULN, atezolizumab therapy should be permanently discontinued.^[1][31]

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis occurs, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage has been tapered.^[1] Atezolizumab should be permanently discontinued if immune-mediated colitis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis occurs, atezolizumab therapy should be permanently discontinued.^[1]

Immune-mediated Endocrine Effects

If grade 3 or 4 immune-mediated endocrinopathies (e.g., hypophysitis, adrenal insufficiency, thyroid disorders, type 1 diabetes mellitus) occur, atezolizumab therapy should either be interrupted until the patient is clinically stable or permanently discontinued according to the severity of the adverse effect.^[1] (See Immune-mediated Endocrine Effects under Cautions.)

Immune-mediated Renal Effects

If immune-mediated nephritis characterized by grade 2 or 3 elevations in serum creatinine concentration occur, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is tapered.^[1] Atezolizumab should be permanently discontinued if immune-mediated nephritis does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Immune-mediated Renal Effects under Cautions.)

If immune-mediated nephritis characterized by grade 4 elevations in serum creatinine concentration occurs, atezolizumab therapy should be permanently discontinued.^[1]

Immune-mediated Dermatologic Effects

If exfoliative dermatitis (i.e., Stevens Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], drug rash with eosinophilia and systemic symptoms [DRESS]) is suspected, therapy with atezolizumab should be temporarily interrupted; if the diagnosis is confirmed, atezolizumab therapy should be permanently discontinued.^[1] (See Immune-mediated Dermatologic Effects under Cautions.)

Immune-mediated Cardiac Effects

If grade 2-4 immune-mediated myocarditis occurs, atezolizumab therapy should be permanently discontinued.^[1]

Immune-mediated Neurologic Effects

If grade 2 immune-mediated neurologic toxicity (e.g., meningitis, encephalitis, myasthenia gravis, Guillain-Barre syndrome, autoimmune neuropathy) occurs, atezolizumab therapy should be interrupted until the toxicity resolves to grade 0 or 1 and the corticosteroid dosage is tapered.^[1] Atezolizumab should be permanently discontinued if toxicity does not resolve to grade 0 or 1 within 12 weeks of starting corticosteroids or if the patient is unable to reduce corticosteroid dosage to 10 mg or less of prednisone daily (or equivalent) within 12 weeks of initiating corticosteroids.^[1] (See Other Immune-mediated Effects under Cautions.)

If grade 3 or 4 immune-mediated neurologic toxicity occurs, atezolizumab therapy should be permanently discontinued.^[1]

Infusion-related Reactions

If grade 1 or 2 infusion-related reactions occur, the infusion should be interrupted or the infusion rate should be reduced.^[1] (See Infusion-related Effects under Cautions.)

If grade 3 or 4 infusion-related reactions occur, atezolizumab therapy should be permanently discontinued.^[1]

Special Populations

The manufacturer makes no special dosage recommendations for patients with hepatic or renal impairment or for geriatric patients.^[1] (See Specific Populations under Cautions: Warnings/Precautions.)

Contraindications

The manufacturer states there are no known contraindications to the use of atezolizumab.^[1]

Warnings/Precautions

Severe and Fatal Immune-mediated Effects

As an anti-PD-L1 monoclonal antibody, atezolizumab interferes with immune response inhibition, potentially eliciting immune-mediated adverse effects, which can be severe or even fatal.^[1] Atezolizumab-related immune-mediated adverse effects can occur in any tissue or organ system; immune-mediated adverse effects usually appear during treatment, but can also occur after discontinuance of therapy.^[1]

Patients should be closely monitored during and following therapy with atezolizumab; it is important to promptly identify and manage immune-mediated adverse effects if they occur.^[1] If an immune-mediated adverse effect is suspected, the patient should be assessed for potential alternative causes, and treatment should begin promptly; consultation with a specialist should be considered if appropriate.^[1]

Temporary interruption or discontinuance of atezolizumab therapy may be necessary to manage immune-mediated adverse effects.^[1] (See Therapy Interruption for Toxicity under Dosage and Administration.) In general, if interruption or discontinuance of atezolizumab is necessary, systemic corticosteroids should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by a taper over at least 1 month when the immune-mediated adverse effect improves to grade 1 or less.^[1] If immune-mediated adverse effects are not controlled with corticosteroid therapy, other systemic immunosuppressants may be considered.^[1] Some immune-mediated effects may not require treatment with systemic corticosteroids (e.g., mild or moderate non-exfoliative dermatologic rash, certain immune-mediated endocrine effects).^[1]

Immune-mediated Pulmonary Effects

Immune-mediated pneumonitis, sometimes fatal, has occurred in patients receiving atezolizumab therapy.^[1] Patients who have received thoracic radiation may be at increased risk.^[1]

In clinical studies, immune-mediated pneumonitis occurred in 3% of patients receiving atezolizumab as a single agent; the reaction was fatal in less than 0.1% of patients.^[1] Grade 2, 3, or 4 immune-mediated pneumonitis occurred in 1.1, 0.8, or 0.2% of atezolizumab-treated patients, respectively.^[1] Temporary interruption of atezolizumab was necessary due to pneumonitis in 1.5% of patients, and therapy was permanently discontinued in 0.5% of patients.^[1] Treatment with systemic corticosteroids was needed in 55% of patients who developed immune-mediated pneumonitis, and pneumonitis resolved in 69% of patients who received corticosteroid therapy.^[1] Of the patients in whom atezolizumab was temporarily interrupted, 64% were able to restart atezolizumab therapy; however, pneumonitis recurred in 4% of these patients.^[1]

In clinical studies evaluating atezolizumab in combination with cobimetinib and vemurafenib, immune-mediated pneumonitis occurred in 13% of patients; immune-mediated pneumonitis was grade 2 or 3 in 7 or 1.3% of patients, respectively.^[1] Temporary interruption of atezolizumab was necessary due to pneumonitis in 7.4% of patients, and therapy was permanently discontinued in 2.6% of patients.^[1] Treatment with systemic corticosteroids was needed in 55% of patients who developed immune-mediated pneumonitis, and pneumonitis resolved in 97% of patients who received corticosteroid therapy.^[1] Of the patients in whom atezolizumab was temporarily interrupted, 59% were able to restart atezolizumab therapy; however, pneumonitis recurred in 50% of these patients.^[1]

Patients receiving atezolizumab should be monitored for manifestations of pneumonitis.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated pneumonitis occurs during therapy with the drug.^[1] (See Immune-mediated Pulmonary Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Immune-mediated Hepatic Effects

Immune-mediated hepatitis, sometimes fatal, has occurred in patients receiving atezolizumab therapy.^[1]

In clinical studies, immune-mediated hepatitis occurred in 1.8% of patients receiving atezolizumab as a single agent; the reaction was fatal in less than 0.1% of patients; immune-mediated hepatitis was grade 2, 3, or 4 in 0.5, 0.5, or 0.2% of patients, respectively.^[1] Temporary interruption or permanent discontinuance of atezolizumab therapy were each necessary in 0.2% of patients.^[1] Treatment with systemic corticosteroids was needed in 25% of patients who developed immune-mediated hepatitis, and resolved in 50% of patients who received corticosteroid therapy.^[1] Among 6 patients in whom atezolizumab was temporarily interrupted, 4 patients were able to restart atezolizumab therapy; hepatitis recurred in none of these patients.^[1]

In clinical studies evaluating atezolizumab in combination with cobimetinib and vemurafenib, immune-mediated hepatitis occurred in 6.1% of patients; immune-mediated hepatitis was grade 2, 3, or 4 in 1.3, 1.7 or, 1.3% of patients, respectively.^[1] Temporary interruption of atezolizumab was necessary due to hepatitis in 1.7% of patients, and therapy was permanently discontinued in 2.2% of patients.^[1] Treatment with systemic corticosteroids was needed in 50% of patients who developed immune-mediated hepatitis, and hepatitis resolved in 93% of patients who received corticosteroid therapy.^[1] Among 4 patients in whom atezolizumab was temporarily interrupted, 3 were able to restart atezolizumab therapy; hepatitis recurred in one of these patients.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of hepatitis (including liver function tests) at baseline and during atezolizumab therapy.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated hepatitis or liver function test abnormalities occur during therapy with the drug.^[1] (See Immune-mediated Hepatic Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Immune-mediated GI Effects

Immune-mediated colitis has occurred in patients receiving atezolizumab therapy.^[1] Manifestations of colitis include diarrhea, abdominal pain, and lower GI bleeding.^[1]

In clinical studies, immune-mediated colitis occurred in 1% of patients receiving atezolizumab as a single agent; immune-mediated colitis was grade 2 or 3 in 0.3 or 0.5% of patients, respectively.^[1] Temporary interruption of atezolizumab was necessary due to colitis in 0.5% of patients, and therapy was permanently discontinued in 0.2% of patients.^[1] Treatment with systemic corticosteroids was needed in 50% of patients who developed immune-mediated colitis, and colitis resolved in 73% of patients who received corticosteroids.^[1] Of the patients in whom atezolizumab was temporarily interrupted, 67% were able to restart atezolizumab therapy; however, colitis recurred in 25% of these patients.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of colitis.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated colitis or diarrhea occurs during therapy with the drug.^[1] (See Immune-mediated GI Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.) Cytomegalovirus (CMV) infection or reactivation has occurred in patients with immune-mediated colitis that is refractory to corticosteroid therapy.^[1] If corticosteroid-refractory colitis occurs, consider assessing the patient for alternative etiologies.^[1]

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, such as thyroid dysfunction (i.e., thyroiditis, hypothyroidism, hyperthyroidism), adrenal insufficiency (primary or secondary), hypophysitis/hypopituitarism, and diabetes mellitus (including ketoacidosis), have occurred in patients receiving atezolizumab therapy.^[1] Immune-mediated hyperthyroidism may be followed by hypothyroidism.^[1]

Thyroid Dysfunction

Atezolizumab can cause immune-mediated thyroiditis that presents with or without endocrinopathy.^[1] In clinical studies, thyroiditis occurred in 0.2% of patients receiving atezolizumab as a single agent; immune-mediated thyroiditis was grade 2 in less than 0.1% of patients.^[1] Temporary interruption or discontinuance of atezolizumab was necessary due to thyroiditis in 1 or 0 patients, respectively.^[1] Thyroid hormone replacement therapy was required in 3 of 4 patients who developed immune-mediated thyroiditis and systemic corticosteroid therapy was required in 1 of 4 patients who developed immune-mediated thyroiditis.^[1] Thyroiditis resolved in 50% of patients.^[1] One patient resumed atezolizumab therapy following temporary interruption, and did not experience recurrence of thyroiditis.^[1]

In clinical studies, immune-mediated hypothyroidism occurred in 4.9% of patients receiving atezolizumab as a single agent; immune-mediated hypothyroidism was grade 2 or 3 in 3.4 or 0.2% of patients, respectively.^[1] Thyroid hormone replacement was required in 81% of patients receiving atezolizumab who experienced hypothyroidism, with the majority of patients remaining on thyroid replacement.^[1] Temporary interruption of atezolizumab was necessary due to hypothyroidism in 0.6% of patients, but no patients required permanent discontinuance of atezolizumab.^[1] Of the patients in whom therapy was temporarily interrupted, 47% were able to restart atezolizumab following improvement of symptoms.^[1] In clinical studies evaluating atezolizumab in combination with platinum-based chemotherapy in patients with NSCLC or SCLC, immune-mediated hypothyroidism occurred in 11% of atezolizumab-treated patients; immune-mediated hypothyroidism was grade 2, 3, or 4 in 5.7, 0.3, or less than 0.1% of patients, respectively.^[1] Thyroid hormone replacement was required in 71% of patients receiving atezolizumab in combination with platinum-based therapy who experienced hypothyroidism, with the majority of patients remaining on thyroid replacement.^[1] Temporary interruption of atezolizumab was necessary due to hypothyroidism in 1.6% of patients, and permanent discontinuance of atezolizumab was needed in 0.1% of patients.^[1] Of the patients in whom therapy was temporarily interrupted, 23% were able to restart atezolizumab following improvement of symptoms.^[1]

In a clinical study evaluating atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma, immune-mediated hypothyroidism occurred in 26% of patients; severity was grade 2 in 9.1% of patients.^[1] Thyroid hormone replacement was required in 52% of patients receiving atezolizumab in combination with cobimetinib and vemurafenib who experienced hypothyroidism, with the majority of patients remaining on thyroid replacement.^[1] Temporary interruption of atezolizumab was necessary due to hypothyroidism in 2.6% of patients, but no patients required permanent discontinuance of atezolizumab.^[1] Of 6 patients in whom therapy was temporarily interrupted for hypothyroidism, 4 patients were able to restart atezolizumab following improvement of symptoms.^[1]

In clinical studies, immune-mediated hyperthyroidism occurred in 0.8% of patients receiving atezolizumab as a single agent; severity was grade 2 in 0.4% of patients.^[1] Treatment with an antithyroid agent was required in 29% of patients receiving atezolizumab who experienced hyperthyroidism, with the majority of patients remaining on antithyroid therapy.^[1] Temporary interruption of atezolizumab was necessary due to hyperthyroidism in 0.1% of patients, but no patients required permanent discontinuance of atezolizumab.^[1] Of 3 patients in whom therapy was temporarily interrupted for hyperthyroidism, one patient was able to restart atezolizumab without recurrence of hyperthyroidism.^[1]

In a clinical study evaluating atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma, immune-mediated hyperthyroidism occurred in 19% of patients; immune-mediated hyperthyroidism was grade 2 or 3 in 7.8 or 0.9% of patients, respectively.^[1] Treatment with an antithyroid agent was required in 53% of patients receiving atezolizumab who experienced hyperthyroidism, with the majority of patients remaining on antithyroid therapy.^[1] Temporary interruption of atezolizumab was necessary due to hyperthyroidism in 10% of patients, and permanent discontinuance was necessary in 0.4% of patients.^[1] Of the patients in whom therapy was temporarily interrupted for hyperthyroidism, 78% were able to restart atezolizumab; hyperthyroidism recurred in 28% of these patients.^[1]

Thyroid function should be evaluated prior to initiation of atezolizumab therapy and periodically during therapy.^[1] In patients who develop immune-mediated hypothyroidism, thyroid hormone replacement therapy should be initiated as clinically indicated.^[1] If immune-mediated hyperthyroidism occurs, medical therapy should be initiated as clinically indicated.^[1] Temporary interruption or permanent discontinuance of atezolizumab may be necessary for immune-mediated thyroid disorders.^[1] (See Immune-mediated Endocrine Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Adrenal Insufficiency

In clinical studies, immune-mediated adrenal insufficiency occurred in 0.4% of patients receiving atezolizumab as a single agent and was grade 2 or 3 in 0.2 or less than 0.1%, respectively, of patients receiving the drug.^[1] Adrenal insufficiency led to permanent discontinuation of atezolizumab in one patient and temporary interruption of therapy in one patient; however, atezolizumab was not restarted in the patient who temporarily interrupted therapy.^[1] Treatment with systemic corticosteroids was needed in 81% of patients experiencing immune-mediated adrenal insufficiency; 33% of these patients remained on systemic corticosteroids.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of adrenal insufficiency.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated adrenal insufficiency occurs during therapy with the drug.^[1] (See Immune-mediated Endocrine Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.) If grade 2 or greater immune-mediated adrenal insufficiency occurs, symptomatic treatment (e.g., hormone replacement therapy) should be initiated as clinically indicated.^[1]

Hypophysitis

In clinical studies, immune-mediated hypophysitis occurred in 2 patients (less than 0.1%) receiving atezolizumab as a single agent; severity was grade 2 in one patient.^[1] Atezolizumab therapy was permanently discontinued in one patient and the other patient received systemic corticosteroid therapy; hypophysitis did not resolve in either patient.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of hypophysitis.^[1] Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field changes; hypopituitarism can be caused by hypophysitis.^[1] If immune-mediated hypophysitis occurs, temporary interruption or discontinuance of atezolizumab may be necessary.^[1] (See Immune-mediated Endocrine Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.) Hormone replacement therapy should be initiated as clinically indicated.^[1]

Diabetes Mellitus

In clinical studies, immune-mediated type 1 diabetes mellitus occurred in 0.3% of patients receiving atezolizumab as a single agent; immune-mediated type 1 diabetes mellitus was grade 2 or 3 in less than 0.1 or 0.2% of patients, respectively.^[1] Temporary interruption of treatment was necessary in 2 patients and permanent discontinuance of therapy was necessary in 1 patient.^[1] Of the patients in whom therapy was temporarily interrupted for type 1 diabetes mellitus, both patients restarted atezolizumab therapy.^[1] Long-term insulin therapy was required in all patients with confirmed type 1 diabetes mellitus.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of diabetes mellitus (e.g., hyperglycemia).^[1] If immune-mediated type 1 diabetes mellitus occurs, temporary interruption or discontinuance of atezolizumab may be necessary and insulin therapy should be initiated as clinically indicated.^[1] (See Immune-mediated Endocrine Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Immune-mediated Renal Effects

Immune-mediated nephritis has occurred in patients receiving atezolizumab therapy.^[1]

In clinical studies evaluating single-agent atezolizumab, 1 of 2616 patients developed immune-mediated nephritis with renal dysfunction; this adverse reaction was grade 3 in severity.^[1] Atezolizumab was permanently discontinued in this patient.^[1]

In clinical studies evaluating atezolizumab in combination with cobimetinib and vemurafenib, 3 patients (1.3%) developed immune-mediated nephritis with renal dysfunction; atezolizumab therapy was temporarily interrupted in 2 patients and permanently discontinued in 1 patient.^[1] Treatment with systemic corticosteroids was required in 2 patients.^[1] Nephritis resolved in all 3 patients.^[1] Both patients in whom atezolizumab was temporarily interrupted were able to restart atezolizumab therapy without recurrence of nephritis.^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of nephritis and renal impairment (including serum creatinine concentration) at baseline and periodically during atezolizumab therapy.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated nephritis or renal dysfunction occurs during therapy with the drug.^[1] (See Immune-mediated Renal Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Immune-mediated Dermatologic Effects

Immune-mediated rash and dermatitis have occurred in patients receiving atezolizumab therapy.^[1] Severe exfoliative dermatitis, including SJS, TEN, or DRESS, has been reported in patients receiving anti-PD-L1 and anti-PD-1 monoclonal antibodies.^[1]

In clinical studies evaluating single-agent atezolizumab, immune-mediated dermatologic effects occurred in 0.6% of patients; grade 2 or 3 immune-mediated dermatologic effects occurred in 0.2 or less than 0.1% of patients, respectively.^[1] Interruption of atezolizumab was necessary due to dermatologic effects in 0.2% of patients, and therapy was permanently discontinued in 0.1% of patients.^[1] Treatment with systemic corticosteroids was required in 20% of patients experiencing immune-mediated dermatologic effects, and symptoms resolved in 87% of these patients.^[1] Among the patients in whom atezolizumab therapy was interrupted, none restarted the drug.^[1]

Topical corticosteroids and/or topical emollients may be adequate to treat mild to moderate non-exfoliative rashes.^[1] Temporary interruption or discontinuance of atezolizumab may be necessary for more severe immune-mediated dermatologic conditions.^[1] (See Immune-mediated Dermatologic Effects under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

Other Immune-mediated Effects

Other immune-mediated adverse effects, including myocarditis, pericarditis, vasculitis, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy, ocular inflammatory conditions (e.g., uveitis, iritis), retinal detachment, visual impairment, blindness, pancreatitis (including elevation of serum amylase and lipase concentrations), gastritis, duodenitis, myositis/polymyositis, rhabdomyolysis (including renal failure), arthritis, polymyalgia rheumatic, hypoparathyroidism, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection, have occurred rarely in patients receiving atezolizumab or other anti-programmed-death ligand-1 (anti-PD-L1) or anti-programmed-death receptor-1 (anti-PD-1) antibodies.^[1] Some cases have resulted in death.^[1]

Temporary interruption or discontinuance of atezolizumab may be necessary if immune-mediated adverse effects occur during therapy with the drug.^[1] (See Therapy Interruption for Toxicity under Dosage and Administration and also see Severe and Fatal Immune-mediated Effects under Cautions.)

If uveitis occurs in conjunction with other immune-mediated adverse effects, a Vogt-Koyanagi-Harada-like syndrome should be considered.^[1] Systemic corticosteroid therapy may be required to reduce the risk of permanent vision loss.^[1]

Allogeneic Stem Cell Transplantation-related Complications

Patients who undergo allogeneic stem cell transplantation either before or after receiving therapy with an anti-PD-1 or anti-PD-L1 monoclonal antibody, including atezolizumab, may experience serious or fatal transplant-related complications, including hyperacute, acute, or chronic graft-versus-host disease (GVHD); hepatic veno-occlusive disease following allogeneic stem cell transplantation with a reduced-intensity conditioning regimen; and corticosteroid-requiring febrile syndrome with no identified infectious cause.^[1] These complications may occur despite other intervening therapy between administration of the anti-PD-1 or anti-PD-L1 monoclonal antibody and transplantation.^[1]

Potential benefits and risks of anti-PD-1 or anti-PD-L1 monoclonal antibody therapy administered before or after allogeneic stem cell transplantation should be considered.^[1] Patients who receive atezolizumab should be monitored closely for early manifestations of stem cell transplantation-related complications, and such conditions should be promptly managed if they occur.^[1]

Treatment-related Mortality

In a clinical trial, a higher rate of mortality was reported in PD-L1-positive patients with metastatic triple-negative breast cancer receiving atezolizumab in combination with conventional paclitaxel compared with patients receiving placebo and conventional paclitaxel.^[1] Efficacy of atezolizumab in combination with conventional paclitaxel in patients with unresectable locally advanced or metastatic triple-negative breast cancer has not been demonstrated.^[1] Albumin-bound paclitaxel should not be substituted with conventional paclitaxel in patients with metastatic triple-negative breast cancer outside of a controlled clinical trial.^[1]

Infusion-related Effects

Severe or life-threatening infusion-related reactions may occur in patients receiving atezolizumab therapy.^[1] In clinical studies, infusion-related reactions occurred in 1.3% of patients receiving atezolizumab as a single agent and were grade 3 in 0.2% of patients receiving the drug.^[1] The frequency and severity of infusion-related reactions were similar regardless of whether atezolizumab was administered as a single agent in patients with various cancers, in combination with other antineoplastic drugs in patients with NSCLC or SCLC, or the dosage administered (i.e. 840 mg every 2 weeks to 1680 mg every 4 weeks).^[1]

Patients receiving atezolizumab should be monitored for signs and symptoms of infusion-related reactions.^[1] In patients experiencing infusion-related reactions, interruption of the infusion, reduction in the infusion rate, or discontinuance of atezolizumab may be necessary.^[1] (See Infusion-related Reactions under Dosage and Administration.) For patients experiencing grade 1 or 2 infusion-related reactions, premedication may be considered prior to subsequent atezolizumab infusions.^[1]

Fetal/Neonatal Morbidity and Mortality

Atezolizumab may cause fetal harm if administered to pregnant women.^[1] Blockade of signaling of the PD-1 and PD-L1 pathway in animals has been shown to disrupt maternal immune tolerance to the fetus and has been associated with increased fetal loss (e.g., abortion, stillbirth) and immune-mediated disorders; however, teratogenicity has not been observed.^[1]

Pregnancy should be avoided during atezolizumab therapy.^[1] The manufacturer states that pregnancy status should be verified prior to initiation of atezolizumab.^[1] Females of reproductive potential should be advised to use an effective method of contraception while receiving atezolizumab and for at least 5 months after discontinuance of therapy.^[1] Females of reproductive potential should be apprised of the potential fetal hazard if atezolizumab is used during pregnancy.^[1]

Immunogenicity

There is a potential for immunogenicity with atezolizumab therapy.^[1] Anti-atezolizumab antibodies were detected at one or more post-dose time points in the OAK, IMvigor210 (cohort 1), IMpower150, IMpassion130, IMbrave150, and IMspire150 studies.^[1] The neutralizing capacity of anti-atezolizumab antibodies has not been established.^[1] Median clearance of atezolizumab increased by 22% in the presence of anti-atezolizumab antibodies.^[1] In general, presence of anti-atezolizumab antibodies did not have a clinically substantial effect on the incidence or severity of adverse effects.^[1] Exploratory analysis of the OAK study (in patients with NSCLC) and the IMbrave150 study (in patients with hepatocellular carcinoma) suggests reduced efficacy in patients who develop anti-atezolizumab antibodies by week 4 and 6, respectively.^[1]

In the OAK study in patients with NSCLC, anti-atezolizumab antibodies were detected in 30% of 565 patients, with a median time to antibody formation of 3 weeks.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies.^[1] Exploratory analysis also suggests that efficacy (i.e., overall survival) is reduced in patients who are positive for anti-atezolizumab antibodies by week 4.^[1] The incidence and severity of adverse effects were not substantially impacted by the presence of anti-atezolizumab antibodies.^[1]

In cohort 1 of the IMvigor210 study in patients with urothelial carcinoma, anti-atezolizumab antibodies were detected in 48% of 111 patients at one or more post-dose time points.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies, but the incidence and severity of adverse effects were not substantially impacted by the presence of anti-atezolizumab antibodies.^[1]

In the IMpower150 study in patients with NSCLC who received atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin, anti-atezolizumab antibodies were detected in 36% of 364 patients at one or more post-dose time points, and 83% of patients had detectable anti-atezolizumab antibodies prior to receiving the second dose of atezolizumab.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies; however, the incidence and severity of adverse effects were not substantially impacted by the presence of anti-atezolizumab antibodies.^[1] Exploratory analysis suggests that efficacy (i.e., overall survival) is similar in patients who develop anti-atezolizumab antibodies by week 4 and those without antibodies.^[1]

In the IMpassion130 study in patients with triple-negative breast cancer who received atezolizumab in combination with albumin-bound paclitaxel, anti-atezolizumab antibodies were detected in 13% of 434 patients at one or more post-dose time points; the rate of detection was 12% among patients whose tumors expressed PD-L1.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies; however, the number of PD-L1-positive patients who developed anti-drug antibodies was insufficient to determine whether patients who develop anti-drug antibodies respond differently than those who do not develop anti-drug antibodies.^[1] The incidence and severity of adverse effects were not substantially impacted by the presence of anti-atezolizumab antibodies.^[1]

In the IMbrave150 study in patients with hepatocellular carcinoma who received atezolizumab in combination with bevacizumab, anti-atezolizumab antibodies were detected in 28% of 315 patients at one or more post-dose time points; 66% of these patients had detectable anti-drug antibodies prior to receiving the third dose of atezolizumab.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies.^[1] Exploratory analysis suggests that efficacy (i.e., overall survival) is reduced in patients who develop anti-atezolizumab antibodies by week 6 compared with those who do not develop anti-drug antibodies at week 6.^[1] The incidence and severity of adverse effects were not substantially impacted by the presence of anti-atezolizumab antibodies.^[1]

In the IMspire150 study in patients with melanoma who received atezolizumab in combination with cobimetinib and vemurafenib, anti-atezolizumab antibodies were detected in 13% of 218 patients.^[1] Systemic exposure was reduced in patients who developed anti-atezolizumab antibodies; however, the number of patients who developed anti-drug antibodies was insufficient to determine whether patients who develop anti-drug antibodies respond differently than those who do not develop anti-drug antibodies.^[1]

Impairment of Fertility

Results of animal studies suggest that atezolizumab may impair female fertility.^[1] In a 26-week general toxicology study, irregular menstrual cycle patterns and absence of corpora lutea were observed in female animals receiving atezolizumab at exposure levels approximately 6 times the human exposure at the recommended dosage; however, these adverse effects were reversible.^[1] Adverse reproductive effects in male animals were not observed.^[1]

Specific Populations

Pregnancy

Atezolizumab may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.^[1] (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Pregnancy status should be verified prior to initiation of atezolizumab.^[1]

Lactation

It is not known whether atezolizumab is distributed into human milk.^[1] Because human immunoglobulin G (IgG) is distributed into milk and because of the potential for serious adverse reactions to atezolizumab in nursing infants, women should be advised to discontinue nursing during atezolizumab therapy and for at least 5 months after discontinuance of therapy.^[1] The effects of the drug on nursing infants or on milk production are unknown.^[1]

Pediatric Use

Safety and efficacy of atezolizumab have not been established in pediatric patients.^[1]

Safety and antitumor activity of atezolizumab were assessed, but not established, in 60 pediatric patients 7 months to less than 17 years of age with relapsed or progressive solid tumors or lymphomas in a phase ½ study (iMATRIX).^[1][26] No new safety signals were observed in this study.^[1] The median duration of atezolizumab therapy was 0.8 months.^[26]

The iMATRIX study also compared the pharmacokinetic parameters of atezolizumab in pediatric patients and adults 18-29 years of age.^[1][26][27] Pediatric patients received a weight-based dose of 15 mg/kg (up to a maximum of 1200 mg per dose) every 3 weeks and adults received a fixed dose of 1200 mg every 3 weeks.^[1][26][27] Overall, steady-state area under the concentration-time curve (AUC) was similar between patients 12 to less than 18 years of age and adults, but systemic exposure trended lower in pediatric patients younger than 12 years of age.^[1] Peak plasma concentrations increased from children to adolescents to young adults.^[27] Terminal elimination half-lives of atezolizumab in pediatric patients and young adults were consistent with those estimated in adults.^[27]

Geriatric Use

In clinical studies evaluating single-agent atezolizumab for the treatment of metastatic urothelial carcinoma, metastatic NSCLC, or other tumor types, 49% of patients were 65 years of age or older and 15% were 75 years of age or older.^[1] In clinical studies of atezolizumab in combination with other antineoplastic agents for the treatment of SCLC and NSCLC, 48% of patients were 65 years of age or older, and 10% were 75 years of age or older.^[1] No overall differences in safety or efficacy were observed between geriatric patients and younger adults.^[1]

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of atezolizumab have not been formally studied.^[4] Analysis of population pharmacokinetic data indicates that clearance and systemic exposure of atezolizumab are similar between patients with mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration more than 1 time but no more than 1.5 times the ULN with any AST concentration) or moderate (total bilirubin concentration more than 1.5 times but no more than 3 times the ULN with any AST concentration) hepatic impairment and those with normal hepatic function.^[1][4] Pharmacokinetic data in patients with severe hepatic impairment are lacking.^[1][4]

Renal Impairment

The effects of renal impairment on the pharmacokinetics of atezolizumab have not been formally studied.^[4] Analysis of population pharmacokinetic data indicates that atezolizumab clearance is not substantially affected by mild or moderate renal impairment (estimated glomerular filtration rate [GFR] 30-89 mL/minute per 1.73 m²).^[1][4] Pharmacokinetic data in patients with severe renal impairment are limited.^[1][4]

Common Adverse Effects

Adverse effects reported in 20% or more of patients receiving atezolizumab as a single agent include fatigue or asthenia, nausea, cough, dyspnea, and decreased appetite.^[1]

Adverse effects reported in 20% or more of patients with NSCLC or SCLC receiving atezolizumab in combination with other antineoplastic agents include fatigue or asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.^[1]

Adverse effects reported in 20% or more of patients with triple-negative breast cancer receiving atezolizumab in combination with albumin-bound paclitaxel include alopecia, peripheral neuropathy, fatigue, nausea, diarrhea, constipation, cough, headache, vomiting, and decreased appetite; laboratory abnormalities occurring in 50% or more of patients include decreased concentrations of hemoglobin, leukocytes, neutrophils, and lymphocytes.^[1]

Adverse effects reported in 20% or more of patients with hepatocellular carcinoma receiving atezolizumab in combination with bevacizumab include hypertension, fatigue, and proteinuria.^[1]

Adverse effects reported in 20% or more of patients with melanoma receiving atezolizumab in combination with cobimetinib and vemurafenib include rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity.^[1]

No formal drug interaction studies have been performed to date.^[1]

Atezolizumab, a humanized anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.^{[1][2][4][10]} The drug is an IgG₁ kappa immunoglobulin.^[1][2][4]

The immune-checkpoint receptor PD-1 is expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.^[6][7][8][9] Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and B7.1 and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production.^{[1][8][9][10]} Atezolizumab blocks the interaction between PD-L1 and the receptors PD-1 and B7.1, resulting in activation of the antitumor immune response without inducing antibody-dependent cell-mediated cytotoxicity (ADCC).^[1][10] The drug also has been shown to reduce tumor growth in syngeneic mouse tumor models.^[1] In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone.^[1]

Systemic exposure to atezolizumab is proportional to dose over the dose range of 1-20 mg/kg, including the fixed dosage of 1.2 g every 3 weeks.^[1][4][10] Following repeated doses of atezolizumab 1200 mg every 3 weeks, steady-state concentrations are reached by 6-9 weeks; systemic accumulation of the drug is 3.3- or 1.9-fold when administered every 2 or 3 weeks, respectively.^[1][4][10] Atezolizumab clearance decreases over time by approximately 17% from baseline values; however, this difference is not considered clinically important.^[1] The terminal half-life of atezolizumab is 27 days.^[1][4][10]

Systemic exposure to atezolizumab does not appear to be affected by age (range of 21-89 years), body weight, sex, serum albumin concentration, tumor burden, geographic region, race, PD-L1 expression, or performance status.^[1][4]

Importance of advising patients to read the manufacturer's medication guide.^[1]

Risk of immune-mediated pneumonitis.^[1] Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.^[1]

Risk of immune-mediated colitis.^[1] Importance of informing clinician immediately if diarrhea or severe abdominal pain occurs or if mucus or blood is present in stool.^[1]

Risk of immune-mediated hepatitis.^[1] Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, severe nausea or vomiting, abdominal pain [particularly in the right upper quadrant], lethargy, easy bruising or bleeding, lack of appetite, dark urine, drowsiness) occur.^[1]

Risk of immune-mediated endocrine effects.^[1] Importance of informing clinician immediately if manifestations of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or diabetes mellitus (including ketoacidosis) occur.^[1]

Risk of immune-mediated nephritis.^[1] Importance of informing clinician immediately if signs or symptoms of nephritis (e.g., pelvic pain, frequent urination, unusual swelling) occur.^[1]

Risk of immune-mediated dermatologic adverse effects.^[1] Importance of informing clinician immediately if skin eruption, generalized rash, or painful lesions on the skin or mucous membranes develop.^[1]

Risk of other immune-mediated adverse effects.^[1] Importance of informing clinician immediately if manifestations of other potential immune-mediated adverse effects occur.^[1]

Risk of infusion-related reactions.^[1] Importance of informing clinician if signs and symptoms of such reactions, including dizziness, chills, fever, breathing difficulty (i.e., shortness of breath, wheezing), pruritus, flushing, feeling of faintness, back or neck pain, and angioedema, occur.^[1]

Risk of allogeneic stem cell transplantation-related complications.^[1]

Risk of fetal harm.^[1] Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving atezolizumab and for at least 5 months after discontinuance of therapy.^[1] Importance of women informing clinicians if they are or plan to become pregnant.^[1] If pregnancy occurs, advise pregnant women of potential risk to the fetus.^[1]

Importance of advising women to avoid breast-feeding while receiving atezolizumab and for at least 5 months after discontinuance of therapy.^[1]

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^[1]

Importance of informing patients of other important precautionary information.^[1] (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Obtain atezolizumab through a limited network of specialty distributors.^[5] Contact manufacturer for additional information.^[5]

AHFS Drug Information®. © Copyright, 1959-2024, Selected Revisions October 18, 2021. American Society of Health-System Pharmacists®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

This AHFS Drug Information Database is copyrighted by the American Society of Health-System Pharmacists, Inc. (C) 2025, ASHP, Bethesda, Maryland 20814. All Rights Reserved. Duplication must be expressly authorized by ASHP, unless such duplication consists of printing or downloading portions of the data inherent in the program for non-commercial use.

The American Society of Health-System Pharmacists, Inc. represents that the database provided hereunder as formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. makes no representations or warranties, express or implied, including, but not limited to, any implied warranty or merchantability and/or fitness for a particular purpose, with respect to such database and specifically disclaims all such warranties and representations. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the database if provided for informational purposes only. The entire monograph for a drug should be reviewed for a throrough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug in the database. The information contained in the database is not a substitute for medical care or treatment by a licensed health care provider.