By Christina Bennett, MS
At the 2020 ASCO Gastrointestinal Cancers Symposium, potentially practice-changing data were presented, including updated data from the IMbrave150 and BEACON trials, as well as additional data on the multi-cancer, early-detection blood test being developed by GRAIL, Inc. The efficacy of larotrectinib in patients with gastrointestinal (GI) cancers was also reported and results from the Japanese iPACS trial settled an important question about the surgical management of patients with asymptomatic, incurable stage IV colorectal cancer.
PROs Favor Combination in IMbrave150
According to the latest data from the phase 3 IMbrave150 trial, not only does atezolizumab plus bevacizumab appear to have a survival benefit over sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma (HCC), the combination seems to also offer superior patient-reported outcomes (PROs).
“IMbrave 150 has been a pivotal trial in advanced HCC,” said Daneng Li, MD, assistant clinical professor, City of Hope. Previously the trial revealed a significant overall survival (OS; HR=0.58; 95% CI, 0.42 – 0.79; P=0.0006) and progression-free survival (PFS; HR=0.59; 95% CI, 0.47 – 0.76; P<0.0001) benefit for the combination.
The current analysis showed that the median time to deterioration in quality of life (QoL) was longer for the combination compared with sorafenib (11.2 vs 3.6 months; HR=0.63; 95% CI, 0.46 – 0.85). The median time to deterioration in physical functioning also favored the combination (13.1 vs 4.9 months; HR=0.53; 95% CI, 0.39 – 0.73), as did the median time to deterioration in role functioning (9.1 vs 3.6 months; HR=0.62; 95% CI, 0.46 – 0.84).
In addition, the median time to deterioration of symptoms, including appetite loss, diarrhea, fatigue, and pain, favored the combination.
“Everything is really kind of making sense,” said Dr. Li. “This treatment is really working as a frontline treatment for patients with advanced HCC, and patients are actually tolerating this treatment.”
View an OBR interview with Dr. Li on the IMbrave150 trial:
BEACON Reveals QoL, With Updated Survival Data
The latest data from the phase 3 BEACON trial showed that in addition to a survival benefit, patients who received the triplet (encorafenib + binimetinib + cetuximab) or doublet regimen (encorafenib + cetuximab) had a slower decline in QoL compared with the control arm (FOLFIRI + cetuximab or irinotecan + cetuximab).
Three PRO instruments—which were the European Organization for Research and Treatment of Cancer (EORTC QLC-C30), the Functional Assessment of Cancer–Colon Cancer (FACT-C), and the EuroQoL-5D-5L–Visual Analog Scale (EQ-5D-5L)—each consistently showed an approximately three-month delay in time to definitive deterioration for the triplet or doublet regimen compared with the control.
A fourth instrument—a single-question instrument called the Patient Global Impression of Change—asked patients whether symptoms were improved: 31% on the doublet regimen, 29% on the triplet regimen, and 15% on the control arm responded with “much improved” or “very much improved.”
“Targeted therapy is not only associated with improvement in overall survival, but also delays the deterioration in the quality of life of those patients,” said Marwan Fakih, MD, medical oncologist at City of Hope.
Updated survival data were also presented, revealing that at nearly 13 months follow-up, the median OS for patients on either the doublet or triplet regimen was approximately 3 months longer than the control arm (9.3 vs 9.3 vs 5.4 months). In an earlier readout of the data in the New England Journal of Medicine, the triplet regimen seemed to be most effective, with a median OS of 9.0 months compared with 8.4 months in the doublet arm and 5.4 months in the control arm.¹
The updated findings also showed a response rate of 27% for the triplet regimen, 20% for the doublet regimen, and 2% for the control arm. Earlier data showed a very similar response rate of 26% for the triplet regimen, 20% for the doublet regimen, and 2% for the control arm.
“We have no data to support that we should use three targeted drugs in this scenario,” Dr. Fakih commented on the updated data.
During the presentation, lead author Scott Kopetz, MD, PhD, MD Anderson Cancer Center, said that “on the basis of these results,” the decision has been made not to submit binimetinib to the FDA. The FDA is currently reviewing a supplemental New Drug Application for the doublet regimen.²
View an OBR interview with Dr. David Ilson on the BEACON trial:
iPACS Settles Surgery Debate
Retrospective data have suggested that surgical removal of the primary tumor leads to better outcomes for patients with asymptomatic, incurable stage IV colorectal cancer. However, the prospective randomized phase 3 iPACS trial revealed that contrary to this evidence, surgical removal of the primary tumor does not improve survival outcomes for patients with asymptomatic, incurable stage IV colorectal cancer.
In fact, the trial stopped early after the first interim analysis with 160 patients showed no survival difference between the group who underwent surgery followed by chemotherapy and the group who received only chemotherapy. In addition, 3 patient deaths were deemed related to surgery.
“I think this is a practice-changing trial because so many investigators have quoted this retrospective data, saying ‘Patients do better when they get the primary [tumor] taken out,’” said David Ilson, MD, Memorial Sloan Kettering Cancer Center. “Now we have level one evidence that this is not the case.”
View an OBR interview with Dr. Ilson on the iPACS trial:
GRAIL Blood Test Gains Traction
A cell-free DNA assay that uses targeted methylation sequencing showed a more than 99% specificity and around 82% sensitivity for the detection of GI cancers. The latest data come from the second preplanned sub-study of the Circulating Cell-free Genome Atlas (CCGA) study, which included 447 participants with GI cancer.
“If you detect something, it’s probably going to be real,” said David Zhen, MD, medical oncologist at Seattle Cancer Care Alliance, about the high specificity. “But if you don’t detect something, there’s still about a 20 percent chance that you may potentially miss something.”
For an early detection screening test, Dr. Zhen said he would prefer a higher sensitivity. “You really don't want to miss patients potentially with cancer.”
When it came to predicting where the tumor was located, the assay had around a 91% accuracy for the training set and 89% for the validation set. Dr. Zhen described the accuracy as “impressive,” adding that the assay could “pretty much” predict where the cancer could be coming from.
However, whether detecting these cancers early can affect the natural history of the disease and lead to better outcomes still needs to be answered. “That’s a critical question,” said Dr. Zhen.
Larotrectinib Makes Headway in GI Cancer
Patients with GI cancer harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion appear to benefit from treatment with larotrectinib, according to a small group of patients pooled from three clinical trials. Larotrectinib was granted an accelerated approval in November 2018 for children and adults who have a solid tumor with an NTRK gene fusion.³
Among the 14 study participants with GI cancer harboring an NTRK gene fusion, 43% had a response. Only partial responses were seen, which included 4 patients with a tumor in the colon, one patient with a tumor in the bile duct, and one patient with a tumor in the pancreas.
Nicholas Rohs, MD, assistant professor of medicine, Hematology and Medical Oncology at The Blavatnik Family-Chelsea Medical Center at Mount Sinai, explained that while the response rates seen in this study weren’t “quite as high” as previously seen—that is, 80% for TRK-fusion solid tumors—the data are still “encouraging” because these patients had multiple treatment lines.
The analysis also showed a duration of response from 3.5 to over 14.7 months, a median PFS of 5.3 months (95% CI, 2.2-9.0), and a median OS of 33.4 months (95% CI, 2.8-36.5). The PFS for the patients with colon cancer ranged from 1.5 to over 16.5 months.
Although the dataset is small, Dr. Rohs said that having a prospective randomized phase 3 clinical trial is “very unlikely” given the rarity of NTRK gene fusions. NTRK gene fusions comprise an estimated 0.3% of GI cancers, including pancreatic and colorectal cancer.
“We’ve already proven across different tumor types that these TRK-targeting drugs have effect and they are generally well tolerated,” he said.
Trial Failures Take Us “Back to the Drawing Board”
Amidst the positive results, the wave of negative data from phase 3 clinical trials presented during the meeting was hard to ignore.
“It was kind of disappointing,” said Tannaz Armaghany, MD, an assistant professor of internal medicine, hematology and oncology at Baylor College of Medicine. She said the negative results mean “we need to go back to the drawing board” to see where the problem is and why these studies did not reach the expected conclusion.
The lackluster trials started on Thursday afternoon with the JAVELIN Gastric 100 trial, which showed that adding avelumab to maintenance chemotherapy did not, in fact, improve outcomes for patients with HER2-negative advanced gastric or gastroesophageal junction cancer. Later that same session, the EXPEL study showed that extensive intraoperative peritoneal lavage after curative gastrectomy did not improve outcomes for patients with gastric cancer. Then came the negative results of the ARTDECO trial, which showed that increasing the dose of radiation did not improve tumor control for esophageal cancer.
Friday afternoon showcased two back-to-back negative studies for metastatic pancreatic cancer. First, the SEQUOIA trial showed that adding pegilodecakin to FOLFOX in the second-line setting did not improve efficacy outcomes for patients with metastatic pancreatic cancer. Next, the HALO 109-301 trial revealed that contrary to what was anticipated, adding pegvorhyaluronidase alfa to nab-paclitaxel/gemcitabine did not improve efficacy outcomes in patients with previously untreated hyaluronan-high metastatic pancreatic ductal adenocarcinoma.
View an OBR interview with Dr. Manish Shah on the JAVELIN Gastric 100 trial:
References
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632-1643.
U.S. FDA accepts and grants priority review to sNDA for BRAFTOVI® (encorafenib) in combination with ERBITUX® (cetuximab) (BRAFTOVI Doublet) for the treatment of BRAFV600E-mutant metastatic colorectal cancer after prior therapy [news release]. Pfizer Inc; December 18, 2019. https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_accepts_and_grants_priority_review_to_snda_for_braftovi_encorafenib_in_combination_with_erbitux_cetuximab_braftovi_doublet_for_the_treatment_of_brafv600e_mutant_metastatic_colorectal_cancer_after_prior. Accessed February 2, 2020.
FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA.gov. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0. Accessed February 3, 2020.
