Hope S. Rugo, MD: I’m Hope S. Rugo, MD. I’m a professor of medicine at the University of California San Francisco’s Comprehensive Cancer Center, where I’m also director of breast oncology and clinical trials education. I’m a breast cancer oncologist. And my clinical research has focused on evaluating novel agents in the treatment of patients with both metastatic and early stage breast cancer and carefully monitoring and evaluating toxicity to better help us improve the quality of life of our patients and their tolerance of therapy over time. And then lastly, my interest is also supporting our laboratory colleagues, both in bringing what we’re learning about the clinic to the lab and bringing what’s being learned in the lab to the clinic.
Aaron Tallent, Interviewer: Can you describe the TROPiCS-02 trial and the results that you presented at ESMO?
Dr. Rugo: So the TROPiCS-02 trial is a phase three trial and I presented the updated overall survival data at ESMO 2022. TROPiCS-02 is a phase three trial that randomized patients with heavily pretreated hormone receptor-positive metastatic breast cancer to receive sacituzumab govitecan or chemotherapy of physician’s choice. Sacituzumab is a first-in-class Trop-2 antibody drug conjugate with a high drug to antibody ratio that carries a topoisomerase I payload. Sacituzumab is already approved for the treatment to patients with metastatic triple negative breast cancer who’ve received at least one line of prior chemotherapy for metastatic disease based on data from the ASCENT trial where it improved progression-free and overall survival.
The TROPiCS-02 trial was designed to look at the efficacy of sacituzumab in patients who had hormone receptor-positive/HER2-negative metastatic breast cancer. And it treated patients who’d received at least two and not more than four lines of chemotherapy for metastatic disease. All patients had to have received a CDK4/6 inhibitor, a taxane in any setting, and one line of endocrine therapy. The patient population received sacituzumab day one and day eight, every 21 days or chemotherapy of physician’s choice. About 540 patients were randomized, and of the patients who received chemo of physician’s choice, a little under 50% received eribulin, most of the patients had already received capecitabine in an earlier line of therapy.
The demographics of the study, I think, give us a window into the heavily pretreated population. And we really don’t have any modern day studies where CDK4/6 inhibitors are being used, and we’ve had our current chemo that have included this heavily pretreated group of patients. 95% of the patients had visceral metastases and the median time from diagnosis of metastatic disease to randomization was four years. So these were patients pretty far out into their treatment course. And of course all of the patients had received CDK4/6 inhibitors.
The primary endpoint of the study was progression-free survival. And we presented that data at ASCO this year. And it’s now been published in the Journal of Clinical Oncology. We showed a statistically significant improvement in progression-free survival with a hazard ratio 0.66. The statistical plan had been powered on a hazard ratio of 0.7. This was highly significant, but the median difference was just 1.5 months, which brought up to question and how clinically important this was. However, when we looked at the data, we saw that 20% of the patients progressed before their first scan in both arms, really attributed to the heavily pretreated and chemotherapy resistant nature of the disease in these patients.
We looked at landmark analyses to better understand the benefit and at six, nine and 12 months, treatment with sacituzumab resulted in many more patients being alive and free of progression than patients treated with chemotherapy of physician choice, and notably at 12 months, three times as many patients were alive and free of progression who were treated with sacituzumab. At that first presentation and publication, we also conducted a first interim analysis of overall survival. At that time, overall survival data was immature and although there was a numeric improvement in overall survival, it was in no way statistically significant.
At ESMO 2022, we presented the second interim analysis of overall survival. At this time there were 100 additional survival events, and this is now a mature overall survival analysis because we reached statistical significance. This is the last formal analysis of overall survival for TROPiCS-02. We showed a significant improvement in overall survival with a hazard ratio 0.79, highly statistically significant and immediate improvement in overall survival of 3.2 months. We also looked at the number of patients who were alive at one year as sort of a landmark analysis that’s important for our patients and important clinically. Patients treated with chemotherapy, 47% were alive, but patients treated with sacituzumab, 61% were alive. So that’s a significant difference, I think, in our clinics and for our patients.
The study employed a hierarchical statistical design. So that means that the progression-free survival had to be significant before you looked at overall survival, overall survival significant before response, and response significant before quality of life and patient reported outcomes. So this time we showed significance with overall survival, so we also looked at overall response, which was significantly greater in patients receiving sacituzumab as was the clinical benefit rate and duration of response. Because that was significant, we looked at quality of life and patient reported outcomes. We saw that there was a significant delay in time to deterioration of global health status and quality of life in patients receiving sacituzumab and also a significant delay in fatigue scores. So this was very encouraging and I think solidifies the role of sacituzumab govitecan in the treatment of patients with pretreated hormone receptor-positive/HER2-negative metastatic breast cancer.
Tallent: Did we learn anything new about the side effects?
Dr. Rugo: So one thing that’s always really important in trials that are looking at novel agents that show improvement in efficacy is to understand the side effects as well. We presented the toxicity analysis at ASCO 2022, and this data was also in our publication in the JCO. At the time of the second interim overall survival analysis, we saw no new safety events. This is very encouraging because it means that there’s not cumulative toxicity, and that’s similar to what was observed in the ASCENT trial. We also noted that the most common toxicity was neutropenia, and the second most common toxicity is diarrhea. We don’t see interstitial lung disease or any cardiac toxicity.
In the ASCENT trial, about 50% of patients require growth factors, and certainly growth factors are an excellent way of managing the neutropenia that’s seen with sacituzumab and seen less frequently when patients who have had less extensive prior treatment use this agent. For diarrhea, it’s mainly managed by dose reductions and use of antidiarrheal agents or anti-propulsives. It’s important to manage these as we saw in the initial analysis of TROPiCS-02 that one patient died from toxicity attributed to sacituzumab. That was due to neutropenia in association with colitis and bowel perforation, and we know that mucosa don’t tolerate neutropenia and diarrhea well. So it’s important in those patients to manage with the growth factors and anti-propulsives as well as antibiotics as indicated because you really can prevent significant toxicity with these relatively simple maneuvers.
Tallent: Are there any next steps for this research?
Dr. Rugo: Of course when we see data that is significant for progression-free and overall survival with new agents, we’re always thinking about the next step for research. And for sacituzumab govitecan, there are a number of ongoing trials and plan studies. So of course, sacituzumab is approved for the treatment of metastatic triple negative breast cancer and we’re awaiting FDA review of the application of sacituzumab in hormone receptor-positive disease based on the TROPiCS-02 trial. (Update: On Oct. 11, 2022, the FDA granted a priority review to sacituzumab govitecan’s sBLA for the indication noted.) There are a number of trials in triple negative disease in the first line setting both with or without pembrolizumab based on PD-L1 status.
There are post neoadjuvant studies, one being run by the German Breast Group in both triple negative and hormone receptor-positive disease and neoadjuvant trials. One was presented at ASCO 2022, a small trial where only four doses were given to patients with triple negative disease with a pathologic complete response rate of 30%. And now the drug is being tested in combination with pembrolizumab in the neoadjuvant setting for triple negative disease. And then there’s a planned Alliance trial in patients who have failed to achieve a pathologic complete response with good neoadjuvant therapy with a checkpoint inhibitor where sacituzumab will be tested to see if we can reduce the chance of distant recurrence in combination with other agents, including checkpoint inhibitors.
For hormone receptor-positive disease, there’s a great interest in planning a first line trial in patients with hormone receptor-positive metastatic breast cancer so we can better understand how to use antibody drug conjugates in the earlier lines of therapy for these patients. And of course, there are trials going on with the antibody-drug conjugate trastuzumab deruxtecan and we’re trying to put all of these trials into context together.
Tallent: Given the findings of this study and the results from DESTINY-Breast04 could sacituzumab govitecan be sequenced in treatment with trastuzumab deruxtecan?
Dr. Rugo: At ASCO 2022 and published in The New England Journal, we saw the remarkable data from DESTINY-Breast04 with trastuzumab deruxtecan in patients, largely hormone receptor-positive/HER2-low metastatic breast cancer. And the question is, how do we interpret this data in context of the TROPiCS-02 data and how can we use these drugs potentially in sequence? So DESTINY-Breast04 treated patients who had centrally confirmed HER2-low disease. This is still of great controversy, the testing for HER2- low and the sort of biologic significance of having a little expression of HER2. But the study showed in a largely hormone receptor-positive population where only 58 patients had triple negative disease that the progression-free and overall survival was markedly improved with trastuzumab deruxtecan or T-DXd compared to chemotherapy of physician’s choice.
The median number of lines of chemo for patients in DESTINY-Breast04 was one versus three in TROPiCS-02. Seventy percent of patients had CDK4/6 inhibitors versus 100% in TROPiCS-02. These are different populations. We also did not centrally confirm hormone receptor status and in a presentation at ESMO 2022, we looked at patients based on HER2-low status to better understand how to use these drugs together. And what we saw was no real difference in efficacy of sacituzumab govitecan based on HER2-low status as we expected, but it was still encouraging to see that data.
So how do we use these together? I think that in patients who have HER2-low hormone receptor- positive disease, we’re going to be using T-DXd and we already are in the second line setting. In patients who then progress, we would use sacituzumab in sequence, and it’s critical that we understand the efficacy of these drugs in sequence. For patients who have HER2-zero disease, we would use sacituzumab because we don’t have efficacy data yet with T-DXd in patients who do not have any expression of HER2 and of hormone receptor-positive disease. For patients who have triple negative disease, we have a large phase 3 randomized trial with sacituzumab, so I would use that agent first.
But the data with triple negative disease, even though it was 58 patients, 18 in the control arm, was still pretty impressive for T-DXd and DESTINY-Breast04. So I would use that drug in sequence after sacituzumab govitecan in that unique setting.
There’s also areas of importance. Some patients may not be able to tolerate one drug or the other. And for example, although the rate of interstitial lung disease for trastuzumab deruxtecan or T-DXd and DESTINY-Breast04 was just over 12%, and there were three deaths, which I think could probably be largely prevented by very careful monitoring, looking for grade one interstitial lung disease, and it represented just 0.8%. But the trial prohibited patients from entering who’d had prior interstitial lung disease. So if a patient had prior ILD from radiation or everolimus or another drug like gemcitabine, then they may not be able to get T-Dxd safely. Although, this is an area that requires further investigation, so I think that there are several settings where we really need to have both antibody drug conjugates, and where we’re going to explore using them in sequence.
The whole thinking about sequencing is intriguing because we know that both drugs have a payload that’s a topoisomerase inhibitor, but the antibody that’s targeting to the cancer cells is quite different, trastuzumab biosimilar and a topoisomerase anti-targeted antibody. And we also use drugs that have the same mechanism of action, for example, drugs that block tubulin and taxanes we can use nab-paclitaxel after... Docetaxel, we can use eribulin after the taxanes and we see efficacy. So I think this is going to be a really important area to investigate as we move forward.
Tallent: And then finally, at a high level, which other breast cancer studies presented at ESMO did you find most clinically significant?
Dr. Rugo: At ESMO 2022, there were a number of really important breast cancer studies, but just to mention a few, I think MONARCH 3, which evaluated abemaciclib in combination with a nonsteroidal aromatase inhibitor in patients with hormone receptor-positive untreated metastatic breast cancer so the first line setting already had shown a significant improvement in progression-free survival. In this analysis, they actually showed a remarkable and huge difference in overall survival of almost a year and a 16 month difference in patients with visceral metastases. Remarkably, that didn’t reach statistical significance based on alpha splitting. And although the P value looks significant, it’s two zeros, it didn’t meet the trial’s requirement for significance for overall survival. So they plan their final update next year. But still seeing that big separation of curves over time was really encouraging. And as we’ve expected with these agents, there weren’t additional cumulative toxicities so that was really encouraging as well.
MonarcHER looked at using abemaciclib with trastuzumab and fulvestrant in patients with hormone receptor-positive/HER2-negative disease. And this was an update analysis that showed that even compared to chemo and trastuzumab, that the triplet therapy resulted in improved progression-free and overall survival. This is a phase 2 trial, so the arms are quite small and the middle arm was abemaciclib with [inaudible]. We didn’t see fulvestrant abemaciclib. Fulvestrant abemaciclib is one of the arms, it was abemaciclib and trastuzumab was the middle arm. But I think the data were impressive in that patients did so well on that triplet arm.
And so how we’re going to apply that to clinical practice, one is, I think we all think of the hormone therapy and HER2 targeted therapy as maintenance after induction, a Cleopatra-like induction of standard of care, but maybe we could add CDK4/6 inhibitors and improve outcome. And the use of palbociclib is being studied in the PATINA trial where palbociclib is being given in combination with trastuzumab pertuzumab and endocrine therapy versus the standard triplet alone. And that trial we hope, which completed accrual some time ago will report out next year. And it’s a really, I think, important thing to see whether or not we could, after a chemotherapy, HER2 targeted induction have longer maintenance therapy by adding the CDK4/6 inhibitor, which is supported by preclinical data.
There also may be a patient population who are elderly, where you might have limited disease and maybe one bone metastasis where you don’t want to give chemo up front and you might choose that sort of triplet approach. So we’ll wait for the PATINA trial, but I think this is really encouraging for a clinical practice already. We saw some quality of life data that was really encouraging for both DESTINY-Breast04 and TROPiCS-02.
And then lastly, a really nice study looking at chemotherapy-induced peripheral neuropathy from Germany where 120 patients were randomized to either use a cold glove on their dominant hand and they used their nondominant hand as the control, no cold glove, or they used a compression glove. So just a latex glove smaller than their size. So it squished their hand a little bit and prevented a lot of blood supply to the small peripheral nerves. Now what they saw was that the use of either technique, either the cold glove, these frozen gloves or the compression glove actually reduced the incidence of grade two or greater chemotherapy induced peripheral neuropathy. Although some people dropped out because they didn’t tolerate the compression gloves, a few more patients than the cold glove. But they looked over time and they actually saw less damage to the nerve by looking at these very careful radiographic studies of the nerve, which is really amazing.
So I think this is important because chemotherapy-induced peripheral neuropathy is terrible for patients. It cannot resolve and we can’t really predict who’s going to have bad neuropathy. So I already recommend that patients use cold gloves and booties. And I think this idea of using a compression glove it’s much less expensive, no special equipment, and really needs to be continued to be evaluated as a way of improving outcome for our patients with early stage breast cancer who are receiving taxanes in the neoadjuvant or adjuvant setting.
