Frontline Therapy: Promising I/O Combinations

Transcript:

Peter Galle, MD: It’s indeed now getting a bit crowded. There have been many signals pursued in phase 3 trials. The story started basically with the CheckMate040, and there were several cohorts. Among those cohorts was the IPI-NIVO combination, ipilimumab and nivolumab, 2 immuno-oncology [I/O] agents tackling CTLA4 and PD-1. The early data for this combination are looking very promising.

A similar concept is the combination of durvalumab and tremelimumab. In fact, we have just seen the abstracts for ASCO [American Society of Clinical Oncology Annual Meeting], showing further data on the DURVAL-plus-TREME [durvalumab, tremelimumab] combination. These data look quite promising, I have to say. Then we have the different combinations of checkpoint inhibitors plus TKIs [tyrosine kinase inhibitors]. Here, we probably have to pay attention to toxicity. That was 1 of the observations when we combined lenvatinib plus pembrolizumab. Relevant objective responses were in the range of 40%, but also quite relevant was toxicity. There were some fatalities, and that needs to be watched. But apparently, this is among the combinations that are working. Cabozantinib is combined with I/O agents, and there are other smaller trials ongoing. Indeed, we have in the palliative setting quite a few combinations. It’s actually going beyond that. There are also adjuvant treatments using combinations. So we expect a lot of new data in the next years.

Kate Kelley, MD: There are 2 general categories of I/O combinations that we’re examining right now, and both are quite promising. The first are the combinations like IMbrave150 of an antiangiogenic agent with a checkpoint inhibitor. Other examples on the horizon, beyond the ATEZO-BEV [atezolizumab-bevacizumab] combo, are the combination of pembrolizumab plus lenvatinib in the LEAP-002 trial. That’s based on phase 1b data from a large 100-patient cohort being presented at the ASCO 2020 Annual Meeting. The combination of pembrolizumab with lenvatinib has shown quite high objective response rates by both RECIST 1.1 as well as modified RECIST. In the phase 1b context, that has been matched by disease-control rates and the longer-than-expected progression-free survival. Of course, the phase 1b data need to be validated and verified in the phase 3 context, so it will be quite interesting to see the results of LEAP-002.

Along those same lines in the antiangiogenic immunotherapy combination category, there’s also the COSMIC-312 trial combining cabozantinib with atezolizumab. That’s an ongoing study whose results will also be quite interesting, bearing in mind that cabozantinib is another tyrosine kinase inhibitor with antiangiogenic properties. But beyond being an antiangiogenic agent, it also has some immunomodulatory activity in reducing or inhibiting some of the immunosuppressive cells in the tumor microenvironment, like tumor-associated macrophages and myeloid-derived suppressor cells.

Beyond the antiangiogenic immunotherapy combinations, there are also the dual immune checkpoint inhibitor combinations on the horizon, and 1 of those trials to watch for is the HIMALAYA trial. The HIMALAYA trial studies the combination of the PD-L1 inhibitor durvalumab with the CTLA4 inhibitor tremelimumab, and it has already completed accrual. Hopefully, we can look to results in the not-too-distant future. The HIMALAYA regimen is based on phase 2 data in the second line from the combination of durvalumab plus tremelimumab in a study called Study 22, which is being presented at this year’s ASCO and as an oral abstract. In the phase 2 second-line context, the combination showed that a novel approach to CTLA4 combination of a single higher priming dose of tremelimumab given just once at the beginning of the regimen, combined with a continued monthly durvalumab backbone, had the highest objective response rate of that combination. It was also matched by the longest median overall survival.

Also, in the dual immune checkpoint inhibitor space is the combination of nivolumab plus ipilimumab. There’s a phase 3 trial of this regimen called CheckMate 9DW, and it also follows up on phase 2 data from the second-line space from the CheckMate040 cohort of nivolumab plus ipilimumab, which showed high objective responses and prolonged overall survival for the combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, given together for 4 doses, followed by nivolumab every 2 weeks as monotherapy. In fact, based on the phase 2 second-line data, the FDA has granted an approval for nivolumab plus ipilimumab in the postsorafenib population.

When we look ahead on the horizon, we see a host of new combinations that may become available if any of these phase 3 trials achieves their primary end point. The clinical implications are that we will have a dramatically expanded landscape in the first-line setting and a new opportunity to really choose a regimen according to patients’ clinical factors, such as bleeding risk in the case of atezolizumab plus bevacizumab, or other comorbidity profiles. Then we will also have an obligation to really do a whole new range of subgroup analyses on the individual trial data themselves, as well as potentially combined or pooled analyses across studies to try to understand whether the clinical biomarkers or clinical risk factors that identify patients more likely to benefit from 1 approach to another.

Transcript Edited for Clarity