Expert Gives Updates on Kidney and Bladder Cancer

Sumanta Kumar Pal, MD

Updates in renal cell carcinoma (RCC) and bladder cancer were abundant at the 2017 European Society for Medical Oncology (ESMO) Congress.

Results from the CheckMate-214 trial, which explored the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), demonstrated that the immunotherapy combination was superior to Sutent (sunitinib) monotherapy as first-line treatment for advanced or metastatic RCC. The median overall survival (OS) was not reached with the combination versus 32.9 months with Sutent.

In intermediate- and poor-risk patients, who constituted about 75 percent of the intent-to-treat (ITT) population, the median OS was not reached in the Opdivo/Yervoy arm and was 26 months in the Sutent arm. However, there was not a benefit for the combination versus Sutent in patients with favorable risk.

Another study presented at ESMO shared findings from an independent review of the phase 2 CABOSUN trial that confirmed the progression-free survival (PFS) benefit with the multikinase inhibitor Cabometyx (cabozantinib) over Cabometyx in the frontline setting. Findings showed that Cabometyx -treated patients had a median PFS of 8.6 months versus 5.3 months for patients treated initially with Sutent. The difference represented a 52 percent reduction in the hazard for progression or death.

Could you compare the findings of the CheckMate-214 and CABOSUN trials in RCC?

Sumanta Kumar Pal, M.D., associate professor, Department of Medical Oncology, City of Hope, covered the scope of exciting genitourinary cancer data presented at the 2017 ESMO Congress, with a sharp focus on the CABOSUN and CheckMate-214 trials.This is a very interesting time in metastatic renal cell carcinoma. At this meeting, specifically, we have two very critical data sets. One pertains to the regimen of Opdivo/Yervoy, which is being evaluated in CheckMate-214—a randomized trial comparing that regimen against Sutent. This study appears to have an OS benefit and a benefit in terms of response rate. There is no significant difference in PFS, but it is still pretty compelling. What we do know is that it looks like there might be a selected benefit in those patients who are PD-L1 positive. That is something worth highlighting.

In contrast, we also have results from the CABOSUN study. This is a very different approach and a very different trial. This is a randomized phase 2 experience conducted by the Alliance Cooperative Group. This trial randomized patients to either Cabometyx or Sutent, and it showed a benefit in terms of PFS with Cabometyx. What I will say is, at this meeting, we have the benefit of independent radiographic review and it seems to confirm the original results.

What are your thoughts on single-agent Opdivo over the combination?

Now, of course, we have a huge dilemma. We know that both of these regimens are actually superior to Sutent. The difficult choice for the practicing clinicians becomes, “What to choose?” I am hopeful that we can use some of these biomarker-based elements. For example, [we could use] the PD-L1 data that we have from CheckMate-214 to identify a subset that is going to selectively benefit from Opdivo/Yervoy. Perhaps for the remainder of patients, it may be worthwhile to consider Cabometyx. Certainly, we need to [examine] the data a little bit more. We have very limited data to date. For monotherapy with PD-1/PD-L1 inhibitors in the context of advanced RCC, some of the data that we do have comes from the IMmotion 150 trial, which looked at Avastin (bevacizumab) and Tecentriq (atezolizumab), Tecentriq alone or Sutent. This is a study we participated in.

Moving to bladder cancer, there were updated results from the KEYNOTE-045 trial. At this point, how do you decide which checkpoint inhibitors to use?

What I will say is it looks as though there is some activity with monotherapy with Tecentriq. Response rates were reasonable at just over 20 percent; it looks as though PFS is just about balanced with Cabometyx in this randomized phase 2 study. There is certainly some merit to using monotherapy in the frontline setting, although it is not something that was explored in the context of CheckMate-214. We have a whole host of drugs that are approved for metastatic urothelial cancer. The real key is a physician’s comfort level with using these agents. At this point in time, the highest levels of evidence seems to sit with Tecentriq and Keytruda (pembrolizumab), and, in my opinion, that is based on presence of phase 3 data to support both of those regimens.

How could the results of the RANGE trial change the sequencing agents?

Some look at Tecentriq and the associated IMvigor211 study as being completely negative. When I look at this as a US-based practicing physician, I really look at the subset of patients who had Tecentriq compared with agents like taxanes. We don’t have vinflunine, for instance, which was one of the arms assessed in IMvigor211. Therefore, that taxane comparison becomes particularly relevant. I actually construed that particular subset as having better outcomes with Tecentriq. Therefore, either Tecentriq or Keytruda are reasonable choices in the second-line setting. It is really interesting. The results of the RANGE study come at a time where immunotherapy is really in vogue. It is hard to note what to know with single-agent taxane-based regimens. Typically, we use single-agent taxanes following cisplatin-based chemotherapy, and, of course, that has gotten pushed even further back thanks to the presence of immunotherapy.

For a patient who is cisplatin-eligible right now in 2017, the sequence that I foresee is cisplatin/gemcitabine followed by immunotherapy, followed by docetaxel/ Cyramza (ramucirumab). It becomes a little trickier in the cisplatin-ineligible setting. Patients may receive Tecentriq or Keytruda upfront, and, beyond that, perhaps there is a role for docetaxel with Cyramza.

Could you discuss any ongoing biomarker research?

However, I will say that by and large, we are probably going to defer platinum-based chemotherapy even in that setting—using carboplatin/gemcitabine, for instance. Then, perhaps it will be docetaxel/ Cyramza in those patients who may get the third-line treatment. We have multiple data sets that suggest PD-L1 staining has varying potential in terms of predictive capabilities across the spectrum of agents that are approved for metastatic urothelial cancer. Quite frankly, at the present time, the presence or absence of tumor mutational burden probably won’t die in clinical practice—in the sense that the only options that we have available are chemotherapy and immunotherapy.

On the other hand, where tumor mutational burden may be relevant is down the line in selecting ideal pairings of drugs and the poster that we presented at the 2017 ESMO Congress will actually look at the presence or absence of specific driver mutations — FGFR3, HER2, etc — as a means of determining whether or not those patients have a high mutation burden and should, therefore, be treated with a combination of targeted therapy and immunotherapy. This is all speculative and hypothesis generating, but hopefully the data that we have will inform prospective trial designs.