Progress in First-Line mRCC

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Ulka Vaishampayan, MD: This brings us to the last portion of our discussion, which is on cutting-edge therapies in metastatic kidney cancer.

Which trials in progress excite you, in terms of new therapies and new combinations? Which trials are reading out soon, and how will those data sets factor into decision making? Rana?

Rana R. McKay, MD: It’s really an exciting time in RCC [renal cell carcinoma]. I feel like every couple of months we have another phase III study reading out. We’re all awaiting the data from the CLEAR trial of the combination of lenvatinib and pembrolizumab in the frontline space to see how that’s going to augment outcomes for patients. Additionally, we’re awaiting the data from CheckMate 9ER, which is looking at the combination of nivolumab and cabozantinib compared with sunitinib in the frontline space. Long-term data are still awaited regarding the maturing OS [overall survival] data from the avelumab-axitinib JAVELIN Renal 101 trial, which is also expected to come forward within the next year.

As these data get presented, it’s going to continue to shake up the frontline landscape. Also, as we’re moving our second- and third-line agents into the frontline space, it’s going to open up even more questions in the field regarding what to do in the second-line setting. With the combination of nivolumab-cabozantinib—you know, if that trial were to be positive, and now we move nivolumab-cabozantinib into the frontline space, what is going to be the best next agent to use after somebody has already received cabozantinib in the frontline setting?

Similarly, with lenvatinib potentially moving into the frontline space—with pembrolizumab-lenalidomide—what do we do with the combination of lenalidomide and avelumab? While it’s exciting to see more options for patients in these trials reading out, I think it will also open up an entire set of questions regarding which agent to choose. We certainly don’t have any comparative data in the frontline space comparing nivolumab-ipilimumab, pembrolizumab-axitinib, or avelumab-axitinib, or what may be another I/O [immuno-oncology]–VEGF combination. And then what actually do you use for second-line therapy? It’s exciting, but there may also be many more questions to answer.

Ulka Vaishampayan, MD: The other study that is looking at sequencing depending on response to initial immunotherapy is the PDIGREE trial. Tian, can you take us through that study?

Tian Zhang, MD: Absolutely. This is a cooperative-group-based study based out of the Alliance [for Clinical Trials in Oncology] called PDIGREE. It’s a phase III adaptive trial that really adapts based on patients’ responses at the 3-month time point. We’re enrolling patients with IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] intermediate-risk or poor-risk metastatic clear-cell renal cell carcinoma. Everyone is being treated up front with ipilimumab and nivolumab. Then, based on their 3-month responses, we’re adapting further treatments for their response. Complete response patients receive nivolumab alone, and progressive disease patients receive cabozantinib alone.

As I alluded to earlier, we have some sequencing data from those patients. And then everyone who did not have a complete response or progressive disease—in other words, anybody with a partial response or stable disease—those patients are then randomized to receive either nivolumab alone or nivolumab with cabozantinib.

The primary outcome is improvement in the 3-year overall survival rate, and we’re hypothesizing that to be increased—60% with nivolumab, to 70% with the nivolumab-cabozantinib combination.

To get to that primary hypothesis, our number needed to randomize is about 696. A number needed to enroll with some dropouts from the early time point is about 1046. And so this is an ongoing trial that is enrolling across all NCTN [National Cancer Institute National Clinical Trials Network] study sites.

There’s also another up-front trial, COSMIC-313. This is a phase III trial randomizing patients to the combination of ipilimumab-nivolumab-cabozantinib versus ipilimumab-nivolumab with placebo. Again, there are all IMDC intermediate- and poor-risk disease patients. The primary end point of the study is progression-free survival. The number needed to randomize is about 676.

What’s unique about these trials, Ulka, is that they’re really the first trials that don’t have sunitinib as a control arm. There are also some unique features in regard to the PDIGREE trial. One of the key secondary end points is the 1-year complete response rate. We’re asking for the patients who have a complete responses at 1 year to discontinue treatment. I think this is 1 of the first trials in renal cell carcinoma where we’re proactively and prospectively studying the discontinuation question of who can stop treatment. Of those patients, who will recur and when will they recur after discontinuing treatment?

Ulka Vaishampayan, MD: That is a great description of each of these trials. You also bring up an excellent point of actually having a duration and not just keeping therapy going until progression, which was in the study design of the previous trials. What about other novel immunotherapy agents that are being tested? Matt?

Matthew T. Campbell, MD, MS: My colleague and partner, Dr Nizar Tannir, and Dr Adi Diab have been investigating NKTR-214 for some time now. We’re now seeing NKTR-214, which is a pegylated interleukin-2, given alongside nivolumab. High-dose interleukin-2 has been a very specialized treatment for a long time. It has required a lot of hospital support equipment and a lot of experience in giving it safely. The idea of giving it pegylated is that you’re moving it from the inpatient setting to the outpatient setting.

In terms of early studies that have been done, the response rate is very promising. The complete response rate also appears promising. Now we are moving this into a phase III trial. The trial combines nivolumab and NKTR-214 versus either cabozantinib or sunitinib.

I completely second Tian’s thoughts about both the COSMIC-313 trial and the PDIGREE study. It’s important to mandate that patients get immunotherapy in current and future trials, just because we’ve repeatedly seen that sunitinib is not an ideal comparison agent as a frontline option, unless you’re talking favorable-risk disease.

Ulka Vaishampayan, MD: That’s a very good point. This study actually has sunitinib or cabozantinib as the control arm.

Matthew T. Campbell, MD, MS: Yeah. I think what that really means is that in the United States, as well as some of the Western European countries and potentially Canada, cabozantinib will be an option. For the rest of the world, sunitinib will likely till be the option. So it’ll be interesting, as that trial accrues, to see how many patients end up getting sunitinib in the control arm.

Transcript Edited for Clarity

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