Immunotherapy Combinations Taking Shape in RCC

Asim Amin, MD

Since the FDA approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for patients with advanced intermediate- and poor-risk advanced renal cell carcinoma (RCC), other immunotherapy regimens are moving through the pipeline with encouraging activity.

For example, the combination of avelumab (Bavencio) and axitinib (Inlyta) doubled objective response rates (ORRs) and significantly improved progression-free survival (PFS) compared with sunitinib (Sutent) in patients with treatment-naïve advanced RCC regardless of PD-L1 expression, according to findings from the phase III JAVELIN Renal 101 trial.¹

In the PD-L1—positive population, the median PFS was 13.8 months (95% CI, 11.1-NE) with avelumab/axitinib compared with 7.2 months (95% CI, 5.7-9.7) with sunitinib, leading to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95%, 0.475-0.790; P <.0001). The ORR with the combination was 55.2% (95% CI, 49.0-61.2), which included 4 complete responses (CRs) and 51 partial responses (PRs); the ORR with sunitinib was 25.5% (95% CI, 20.6- 30.9).

Moreover, topline findings from the phase III KEYNOTE-426 trial showed that the combination of pembrolizumab (Keytruda) with axitinib significantly improved survival versus sunitinib as a first-line treatment for patients with advanced or metastatic RCC.²

In the phase III CheckMate-214 trial, which was the basis for the nivolumab/ipilimumab approval, overall survival (OS) and response rates were significantly higher with the combination than with standard sunitinib. At a median follow-up of 25.2 months, the 18-month OS rate was 75% for the combination versus 60% with sunitinib.³ The ORR was 42% versus 27%, respectively, for nivolumab and ipilimumab compared with the VEGF tyrosine kinase inhibitor (TKI).

Asim Amin, MD, PhD, said the next steps in this field are combining immunotherapy with VEGF inhibitors. But doing so would require oncologists to educate themselves on the adverse events (AEs) associated with both class of agents.

OncLive: What is the current landscape for frontline immunotherapy in advanced RCC?

What was the impact of the CheckMate-214 trial?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Amin, director of immunotherapy at the Levine Cancer Institute, discussed the current role of checkpoint inhibitors in advanced RCC and where the future is heading in this space.Amin: I took the liberty of adding the word "evolving" to the name of my presentation because this field is rapidly evolving. Every day there is a new development. I discussed how we got to the approval of the first immunotherapy combination in this space: nivolumab and ipilimumab. I also briefly discussed the next steps that are following this combination.The CheckMate-214 study took root when the initial phase I data in advanced RCC showed clinical benefit and tolerability with the combination of nivolumab and ipilimumab. The combination had previously shown significant clinical activity in advanced melanoma and was approved in that space. One of the standards of care for frontline treatment in advanced RCC has been sunitinib, which is a VEGF TKI.

CheckMate-214 compared the immunotherapy combination with the standard dose of sunitinib; this was a phase III study. The eligibility criteria included patients with advanced RCC who had not been previously treated. The stratification was based on the International Metastatic Renal Cell Carcinoma Database Consortium risk criteria and the geographic location. Patients were randomized in a 1:1 fashion to either receiving nivolumab 3 mg/kg intravenously every 3 weeks with ipilimumab 1 mg/kg every 3 weeks for a total of 4 doses. That was followed by nivolumab as a single agent for maintenance therapy continued on a 2-week interval. Sunitinib was administered at a dose of 50 mg orally daily on a 4-week-on/1-week-off schedule—this was the standard dose.

What are the next steps?

The primary endpoints were to look at OS for those patients who were intermediate and poor risk; secondary endpoints included PFS. The trial accrued very rapidly and was first reported in the New England Journal of Medicine. There was a statistically significant difference in OS and response rate in favor of the immunotherapy combination. The toxicity was very manageable. With those data, it was FDA approved.With the proof of concept for combination immunotherapy, there has been significant interest in exploring other combinations. As we mentioned, the response rate for CheckMate-214 with nivolumab and ipilimumab was 40%. That essentially means that 60% of patients did not respond. This is still an area of unmet need.

There has been significant interest in identifying the underlying mechanisms of resistance to immunotherapy. There has been great interest in looking at the tumor microenvironment. We know that in RCC, mechanistically there is an increased VEGF, which can be immunosuppressive.

What are some considerations for immune-related AEs?

This can happen several different ways. VEGF has been known to suppress dendritic cell function, and it can increase the regulatory T cells. In addition, VEGF can alter the vasculation of the tumor and make it less likely for the tumor cells to be infiltrated by immune cells. If we already have VEGF inhibitors that are approved for RCC, then it makes logical sense to combine these agents with immunotherapy. This seems like it would be the right approach to get the T cells to work. Therefore, a number of clinical trials are underway. One is with the combination of pembrolizumab and axitinib, which showed that it met all of its primary endpoints.It is an interesting field. First, oncologists in the community need to re-learn how to deal with these toxicities. It is going to become even more interesting because the mechanisms of toxicity for VEGF TKIs are very different. When you start combining these 2 modalities, there will be a learning curve.

Just to give an example, the diarrhea that is associated with immunotherapy and deemed to be a very ominous AE is due to the activated T cells affecting the colon. The VEGF TKIs as a class can have diarrhea as a dose-limiting toxicity, and that is a chemical effect. The 2 mechanisms are very different, and so is the management. For sunitinib or cabozantinib (Cabometyx), when you treat the colitis that is associated, it is vastly different than how you treat autoimmune-related colitis. You would not want patients to have masked symptoms when being treated with immunotherapy. You would need to treat them with steroids. These conundrums will need to get into everyday oncology practice and be dealt with.

There is also going to be a learning curve for evaluating responses. Traditionally, we have used the RECIST criteria, which were based on chemotherapy-induced responses. Now, we are talking about responses to a combination of immunotherapy and VEGF inhibition or other targeted therapy. The reporting and evaluation criteria will need to be modified. We usually look at tumor shrinkage as a sign of response. Now, we know from the melanoma experience that stable disease is just as good; this could induce longevity.

The scans do not always have to be clear and complete responses. It is going to be an interesting time; the waters are going to get muddy. However, for patients, it is an exciting time.

References

1. Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.
2. Merck’s KEYTRUDA® (pembrolizumab) in combination with Pfizer’s Inlyta® (axitinib) significantly improved overall survival (os) and progression-free survival (pfs) as first-line therapy for advanced or metastatic renal cell carcinoma. Merck. Published October 18, 2018. https://bit.ly/2yLtWaC. Accessed October 18, 2018.
3. 3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. N Eng J Med. 2018;378:1277-1290. doi: 10.1056/NEJMoa1712126.