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New Approaches in RCC
Joining Forces: How New Approaches and Combinations Are Likely to Improve Treatment of RCC

Released: November 09, 2017

Expiration: November 08, 2018

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The landscape for treatment of metastatic renal cell carcinoma (RCC) is continuing to evolve as new data with immune checkpoint inhibitors and novel tyrosine kinase inhibitor (TKI) therapies are presented, and more approvals are expected soon. In a recent survey of international RCC experts by Clinical Care Options, many of these experts are beginning to consider the combination nivolumab plus ipilimumab as first-line therapy for patients with intermediate-risk or poor-risk RCC, even in the absence of an FDA approval for this indication. In addition, experts would also consider the TKI cabozantinib as first-line therapy for some patients in this setting.

In this commentary, I discuss the data behind these expert decisions and how clinicians can best use these approaches in their practice. To see more about the expert recommendations from the survey, check back in on the CCO Web site for a new international treatment decision tool for RCC that I am developing along with my international colleagues (Bernard Escudier, MD; Michael Staehler, MD, PhD; and Cora N. Sternberg, MD, FACP).

Nivolumab Plus Ipilimumab: First-Line Treatment Option
Escudier and colleagues conducted the phase III CheckMate-214 study of nivolumab/ipilimumab vs sunitinib for first-line treatment of advanced or metastatic RCC (N = 1096). In this trial, patients were stratified by their IDMC prognostic score, and the primary endpoints included ORR, PFS, and OS in the intermediate-risk/poor-risk subgroup. This was the first demonstration of an OS advantage vs sunitinib in many years. The median OS for intermediate-risk/poor-risk patients treated with the combination was not reached vs 26.0 months for sunitinib alone (HR: 0.63; P < .0001). There was also a significant ORR advantage with nivolumab/ipilimumab vs sunitinib in this patient subgroup (42% vs 27%, respectively; P < .0001). The CR rate was 9% with nivolumab/ipilimumab vs 1% with sunitinib, which is also higher than historical data with the more toxic interleukin-2 treatment.

This impressive efficacy advantage did not appear to extend to the favorable-risk subgroup, however, as these patients seemed to benefit more with sunitinib therapy in an exploratory analysis of PFS and ORR. Focusing on the favorable-risk patients, the ORR was 29% with nivolumab/ipilimumab vs 52% with sunitinib (P = .0002). Similarly, the median PFS was 15.3 months with nivolumab/ipilimumab vs 25.1 months with sunitinib therapy (P < .0001).

The dual checkpoint inhibitor combination did report higher incidence of immune-related adverse events compared with single-agent nivolumab, with approximately 60% of patients receiving steroids as part of aggressive adverse event management. Although there is a strong learning curve for the optimal use of the nivolumab/ipilimumab combination, severe toxicities from checkpoint inhibitors tend to affect fewer than 10% of patients and can be managed with prompt recognition and early intervention. These results also remind us that the use of steroids does not jeopardize the efficacy of checkpoint inhibition, can substantially help patients cope with these toxicities, and ensures that patients can receive this effective treatment.

In my opinion, the survival benefit in intermediate-risk/poor-risk patients in CheckMate-214 combined with the impressive ORR rate suggest that nivolumab/ipilimumab will quickly be integrated into use as first-line RCC therapy. It will be important to see the published data regarding the final OS data, the role of PD-L1 testing for selecting optimal patients, and the final magnitude of benefit across all patient subgroups. We have not yet adopted nivolumab/ipilimumab in our clinic, both because of access issues and because this combination is not yet approved in RCC, but I am currently enrolling my patients on the ongoing phase II OMNIVORE trial for access to first-line immune checkpoint inhibitor therapy and look forward to the upcoming PEDIGREE trial. In any case, it is my opinion that the combination of nivolumab/ipilimumab is poised to become a standard of care for first-line treatment of patients with intermediate-risk/poor-risk metastatic RCC.

Cabozantinib as an Alternative First-line Treatment for Some Patients With RCC
Regardless, TKI therapy will still play a role in the front line setting. In the phase II CABOSUN study, there was also a significant PFS improvement for first-line cabozantinib vs sunitinib in patients with intermediate-risk/poor-risk RCC (median PFS: 8.2 vs 5.6 months; HR: 0.66; P = .012). Although there was no statistically significant difference in OS (median: 30.3 months with cabozantinib vs 21.8 months with sunitinib), there was an increase in ORR with cabozantinib vs sunitinib (46% vs 18%, respectively).

For patients with intermediate-risk/poor-risk RCC who may not be able to tolerate treatment with nivolumab/ipilimumab or interleukin-2 or who are at risk of autoimmune complications, cabozantinib is an alternative. For patients with good-risk disease, sunitinib and pazopanib remain the standard of care.

Cabozantinib After Progression on First-line Therapy
For patients with RCC who progress after first-line nivolumab/ipilimumab—or even single agent nivolumab in second or third line—clinicians must select additional therapy to try to optimize the patient’s OS. Based on phase III data from the METEOR trial of cabozantinib vs everolimus in patients with advanced RCC (with any clear-cell component) and at least 1 previous VEGFR-targeted TKI (with no limit on number and type of previous therapies), cabozantinib can be used to prolong OS. In my clinic, I will often recommend cabozantinib for patients with RCC who progress on nivolumab or, now, nivolumab/ipilimumab. I would choose cabozantinib over axitinib, pazopanib, sunitinib, or tivozanib as second-line therapy or beyond, given the proven survival benefit in this setting.

In addition to the use of cabozantinib after progression on immune checkpoint inhibitors, some clinicians choose cabozantinib for their patients with RCC who are progressing after first-line TKIs, if they have a high tumor burden or accelerated tumor growth and need a fast response to gain control of the disease. For other patients who are progressing after first-line TKIs but have less tumor burden or a slower tumor growth rate, most physicians will start with nivolumab.

Ongoing Clinical Trials
Even with these exciting data, unanswered questions still remain. The OMNIVORE study, mentioned above, is exploring optimal treatment schedules of immune checkpoint inhibitors for first-line therapy. While the data presented from Checkmate-214 is certainly intriguing, it may be that not everyone needs to be treated with the more costly and toxic combination of nivolumab and ipilimumab. In the OMNIVORE trial, patients receive 4 cycles of first-line nivolumab, and then their response is assessed. Patients with stable disease or progressive disease continue on nivolumab with the addition of ipilimumab. Those who achieve a true response—PR or CR—can continue nivolumab alone for an additional 4 cycles with a subsequent break in therapy if the response is sustained. Upon progression, these patients are reinitiated with both nivolumab and ipilimumab.

Enrollment for CheckMate 214 was completed prior to approval of nivolumab, and it remains unclear whether patients benefit most from use of first-line nivolumab/ipilimumab before a TKI or just that immunotherapy is beneficial. Hopefully, future studies will examine whether a first-line TKI followed by second-line immunotherapy is as effective as first-line immunotherapy followed by second-line TKI.

Finally, the results of ongoing studies with combinations of TKIs plus immune checkpoint inhibitors for the treatment of metastatic RCC are anxiously awaited. It will be interesting to see whether the CR rates and durability of responses will be similar to the nivolumab/ipilimumab combination and how these novel combinations may compare with sunitinib. It is an exciting time in RCC treatment right now.

A New Tool to Help Guide RCC Treatment Decisions
To help you address the challenges associated with treatment decisions for your patients with RCC, my colleagues (Bernard Escudier, MD; Michael Staehler, MD, PhD; and Cora Sternberg, MD, FACP) and I are creating an international treatment decision tool along with additional education on managing patients with RCC, so check back in on the CCO Web site for more information soon. This tool will help you rapidly select individualized treatment options for patients based on their characteristics by offering recommendations from each of the experienced faculty members specifically for the case you enter into the tool.

What has been your clinical experience with immune checkpoint inhibitors and cabozantinib in the treatment of patients with metastatic RCC? Share your thoughts in the comment box below.

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