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Multinational study to compare three regimens for first-line treatment of advanced renal cell carcinoma
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A multinational study is underway to compare three treatment strategies for patients with previously untreated advanced or metastatic kidney cancer.
The CheckMate 9ER trial will evaluate the efficacy of two combination regimens — nivolumab (Opdivo, Bristol-Myers Squibb) plus cabozantinib (Cabometyx, Exelixis), and nivolumab with ipilimumab (Yervoy, Bristol-Myers Squibb) and cabozantinib — compared with sunitinib (Sutent, Pfizer) monotherapy.
The randomized phase 3 trial — which will include approximately 1,014 patients — will build off the phase 2 CABOSUN trial, which compared cabozantinib monotherapy with sunitinib monotherapy as first-line treatment for patients with poor- or intermediate-risk advanced clear cell renal cell carcinoma.
As HemOnc Today previously reported, cabozantinib proved superior, significantly extending PFS as determined by independent review and investigator assessment.
“[CheckMate 9ER] is a very exciting and potentially transforming trial for the field of advanced kidney cancer,” Toni K. Choueiri, MD, director of Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, told HemOnc Today. “I am thrilled that the community came together for a study such as this — one that includes modern agents and truly makes sense.”
HemOnc Today spoke with Choueiri about how the study will be conducted, the anticipated timeline for results, and the rationale for why the two combination regimens may be more effective than sunitinib alone.
Question: How will the study be conducted?
Answer: This trial will be conducted in approximately 1,014 patients with metastatic renal cell carcinoma whose tumors must have a clear cell component — the most common type of kidney cancer — and have had no prior systemic therapy. Patients will be randomly assigned to one of three arms: cabozantinib, nivolumab and ipilimumab; cabozantinib and nivolumab; or sunitinib alone. These are all drugs that have activity in renal cell cancer. The primary endpoint is PFS, and the secondary endpoint is OS.
Q: What is the anticipated timeline of the study?
A: This is an event-driven trial, so it is difficult to predict exactly when to anticipate data. The study is starting to accrue patients. We are targeting to complete the study in 2021, though this could vary.
Q: Can you describe the need for additional or more effective treatment options in this patient population?
A: Metastatic renal cell carcinoma is still largely incurable. We now have new treatments available that were approved within the past year or so, but patients are not cured. We have to think about how to identify better options for these patients. This approach will allow us to test drugs that are highly active, and the hypothesis is that, with the combination strategy we are undertaking, the drugs would have synergy and perhaps better chances for durable responses.
Q: Why do you think the combinations may be more effective than sunitinib alone?
A: Compared with sunitinib, the other drugs are active drug combinations. Not only is each drug active, but cabozantinib potentially has some synergistic qualities. In addition to inhibiting AXL and MET, both involved in resistance to antiangiogenic agents, cabozantinib interestingly has an effect on the immune system. In mouse models with prostate cancer, cabozantinib can trigger an anticancer innate immune response, driven by neutrophils, resulting in tumor clearance. There is data in breast cancer to suggest that cabozantinib results in a persistent decrease in CD14-positive monocytes, a mixed population that encompasses immunosuppressive and proangiogenic myeloid cells. In a nutshell, there is evidence that cabozantinib can potentially synergize with immunotherapy.
Q: How did the CABOSUN trial help set the stage for CheckMate 9ER?
A: The smaller, randomized phase 2 CABOSUN trial compared cabozantinib with sunitinib in patients with intermediate- or poor-risk disease. Cabozantinib provided a clinically meaningful and statistically significant improvement in PFS. Therefore, we want to build on cabozantinib, and that is what we are trying to do with this study. Adding to this, we have safety data from the doublet and triplet combinations from researchers at NCI. These combinations have some toxicities but so far, it seems they can be combined safely and are active.
Q: Is there anything else that you would like to mention?
A: This is an international study. Robert J. Motzer, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and I are co-principal investigators. The study has wide implications and can potentially result in a new standard of care. – by Jennifer Southall
References:
Apolo AB, et al. J Clin Oncol. 2017;doi: 10.1200/JCO.2017.35.15.
Choueiri TK, et al. Abstract LBA30_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
For more information:
Toni K. Choueiri, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215.
Disclosure: Choueiri reports institutional funding from Exelixis and Pfizer, as well as advisory board compensation from Pfizer.