Immunotherapy combination for kidney cancer doubles response rate in patients: A discussion with Hans J. Hammers, MD, PhD
Key Takeaways
Background Researchers have shown that a combination of two immunotherapeutic agents—nivolumab plus ipilimumab—provide complementary activity against metastatic renal cell carcinoma (mRCC). The combination of these two immune checkpoint inhibitors doubled the objective response rate, from 20% to 40%, compared with nivolumab alone.
The results of this open-label phase 1 trial—CheckMate 016—also showed durable responses with about two-thirds of patients surviving two years, according to study results published in the Journal of Clinical Oncology. Side effects were also manageable, the authors noted.
"For this group of patients, these are very significant results," said lead author Hans J. Hammers, MD, PhD, Associate Professor of Internal Medicine and co-leader of the Kidney Cancer Research Program at University of Texas (UT) Southwestern Medical Center in Dallas, TX.
Treatment options for mRCC have been limited. Chemotherapy has not been effective and is often used only after other kidney cancer treatments have already been tried. VEGF and mammalian target of rapamycin inhibitors are not usually durable and can result in significant toxicities. Newer, single-agent immunotherapies show durable responses, improve overall survival, and are more tolerable—but only benefit a subset of patients.
The immunotherapy combination of nivolumab plus ipilimumab has already been investigated for use in metastatic melanoma and lung cancer, where the combo demonstrated greater and more durable responses compared with either agent alone.
In the current study, Dr. Hammers and colleagues investigated the safety and efficacy of nivolumab and ipilimumab in 94 patients with mRCC. In this interview, Dr. Hammers discusses the safety and side effect outcomes, as well as the efficacy results, of this new treatment.
MDLinx:What was the difference between the two study arms?
Dr. Hammers: The main difference was that patients in one arm received a higher dose of nivolumab (3 mg/kg) and a lower dose of ipilimumab (1 mg/kg), while patients in the other arm received a lower dose of nivolumab (1 mg/kg) with a higher dose of ipilimumab (3 mg/kg).
We did see a significant difference in the safety profile of these two arms in that the high-dose ipilimumab arm had a significantly higher rate of side effects—hepatitis, colitis, and high grade diarrhea. Interestingly, the response rate between these two arms was the about same although the toxicity profile was markedly different. So this study let us know that the low-dose ipilimumab arm would be preferable, and in fact it was chosen for a phase 3 trial that is now fully accrued. We hope to have the results over the next year or so and, if it duplicates the results of this phase 1 study, it could potentially change the standard of care.
MDLinx:What was the side effect profile for the combination therapy compared to nivolumab alone?
Dr. Hammers: That's a very good question. I would say nivolumab has a clearly lower rate of colitis, high-grade diarrhea as well as hepatitis in comparison with the combination. So the combination side effect profile is really driven by the ipilimumab. Other toxicities that we typically think about to be more nivolumab-associated, like pneumonitis, for example, were similar to monotherapy.
MDLinx:How did overall survival with the combination therapy compare with overall survival with nivolumab therapy alone?
Dr. Hammers: That's difficult to interpret as the study was not really designed to look at overall survival, although we did note in the report. It's also a mixed population, so half of the patients were previously treated with tyrosine kinase inhibitors and the other half of patients were previously untreated. So while it looks encouraging, it's difficult to interpret.
I think the more important efficacy data is actually the response rate. The confirmed objective response rate for nivolumab was 21% and the confirmed objective response rate for each of the arms in this study was 40%, so it's almost double as high. And importantly, the quality of response that we like to see with immunotherapy was durable.
Also, there's a number of patients who came off treatment altogether because of side effects but continued to respond, meaning they had a prolonged treatment-free interval where they didn't need any further therapy.
About Dr. Hammers: Hans Hammers, MD, PhD, is an Associate Professor of Internal Medicine in the Division of Hematology-Oncology at UT Southwestern Medical Center. He is co-leader of clinical research and immunotherapy for the Kidney Cancer Research Program and is the first Eugene P. Frenkel, MD, Scholar in Clinical Medicine at UT.
This study was funded by Bristol-Myers Squibb (BMS), the maker of Opdivo® (nivolumab) and Yervoy® (ipilimumab).