Combination Therapy Continues to Demonstrate Efficacy in Advanced Renal Cell Carcinoma

Rana R. McKay, MD

The combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) induced promising responses compared with sunitinib (Sutent) as treatment of patients with treatment-naïve advanced or metastatic renal cell carcinoma (RCC) in the phase 3 CheckMate-9ER study (NCT03141177), demonstrating the growing role of combination regimens for the treatment of patients with RCC.

The combination induced a 49% reduction in the risk of disease progression or death and was also able to double the objective response rate (ORR), according to the results that were presented during the 2020 European Society for Medical Oncology (ESMO) Virtual Congress. The median progression-free survival (PFS) was 16.6 months with the combination versus 8.3 months with sunitinib (HR, 0.51; P <.0001).

In addition to these positive efficacy findings, the combination also appeared to have a manageable safety profile with a low rate of treatment-related discontinuations. Health-related quality of life (QoL) was also maintained over time with the combination compared with sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 total score.

In an interview with Targeted Oncology, Rana R. McKay, MD, associate professor of Medicine and medical oncologist at the University of California, San Diego, discussed the findings from the CheckMate-9ER study of nivolumab plus cabozantinib in patients with advanced or metastatic RCC who had not been previously treated.

TARGETED ONCOLOGY: Could you discuss the current treatment landscape for patients with advanced RCC?

McKay: The current treatment options for patients with advanced RCC has been rapidly evolving over the last several years, especially the frontline options since the presentation of the CheckMate-214 data of the combination nivolumab plus atezolizumab (Tecentriq) for patients with advanced disease. From then, we see the presentation of the KEYNOTE-426 data of pembrolizumab (Keytruda) plus axitinib (Inlyta), then JAVELIN Renal 101 study of avelumab (Bavencio) plus axitinib for patients with advanced disease.

In 2005, we entered into the tyrosine kinase inhibitor era, and we're treating patients with targeted therapies, and that was the gold standard up until 2018. Now, combinations have entered into the frontline space.

TARGETED ONCOLOGY: What was the rationale for evaluating nivolumab in combination with cabozantinib in this patient population?

McKay: Both nivolumab and cabozantinib are each approved for the treatment of advanced RCC in the second-line space. The combination of nivolumab plus ipilimumab (Yervoy) was approved in the frontline. There was a phase 1 trial that was largely conducted the team at the National Cancer Institute that provided the early clinical data about efficacy with the combination of nivolumab plus cabozantinib. The results of that trial were recently published in the Journal of Clinical Oncology earlier this year, but that provided the clinical rationale for combining these agents. We know that cabozantinib has anti-angiogenic properties and immunomodulatory properties that counteract the tumor induced immunosuppressive environment. Obviously, nivolumab promotes anti-tumor responses and prevents cancers from evading the immune system and immune detection, so there's rationale for the combination.

TARGETED ONCOLOGY: How was this study designed?

McKay: The CheckMate-9ER study was a randomized phase 3 trial that was conducted internationally. It randomized patients 1:1 to treatment with nivolumab plus cabozantinib. The cabozantinib dose was 40 mg once daily as opposed to the standard starting dose of 60 mg once daily, and the control arm of sunitinib was given on a 4-week on, 2-week off schedule at 50 mg. The primary end point of the study was PFS, and secondary end points included overall survival (OS), ORR safety, and toxicity. In total, 651 patients were enrolled in the trial, which included patients with previously untreated locally advanced or metastatic RCC. They did not have to have a clear cell component to be eligible, and any risk category was eligible.

TARGETED ONCOLOGY: What were the findings from this study?

McKay: The topline findings were that the combination of nivolumab plus cabozantinib resulted in a statistically significant improvement in radiographic PFS, OS, and ORR compared to the control arm of sunitinib. When we dive deeper into that, the PFS by independent radiology review, which was the primary end point of the study, was 16.6 months with the combination compared to 8.3 months, with a hazard ratio of 0.51. When we look at PFS by investigator assessment, we see a similar trend. The combination PFS is 19.4 months compared to 9.2 months [in the control], with a hazard ratio of 0.46.

With regards to OS, again, we saw a statistically significant improvement with the combination of nivolumab plus cabozantinib compared to sunitinib. The medians have not yet been reached for OS, but the hazard ratio was 0.60. There was a 40% reduction in the risk of death with the combination.

When we look at the response data, we again saw a statistically significant improvement in ORR at 55.7% compared to 27.1% with sunitinib. The complete response rate was at 8% with the combination, keeping in mind that this trial enrolled a larger percentage of patients who had their primaries intact. About 30% of patients had their primaries intact, and 15% of patients had bone metastases. The median time to response was also improved over sunitinib, and the duration of response was 20 months, close to 2 years with the combination.

TARGETED ONCOLOGY: What does the safety profile look like for this combination?

McKay: The safety profile, even though patients were on therapy for twice as long with the doublet, was similar to that seen with sunitinib. Overall, 56% of patients underwent a dose reduction with the combination compared to 51.6% of patients with sunitinib. Any grade treatment-related adverse events that resulted in discontinuation of both nivolumab and cabozantinib was really low actually at 3.1%, and the number of patients who discontinued cabozantinib only was 6.6% compared to 8.8% for people needing to discontinue sunitinib. When we look at the grade 3 or more toxicity, it's comparable to what is seen with sunitinib, and the rate of all-cause grade 3 toxicity was 75% and 71%. With sunitinib, there was more diarrhea and more LST elevation that was observed, but most of this was grade 1 or 2 over sunitinib.

I think something that was striking from this study was the health-related QoL, which demonstrated that there was no deterioration in QoL for people receiving the combination, where we saw a deterioration in QoL metrics for people receiving sunitinib, and there was a statistically significant improvement in QoL across most parameters for patients receiving the combination.

TARGETED ONCOLOGY: Where do you see this therapy fitting into the treatment landscape?

McKay: It represents a potential new first-line option for patients with advanced disease. The PFS is improved, the OS is improved, the response rates are improved, across all risk categories, independent of PD-L1 status, independent of site of metastasis, so I think this is an active combination for patients with advanced disease. It's really hard to compare head to head against the CheckMate-214 and pembrolizumab/axitinib data, but this is definitely an efficacious regimen that could be a potential option for patients.

TARGETED ONCOLOGY: What are the remaining questions that need to be addressed in this space?

McKay: There’s lots of remaining questions in the field. Now that we have combination therapies, is there a way to even advance on top of that? The COSMIC-313 trial is actually looking at the combination of nivolumab plus cabozantinib versus nivolumab/ipilimumab in patients with intermediate- and poor-risk RCC. In that patient population, we see for the first time a non-sunitinib control arm in the first-line space. I think that trial is going to be illustrative regarding the role of triplet therapy for frontline disease.

Additionally, the PDIGREE trial was designed through the Alliance and also answers a very critical question of what do we do with those patients who don't achieve a complete response and don't have progressive disease to upfront nivolumab/ipilimumab, is there an opportunity to induce a response by adding cabozantinib to the nivolumab maintenance regimen? This study is looking at answering that question.

With the frontline space evolving, I think it's also resulting in lots of questions around, what do I do next? Multiple studies are looking at investigating sequential therapies. Specifically, the CONTACT-03 study is going to be looking at the combination of cabozantinib with atezolizumab versus cabozantinib alone in the second-line space, and that trial is quite interesting because in addition to including clear cell patients, it will also include patients with unclassified and papillary RCC.

_Reference

_{Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.}