Health-Related QoL Data Stand Out in Support of Nivolumab Plus Cabozantinib in Advanced RCC

Bradley McGregor, MD

The combination of immune checkpoint inhibitor nivolumab (Opdivo) plus VEGF tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) recently received a Priority Review designation from the FDA for the potential treatment of patients with advanced renal cell carcinoma (RCC), with a Prescription Drug User Fee Act target action date of February 20, 2021. This decision is based on the supportive findings from the pivotal phase 3 CheckMate-9ER study (NCT03141177), in which the combination reduced the risk of disease progression or death by 49%.

The study ultimately improved overall survival (OS) and doubled both the median progression-free survival (PFS) and the overall response rate (ORR). The median PFS, which was the primary end point of the study, was 16.6 months with the combination versus 8.3 months with sunitinib (Sutent; HR, 0.51; P <.0001). The secondary end points included OS, ORR, and safety. The median OS had not yet been reached, but the ORR was 55.7% with the combination versus 27.1% in the control arm, with complete responses (CRs) observed in 8.0%, partial responses in 47.7%, and stable disease in 32.2% among patients in the combination arm.

The safety profile appeared to be manageable with the combination in the study with a low rate of treatment-related discontinuations.

An exploratory end point of the study was also health-related quality of life (QoL). In terms of health-related QoL, investigators noted an improvement with the combination compared with sunitinib, and the health-related QoL was found to be maintained over time with nivolumab and cabozantinib. These findings showed a consistent deterioration per Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 total score, and the between-arm differences were significant at nearly all time points.

In an interview with Targeted Oncology, Bradley McGregor, MD, clinical director of Lank Center for Genitourinary Oncology, senior physician at Dana-Farber Cancer Institute, and instructor of Medicine at Harvard Medical School, discussed the findings from the CheckMate-9ER study of nivolumab and cabozantinib as treatment of patients with advanced RCC, as well as the health-related QoL data supporting the use of this combination.

TARGETED ONCOLOGY: What is the prognosis typically like for patients with advanced or metastatic RCC? What are the treatment options in this setting?

McGregor: When we look at the treatment for advanced RCC, it certainly has changed significantly in the past several years. We know that RCC does respond to judicial cytotoxic chemotherapy, and we had the advent of the first targeted therapies with the VEGF TKIs over close to 15 years ago that showed improvement in PFS, and for a while, that was the mainstay. Back in 2017, we saw the first data showing that immunotherapy has a role in the frontline treatment with the presentation of nivolumab, and it showed improvement in overall survival and anemia versus sunitinib

Since then, we've had other VEGF/immunotherapy combinations with both axitinib (Inlyta) and pembrolizumab (Keytruda) and axitinib/avelumab (Bavencio) approved by regulatory agencies, given in the case of acupuncture, improving OS and PFS versus sunitinib in all patients.

There's a wide variety of options to offer our patients now with TKI monotherapy being used less and less given these data, in both nivolumab/ipilimumab (Yervoy), axitinib/pembrolizumab. These are becoming new standards of care given the OS benefit in patient with RCC.

TARGETED ONCOLOGY: How was the CheckMate-9ER study designed?

McGregor: As these trials are being designed, there are several being designed simultaneously, and so in addition to data that has been presented before, we have this type of study of nivolumab and cabozantinib, and there's an ongoing trial looking at lenvatinib (Lenvima) and pembrolizumab. This was a similar design to what's been looked at before with other VEGF/immunotherapy combinations, to look at the combination of cabozantinib with the PD-1 inhibitor, nivolumab, versus sunitinib in those patients with metastatic clear cell RCC.

This was an international trial that looked to enroll 651 patients, and randomized patients to the nivolumab/cabozantinib versus sunitinib at the standard dose, with a primary end point of PFS, but secondary end points include OS, response rates, and safety. I think what's unique about this trial design in some ways is that when we look at the studies for other TKI/immunotherapy combinations, for instance, axitinib/pembrolizumab or axitinib/avelumab, the axitinib dose is at the same dose that would be used without a checkpoint inhibitor. The standard FDA-approved dose for cabozantinib in monotherapy is 60 mg daily, and this trial looked to give a dose of 40 mg daily, with the thought that there's some synergy and at the 40 mg dose, maybe better tolerability.

TARGETED ONCOLOGY: What did the study population look like in this study?

McGregor: The study included patients across International Metastatic RCC Database Consortium (IMDC) risk groups, comparable to what we see in practice about 20% to 25% were favorable-risk disease, about 60% intermediate-risk disease, and about 20% were poor-risk disease. Enrollment was evenly distributed in the United States, Europe and the rest of the world.

When we look at the data from the initial analysis, with a medium follow-up of 18+ months, we see marked improvement in PFS with a hazard ratio (HR) of 0.51. The median PFS was 16.6 months with nivolumab/cabozantinib versus 8.3 months with sunitinib, so doubling the PFS. When we look at OS, while median OS had not yet been reached, the HR certainly favors the combination of nivolumab and cabozantinib with a HR of 0.60 and a P value that's statistically significant. When we look at the breakdown of both these by subgroups, I think that the benefit seems to be independent of subgroups. There seems to be a benefit in favorable-risk disease, as well as all the other subgroups.

This is a highly effective regimen, so when you look at the results, the ORR was 56% with the combination, with a CR rate of 8%, which is quite significant. These are quite encouraging efficacy results, and the median DOR was quite long as well.

TARGETED ONCOLOGY: What did the safety look like in this trial?

McGregor: The safety is certainly of interest. When we look at these combinations, this is great and effective, but in this setting where we may not be able to cure the patient, what is the quality of life? What is the safety? I think what we've seen overall is this was a reasonably well-tolerated regimen with the toxicity we expect to see, such as diarrhea, hand-foot syndrome, hypertension. However, when we look at those patients with immune-related adverse events (AEs), it is always a concern when we start thinking about immunotherapy.

Only 19% of the patients required corticosteroids to manage any grade immune-related AEs, and only 4% of them had to receive that for over 30 days, which is quite encouraging. The other thing I would add is that we've seen data with these regimens, but how do patients feel independent of toxicities, I think what's most striking in this is they look at the quality of life. Overall there was an improvement in QoL with the combination versus sunitinib, so it's a highly effective regimen with an improvement in QoL. This is quite encouraging

TARGETED ONCOLOGY: What are the implications of these findings?

McGregor: I think this becomes another standard of care. When we look at PFS, we had a risk of disease progression or death by close to 50%. OS risk of death was decreased by 40% with an increase in ORR by 30% compared to sunitinib, and this was consistent across all baseline characteristics, such as IMDC, PD-L1, and presence of bone metastasis. It was also well tolerated, so I think this just gives us another standard of care for those patients who present with a new diagnosis, of metastatic RCC independent of their IMDC classification.

TARGETED ONCOLOGY: Are there any next steps planned for this research?

McGregor: This is exciting data, and it offers a new standard of care. I think 1 of the questions we have though as clinicians and patients, is the long-term follow-up looking at the durability of response. The second question is since we have nivolumab/ipilimumab, the dual immune checkpoint inhibitors. We have TKI/immunotherapy combinations that show improvement. What about looking at all of these together? We're looking at these in the monotherapy comparative arm, so we look forward to the COSMIC-313 which is looking at the combination of nivolumab and ipilimumab plus or minus cabozantinib. I think seeing these results with excellent tolerability of cabozantinib combined with immunotherapy, we're excited about this regimen and also the ongoing trial looking at the addition of cabozantinib to dual checkpoint blockade in RCC.

TARGETED ONCOLOGY: What do you hope oncologists take away from these data?

McGregor: At the end of the day, this is another regimen that we can use in our armamentarium and discuss with patients about when they present with a new diagnosis of RCC. I think now we have 3 different TKI/immunotherapy combinations that have shown improved PFS and improvements in OS, so I think that this gives us another option to consider. When we look at when we do cross-trial comparisons to other trials, I think this seems to be a highly effective regimen, and what really stands out to me is the safety profile and the QoL analysis.

_References

_{1. U.S. Food and Drug Administration accepts for Priority Review applications for Opdivo® (nivolumab) in combination with Cabometyx® (cabozantinib) in advanced renal cell carcinoma. News Release. Bristol Myers Squibb. October 19, 2020. Accessed October 19, 2020. https://bit.ly/3jac9z6}

_{2. 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.}