IO/TKI Combination Offers New Treatment Option For Patients With RCC

Andrea Apolo, MD

The treatment of patients with renal cell carcinoma (RCC), a type of kidney cancer, has seen major strides in the past few years, moving toward immunotherapy-based combination regimens. The newly approved combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) offers oncologists another treatment options for their patients with advanced RCC in the first-line setting.

Nivolumab and cabozantinib were approved by the FDA for the treatment of treatment-naïve advanced RCC based on findings from the phase 3 CheckMate 9ER trial (NCT0314117). This open-label, randomized study compared the combination versus standard of care sunitinib (Sutent) and found an improvement in outcomes with nivolumab/cabozantinib versus sunitinib as well as a manageable safety profile. 

Andrea Apolo, MD, an investigator at the National Cancer Institute, discussed with Targeted Oncology the impact of the combination of nivolumab and cabozantinib as a new treatment for patients with advanced RCC.

TARGETED ONCOLOGY: In advanced RCC, what were the options oncologists had to treat their patients prior to this combination of nivolumab and cabozantinib being approved?

Apolo: In advanced metastatic RCC, there were several treatments available for the treatment of different subsets of RCC, which are favorable for an intermediate risk. And we already had the approval of axitinib (Inlyta) and pembrolizumab (Keytruda), which is also a tyrosine kinase inhibitor (TKI) and an immunotherapy, available for all risk groups. So, this combination is active, and the combination of cabozantinib and nivolumab add on to the current agents that are approved for the metastatic treatment in the first-line setting. There's now another option, another TKI plus immunotherapy available for the treatment of these patients. In addition to that, there's the combination of nivolumab and ipilimumab (Yervoy), what we call an IO-IO combination. And that was approved for poor and intermediate patients. Also, tyrosine kinases are approved, both in the favorable and in the poor and intermediate risk groups for patients with metastatic RCC in the first-line setting. We do have a lot of options. And the combination of cabozantinib and nivolumab, now that it's been FDA approved, is now another treatment options in all risk groups.

TARGETED ONCOLOGY: Why was it important to have this new treatment option?

Apolo: It's important to have options that are very effective and the combination of cabozantinib and nivolumab showed a survival benefit. It showed a progression-free survival benefit, it showed an overall response benefit, and it also showed an improvement in quality of life. So, it is important to have more treatment options for our patients with advanced metastatic RCC.

TARGETED ONCOLOGY: Can you give an overview of the results from the phase 3 CheckMate 9ER clinical trial?

Apolo: In January 22, 2021, the FDA approved the combination of cabozantinib and nivolumab for the first-line treatment of RCC, and this was based on the CheckMate 9ER study, which was a randomized phase 3 trial of cabozantinib and nivolumab versus sunitinib for patients with metastatic RCC in the first-line setting. The study found that the combination of cabozantinib and nivolumab improved progression-free survival by doubling the progression-free survival from 8 to 16 months. Improvement in overall survival was also seen, both arms didn't reach the median overall survival, but there was an improvement, with a hazard ratio of 0.6. There was also an improvement in overall response rate. That was remarkable with the combination of cabozantinib and nivolumab versus sunitinib, and there was an improvement in the quality of life. And these data were presented as a plenary session at ESMO (European Society of Medical Oncology Congress) 2020. And we have updated data that will be presented at ASCO GU (the American Society of Clinical Oncology’s Genitourinary Cancers Symposium) next month in February, with longer follow-up, a 16 month follow-up, and also specifically an exploratory analysis, looking at the sarcomatoid feature in patients with RCC.

TARGETED ONCOLOGY: What is important to note about the safety profile of this combination?

Apolo: I was the lead investigator in the phase 1 trial [for] the combination of cabozantinib and nivolumab and cabozantinib, nivolumab, and ipilimumab and we tested it in all GU (genitourinary) tumors. And we did initially have some concerns about the overlapping toxicity. Both agents can cause some form of diarrhea, they can cause some elevation of the liver enzymes. So that was a concern that we had initially. But I did find that with dose modifications, holding or dose reductions of the cabozantinib that actually it was a very tolerable combination, the combination of cabozantinib and nivolumab, and also the combination of cabozantinib, nivolumab, and ipilimumab.

TARGETED ONCOLOGY: Since there were so few dose reductions in this study, would you attribute that to the dose selected for each agent in the study?

Apolo: Based on our phase 1 study of cabozantinib and nivolumab and cabozantinib, nivolumab, and ipilimumab, we selected a lower dose of cabozantinib 40 milligrams daily instead of the standard cabozantinib 60 milligrams daily. And I think that the low number of dose reductions that we saw in the CheckMate 9ER study for cabozantinib was due to the tolerability of this lower dose of cabozantinib 40 milligrams that we selected in the phase 1 study.

TARGETED ONCOLOGY: These data comes shortly after the announcement of the phase 2 CANTATA study (NCT03428217), which failed to show improvement in progression-free survival. Can you explain what might be the difference in terms of the mechanism of action of nivolumab and telaglenastat, and what does this say about whether or not we should be treating these patients earlier on in their disease course?

Apolo: This approval of cabozantinib and nivolumab comes soon after the announcement that the CANTATA study was negative and that was a different combination. I think one of the successes of our study was that we have a good scientific rationale for the combination. In an initial trial that I did, where I looked at patients receiving cabozantinib, I saw that cabozantinib, in addition to its targeted effect, also had immunomodulatory effects. So, it affects the microenvironment of the patients being treated with it. And it really provided a very strong rationale for combining it with an immunotherapeutic strategy. And when you combine them, you see really great responses in patients being treated with a combination. So, we have a great rationale for the combination. These are different agents, and, like you said, this study was in the first-line setting, the CheckMate 9ER study was in the first-line setting of patients with advanced RCC. And that is our goal is, is we see the really high activity of patients receiving immunotherapy in the advanced and later-line settings. Our goal is to bring this to earlier states of disease to see if we can potentially improve the outcomes of patients early on so they don't develop such advanced disease and the disease may be easier to treat.

TARGETED ONCOLOGY: How would you invite advise community oncologists who are using this combination in their clinics for the first time.

Apolo: I would say, cabozantinib and nivolumab is very tolerable, but you do have to monitor the patients, I would say in closely for [adverse] effects of cabozantinib for decreased appetite, for weight loss, and just really stay on top of electrolytes, stay on top of symptoms that could potentially be difficult to distinguish which agent is causing it, for example, diarrhea. When you see diarrhea, sometimes it can be hard to pinpoint is it coming from the cabozantinib, which is a very common [adverse] effect. And usually, I suggest holding the cabozantinib, and then kind of following the patient to see how they do using anti-diarrhea agents to make sure that this is not an immune-related process from the nivolumab. And same thing with other toxicities, like elevation of liver enzymes, hold the cabozantinib and monitor more frequently to see if it resolves. Because cabozantinib has a shorter half life, usually [adverse] effects resolved within days, as opposed to immune-related [adverse] effects that can persist for weeks. I would say close follow-up with patients receiving the combination. It is tolerable, but it does require diligence and close follow-up.

TARGETED ONCOLOGY: Is there anything else you'd like to add?

Apolo: I think that it's a very exciting time right now, in kidney cancer research. There's a lot of new agents that are being tested and having this new approval of cabozantinib and nivolumab is just wonderful. And it gives our patients another option for combination therapy that is very active.

_Reference:

_{Choueiri TK, Powles T, Burotto M, et al. 696O_PR 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(suppl 4).S1159. doi:10.1016/j.annonc.2020.08.2257}