Updated Data Shows Durable Efficacy of Cabozantinib/Nivolumab in mRCC

Neeraj Agarwal, MD

Professor of Medicine

Presidential Endowed Chair of Cancer Research

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah

Targeted Oncology: What was investigated in the CheckMate 9ER trial (NCT03141177) of patients with metastatic renal cell carcinoma (mRCC)?

NEERAJ AGARWAL, MD: This was a phase 3 trial of patients with newly diagnosed mRCC and they were randomly assigned to nivolumab [Opdivo] plus cabozantinib [Cabometyx] vs sunitinib [Sutent]. Nivolumab [was given for a] duration of 2 years. In all the immunotherapy-based trials, there is a fixed duration of treatment for immunotherapy, so nivolumab could only be given for 2 years, and cabozantinib and sunitinib could have been continual.

What was found in terms of efficacy in the most recent update from this trial?

The mature survival data after 44 months [showed median] progression-free survival [PFS] was twice as much as sunitinib: 16 months vs 8 months with an HR of 0.58 [95% CI, 0.48-0.71;P < .0001].¹ What matters is how much better it is doing compared with sunitinib and clearly it is superior. What was interesting was the overall survival [OS]. After 44 months, I used to think that ultimately the [Kaplan-Meier] curves would merge, but it did not in this case. In patients who received cabozantinib plus nivolumab, they continued to have this wide separation of the curve. And now after 44 months, we saw a [14]-month median OS benefit. If you look at the absolute numbers, it is 35.5 months vs 49.5 months in this [intent-to-treat] trial population.

If you look at the subgroup analysis, we see all subgroups seem to be benefiting.² We don’t see any outliers here. These subgroups are not powered to have a P value…but it looks like everybody seems to be benefiting. If you look at the IMDC [International Metastatic RCC Database Consortium] risk categories, in the favorable-risk patients, OS was not clearly superior, which I think is because 300 patients are not enough to show OS benefit in a patient population which has a median OS of 7 or 8 years.³ But if you look at intermediate- and poor-risk patients, there was a clear separation of the [Kaplan-Meier] curve.

What was the significance of the best response to each of these regimens on the trial?

Response [rate] is one reason I use these drugs compared with sunitinib or pazopanib [Votrient]. If I cannot induce response in these patients within the first 3 or 4 months, these patients are likely going to have progressive disease [PD]. The moment we see PD as the best response, then I know that we are probably going to lose the patients. In most of these patients, high attrition is driven by PD in my view. Patients who have a complete response, partial response, or stable disease tend to receive second-line therapy or subsequent-line therapy. But patients with PD do not do very well. We know that they do not get second-line therapy. So if you look at the primary PD rates—and this is often overlooked—PD is [more than] double with sunitinib [13.7% vs 6.2% with cabozantinib plus nivolumab].² That’s one reason I do not use sunitinib compared with this combination of agents.

What was seen in terms of the different risk groups on the trial?

The intermediate-risk patients who were treated with sunitinib had a median OS of 36 months vs 49.5 months; this is a [13]-month difference in OS, which is quite remarkable.¹ If you look at objective response rate [ORR] with 4-year follow-up, there was almost doubling of ORR [56% with cabozantinib/nivolumab vs 28% with sunitinib]. If you look at the response in poor-risk patients, the ORRs were [41% for cabozantinib/nivolumab vs 10% with sunitinib]. The survival in poor-risk patients with sunitinib vs cabozantinib plus nivolumab [was a median OS of 10.5 months vs 34.8 months, respectively]. It is dramatically different. I think this is already a very established combination, and there is no doubt that this should be considered when you’re making the decision.

What impact did site of metastasis have on treatment outcomes in the trial?

If you look at the patients with liver, bone, and lung metastases, in my view, lung metastases behave in the best fashion. The prognosis of patients with lung-only metastasis was the best, [whereas] liver was the worst, and bone metastasis was somewhere in the middle. In all these categories, the cabozantinib plus nivolumab combination seemed to be doing quite well.³

What is the risk level of a patient with a metastasis to the colon?

I would say as long as they do not have peritoneal metastasis, like omental metastasis, [prognosis is not as bad]. For example, there was a study from University of Colorado looking at patients who have pancreatic-only metastasis, and they had better prognosis than most of the other groups.⁴ We would imagine that pancreatic metastasis must be very bad. Isolated colon metastasis without involvement of the omentum does not have as bad prognosis as omental metastasis or peritoneal metastasis. Usually, I get the metastasis resected. [If it can’t be resected], I’ll be worried about the VEGF TKIs, because they have a very high risk of perforation in patients who have colon wall metastasis who get VEGF-TKI. So I would lean towards ipilimumab [Yervoy] plus nivolumab in those patients.

I’ve never seen a patient with colon metastasis. I’ve had patients with appendix metastasis, pancreatic metastases, stomach metastasis, but I have been lucky so far, because that’s the No. 1 challenge I see with progression of the tumor.

How valuable is the CheckMate 9ER’s data on time to subsequent therapy?

These patients were allowed to continue cabozantinib after completion of 2 years of nivolumab and 88% of patients continued cabozantinib.¹ Think about what we were doing 10 years ago or 15 years ago. When I was a fellow, we were using interleukin therapy. This is 88% of patients going past 2 years. I noticed in the most recent analysis of the ipilimumab/nivolumab trial, which has the longest follow-up, almost 6 years now, that the median OS has exceeded 55 months.⁵ All these trials will exceed 55 or 60 months [median OS]. This is unprecedented. I never thought I would be telling patients their median survival is 5 years now, because of these combination agents.

_References:

_{1. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl_6):603. doi:10.1200/JCO.2023.41.6_suppl.603}

_{2. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898. doi:10.1016/S1470-2045(22)00290-X}

_{3. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl_15):4553. doi:10.1200/JCO.2021.39.15_suppl.4553}

_{4. Duarte C, Hu J, Beuselinck B, et al. Metastatic renal cell carcinoma to the pancreas and other sites-a multicenter retrospective study. EClinicalMedicine. 2023;60:102018. doi:10.1016/j.eclinm.2023.102018}

_{5. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180}