Cabozantinib/Nivolumab Efficacy, Safety Considered for Metastatic RCC

Guru P. Sonpavde, MD

Medical Director of Genitourinary Oncology

Assistant Director of the Clinical Research Unit

Christopher K. Glanz Chair for Bladder Cancer Research

AdventHealth Cancer Institute

Orlando, FL

CASE SUMMARY

• A 65-year-old man presented with back pain for past 6 months and hematuria for 1 week.
• Laboratory results: hemoglobin, 11.4 g/dL; lactate dehydrogenase, 980 U/L; all others within normal limits
• CT scan of chest/abdomen/pelvis: multiple mediastinal and hilar nodes, deposits in left lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium
• Biopsy of renal mass and bone biopsy confirmed metastatic clear cell renal cell carcinoma (RCC).
• The patient received cabozantinib (Cabometyx) plus nivolumab (Opdivo).

Targeted Oncology^TM: What are the data behind a choice such as this for this patient with RCC?

Guru P. Sonpavde, MD: The CheckMate 9ER trial [NCT03141177] is the randomized phase 2 trial that compared cabozantinib/nivolumab vs sunitinib [Sutent].¹ In this case, in the cabozantinib/nivolumab arm, nivolumab was given every 2 weeks, and it was given for a total of up to 2 years. So it was not unlimited nivolumab dosing till progression. Two years was stated by the trial [investigators], and the sunitinib was given at 50 mg daily for 4 weeks on, 2 weeks off. One more point I want to highlight with cabozantinib/nivolumab is that the cabozantinib dose was 40 mg daily. That's less than the single-agent full dose, which is 60 mg daily. The dosing was designed to get a balance of efficacy and toxicity. The primary end point was progression-free survival [PFS].

What were the response and other efficacy outcomes observed on the CheckMate 9ER trial?

The overall response rate was 55.7% vs 27.4% for sunitinib. There were around 325 patients per arm. The median PFS was 8.3 months with sunitinib vs 16.4 months with cabozantinib/nivolumab, with an HR of 0.58. When you look at the median overall survival [OS]...it was 46.5 months [for those receiving] cabozantinib/nivolumab], close to 4 years. For sunitinib, it was closer to 3 years at 35.5 months, and the HR for survival improvement was 0.79, which was significant.

One of the interesting things to see in this survival curve is that the separation has remained 6 years out. I want to highlight the median duration of response. In the patients who responded, the median duration was close to 2 years, 22 months, and this is a similar theme we see across all the VEGF/immunotherapy trials: the median duration of response is approximately 2 years, give or take a few months.

How were the survival outcomes affected by International mRCC Database Consortium risk and site of metastases?

The trial was not powered to make any statistical judgments here. It was an unplanned look at the groups. There was a separation of the outcomes across all these groups. The favorable risk is a small group, between 20% to 30% favorable-risk patients, so it is not powered for survival. So, you don't see a survival separation specifically. But again, this was a post hoc, statistically unplanned, unpowered look.

When they looked at the site based on liver, bone, or lung metastases, there is an improvement in the PFS as well as OS across all these metastatic sites. It's tough to compare when you're doing this kind of subgroup analysis. But the HR in patients with bone metastasis is somewhat more impressive. But again, this is hypothesis generating and not statistically powered for this kind of comparison between these groups—just to say that regardless of the site of metastases, even unfavorable metastases like bone metastases, there was a significant improvement in PFS and OS.

What was the safety profile of cabozantinib/nivolumab on this trial?

As you can expect, you get the toxicities of cabozantinib and nivolumab, the diarrhea, the hypertension is important, the fatigue, the hypothyroidism, and liver enzyme elevations. You do get some myelosuppression, more with sunitinib than cabozantinib, and some rash in some patients, as we all see sometimes with these VEGF/immunotherapy combinations.

REFERENCE:

1. Motzer RJ, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate 9ER trial. J Clin Oncol. 2025;43(suppl 5):439. 10.1200/JCO.2025.43.5_suppl.439