Efficacy and safety of cabozantinib/nivolumab in the treatment of metastatic renal cell carcinoma

A 65-year-old man presented with back pain for the 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 lymph nodes, left lung lower lobe deposits, axillary lymphadenopathy, left renal parenchymal enhancement mass with renal vein infiltration; lytic destruction of L4 and L5 vertebral bodies, left superior pubic rami, and right ischium. Renal mass biopsy and bone biopsy confirmed metastatic clear cell renal carcinoma (RCC). The patient received cabozantinib (Cabometyx, cabozantinib) combined with nivolumab (Nivolumab).

The CheckMate 9ER trial [NCT03141177] was a randomized phase 2 trial comparing cabozantinib/nivolumab with sunitinib. In this case, in the cabozantinib/nivolumab group, nivolumab was administered every 2 weeks for a total of 2 years. Therefore, the dose of nivolumab is not unlimited until progression. The trial [researchers] said that after two years, sunitinib was taken at 50 mg daily for four weeks on and two weeks off. The dose of cabozantinib is 40 mg daily. This is less than the full dose in a single dose, which is 60 mg per day. Dosing is designed to strike a balance between efficacy and toxicity. The primary endpoint was progression-free survival [PFS].

What were the responses and other efficacy outcomes observed in the CheckMate 9ER trial? The overall efficacy rate for sunitinib was 55.7%, compared with 27.4% for sunitinib. Tki has approximately 325 patients. Median progression-free survival was 8.3 months with sunitinib and 16.4 months with cabozantinib/nivolumab, with a heart rate of 0.58. When looking at the median overall survival [OS] for patients who received cabozantinib/nivolumab, it was 46.5 months, which is almost 4 years. The HR for sunitinib improvement in survival at nearly 3 years at 35.5 months was 0.79, which was significant.

An interesting phenomenon in this survival curve is that this separation has lasted for 6 years. I want to highlight the median duration of responses. Among patients who responded, the median duration was nearly 2 years and 22 months, and it's a similar theme we see across all VEGF/immunotherapy trials: the median duration of response is about 2 years, given or taken.

InternationalHow do the risk and metastasis sites of the mRCC Database Consortium impact survival outcomes? The trial has no authority to make any statistical judgments here. This is an unexpected observation about these groups. The results for all these groups are separate. Favorable risk is a small group, between 20% and 30% of patients who are at favorable risk, so it's not conducive to survival. Therefore, no concrete existential separation can be seen. But again, this is an afterthought, statistically unplanned, unmotivated look.

When they looked at the site based on liver, bone or lung metastasis, all of those metastasis sites had improvements in PFS and OS. When you do this kind of subgroup analysis, it's difficult to make comparisons. But the HR in patients with bone metastases was even more impressive. But again, this is a hypothesis and there is no statistical basis for making this comparison between these groups - just to say that there was a significant improvement in PFS and OS regardless of the site of metastasis, even unfavorable metastases like bone metastases.

As expected, you will get toxicities with cabozantinib and nivolumab, diarrhea, significant hypertension, fatigue, hypothyroidism and elevated liver enzymes. You do get some myelosuppression, more so with sunitinib than cabozantinib, and some patients get rashes, as we sometimes see with theseVEGF/immunotherapy combinations.

References:https://www.targetedonc.com/view/cabozantinib-nivolumab-efficacy-safety-considered-for-metastatic-rcc