Nivolumab/Cabozantinib Continues to Showcase Deep, Durable Responses in Advanced RCC

Nivolumab (Opdivo) plus cabozantinib (Cabometyx) continued to significantly improve overall response rate (ORR) vs sunitinib (Sutent) in patients with previously untreated, advanced renal cell carcinoma (RCC), with meaningful response outcomes observed irrespective of dose modifications with cabozantinib and fewer responders in the doublet arm requiring subsequent treatment, according to follow-up data from the phase 3 CheckMate-9ER trial (NCT03141177).¹

Results, which were presented during the 2021 Kidney Cancer Research Summit (KCRS), showed that at a median follow-up of 23.5 months, the ORR per blinded independent central review (BICR) was 54.8% (95% CI, 49.2%-60.3%) with the doublet vs 28.4% (95% CI, 23.5%-33.6%) with the monotherapy (odds ratio, 3.2; 95% CI, 2.3-4.4).

Of those who responded to the combination, 9.3% experienced a complete response (CR) and 45.5% had a partial response (PR). Among those who responded to sunitinib, the CR and PR rates were 4.3% and 24.1%, respectively.

“Meaningful response outcomes were observed regardless of appropriate dose modifications with cabozantinib, and more responders remain on therapy with nivolumab plus cabozantinib vs sunitinib,” study author Amishi Y. Shah, MD, a medical oncologist in the Department of Genitourinary Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a presentation on the data. “Fewer responders required subsequent systemic therapy with nivolumab plus cabozantinib vs sunitinib, and this trend was even more pronounced among patients with a CR.”

Earlier data from the trial indicated that at minimum follow-up of 10.6 months, nivolumab plus cabozantinib demonstrated superiority over sunitinib when used in the frontline treatment of patients with advanced RCC. Based on these data, the doublet was approved by the FDA in January 2021 for use in this population.²

The superior efficacy of the doublet was maintained at a minimum follow-up of 16.0 months, with a median progression-free survival (PFS) of 17.0 months (95% CI, 12.6-19.4), a median overall survival (OS) that was not yet reached, and a median duration of response (DOR) of 21.7 months (95% CI, 17.3–not evaluable [NE]) vs 8.3 months (95% CI, 6.9-9.7), 29.5 months (95% CI, 28.4–NE), and 12.7 months (95% CI, 9.6-20.7), respectively, with sunitinib. 

At the 2021 KCRS, investigators presented results from a post-hoc analysis of patients with a confirmed best overall response of CR or PR on the CheckMate-9ER study to better characterize those who respond to the combination of nivolumab plus cabozantinib vs sunitinib.

CheckMate-9ER enrolled patients with previously untreated, advanced, or metastatic RCC who had a clear cell component. Patients were enrolled irrespective of International Metastatic RCC Database Consortium (IMDC) risk group.

A total of 651 participants were randomized 1:1 to receive either 240 mg of nivolumab every 2 weeks plus 40 mg of cabozantinib daily (n = 323), or 50 mg of sunitinib daily (n = 328), on a 4-weeks-on/2-weeks-off schedule. Treatment was administered until disease progression per RECIST v1.1 criteria or unacceptable toxicity. Stratification factors included IMDC risk score, tumor PD-L1 expression, and geographic region. 

The primary end point of the study was PFS per BICR, using RECIST v1.1 criteria in the intent-to-treat (ITT) population. Secondary end points included OS, ORR per BICR and RECIST criteria in the ITT population, and safety in all treated patients. The median follow-up for OS in the ITT population was 23.5 months.

In the ITT population, the median age of patients was 61.5 years (range, 28-90), and most were male and had a tumor PD-L1 expression that was either less than 1% or indeterminate. Forty-nine percent of patients on both arms were from the United States or Europe, 79% across the arms had 2 or more sites. The most common site of metastasis for patients in both arms was the lung. The median sum of reference diameters of target lesions was 71.5 mm.

On the combination arm, 23% of patients had a favorable IMDC prognostic score, 58% had an intermediate score, and 19% had a poor score, compared with 22%, 57%, and 21%, respectively, of those on the sunitinib arm. Moreover, 74% of patients on the combination arm had metastasis in the lungs, 40% in the lymph nodes, 24% in the bone, and 23% in the liver; these rates were 76%, 40%, 22%, and 16%, respectively, in the sunitinib arm. Most patients in each arm had a PD-L1 expression of less than 1% (74% vs 75%, respectively) and were from a geographic region outside the United States or Europe (51% vs 51%).

Thirty patients on the combination arm, and 14 patients on the sunitinib arm achieved a CR. Additionally, 147 patients on the combination arm and 79 patients on the sunitinib arm achieved a PR.

Among all responders, 63% of patients continued to receive the doublet and 52% continued to receive sunitinib. In the investigative and control arms, the median duration of therapy was 20.4 months (range, 14.9-24.4) and 19.3 months (range, 12.7-21.9), respectively. Among these patients, the most common reason for discontinuing treatment was disease progression.

For those who achieved a CR in the combination arm, 70% of patients continued in the treatment period vs 64% in the sunitinib arm; the median duration of therapy was 23.5 months (range, 19.6-26.1) and 20.4 months (range, 19.3-21.9), respectively. The most common reason for discontinuing treatment was not specified on the combination arm and was disease progression on the sunitinib arm.

For those who achieved a PR in the combination arm, 61% of patients continued in the treatment period vs 49% in the sunitinib arm, and the median duration of therapy was 19.9 months (range, 12.7-23.9) and 18.3 months (range, 10.9-22.1), respectively. The most common reason for discontinuing treatment within this subset was disease progression in both arms.

Additionally, in the ITT population, the median time to response (TTR) was 2.8 months (range, 2.8-3.9) in the combination arm vs 4.2 months (range, 2.8-7.1) on the sunitinib arm. The median DOR was 21.7 months (95% CI, 17.3–NE) in the investigative arm vs 12.7 months (95% CI, 9.6-20.7) in the control arm.

For patients who achieved a CR with treatment, the median TTR was 2.8 months (range, 2.8-2.9) in the combination arm vs 3.7 months (range, 2.8-6.9) on the sunitinib arm, and the median DOR had not yet been reached in either arm. For those who achieved a PR, the median time TTR was 2.8 months (range, 2.8-4.2) in the combination arm vs 4.3 months (range, 2.8-7.3) in the sunitinib arm; the median DOR was 17.5 months (95% CI, 16.5-22.0) vs 11.1 months (95% CI, 7.0-13.8), respectively.

In the combination arm, 76% of patients reported a reduction of target lesions of more than 50%, 36% reported a reduction of more than 75%, and 22% reported a reduction of more than 90%; these reduction rates were 54%, 23%, and 12%, respectively, in the sunitinib arm.

Among all responders, 18% of those in the combination arm went on to receive subsequent therapy vs 27% of those in the sunitinib arm. For those who achieved a CR, 10% went on to receive subsequent therapy on the combination arm vs 21% on the sunitinib arm; these rates were 20% and 28%, respectively, for those who achieved a PR.

In the ITT population, treatment-related adverse effects (TRAEs) of any grade were reported in 99% of patients in each study arm. Sixty-two percent of patients on the combination arm and 57% of those on the sunitinib arm experienced grade 3/4 TRAEs. The most frequently reported TRAEs on the combination and sunitinib arms, respectively, were diarrhea (67% vs 60%), palmar-plantar erythrodysethesia (44% vs 57%), and hypothyroidism (40% vs 47%).

“These results continue to support nivolumab plus cabozantinib as a first-line, immunotherapy-TKI, standard-of-care treatment options for patients with RCC,” Shah concluded.

References

1. Shah A, Powles T, Bourlon M, et al. Characterization of responders in the phase 3 CheckMate 9ER trial: nivolumab plus cabozantinib versus sunitinib in patients with previously untreated advanced renal cell carcinoma. Presented at: 2021 Kidney Cancer Research Summit; October 7-8, 2021; virtual.
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA. January 22, 2021. Accessed October 11, 2021. http://bit.ly/2Mjrt1i