Nivolumab Plus Cabozantinib Improves OS in CheckMate-9ER Frontline RCC Trial

Toni K. Choueiri, MD

Nivolumab (Opdivo) combined with cabozantinib (Cabometyx) improved overall survival (OS) and progression-free survival (PFS) compared with sunitinib (Sutent) in patients with previously untreated advanced renal cell carcinoma (RCC), according to topline results from the phase III CheckMate-9ER trial.¹

The combination of the PD-1 inhibitor and the multikinase inhibitor also improved overall response rate (ORR). There were no new safety signals with any of the study treatments, according to Bristol Myers Squibb (BMS) and Exelixis, Inc, the manufacturers of nivolumab and cabozantinib, respectively.

“Preliminary assessment of the data shows the combination of a 40-mg dose of cabozantinib plus nivolumab demonstrated a favorable safety profile. If approved, this combination may become an important new first-line option for patients with metastatic renal cell carcinoma. We look forward to presenting detailed results at an upcoming congress,” added Choueiri.

The open-label, global phase III CheckMate-9ER trial (NCT03141177) randomized patients with advanced or metastatic RCC in a 1:1 ratio to frontline nivolumab/cabozantinib or sunitinib. PFS was the primary endpoint, with key secondary endpoints including OS and ORR.

“The positive topline results from the phase III CheckMate -9ER trial evaluating Opdivo in combination with Cabometyx build on our understanding of Opdivo-based regimens, and we look forward to working with global health authorities to help bring this new combination regimen to previously untreated patients, a population that despite recent advances, remains in need of additional therapeutic options that extend survival,” Brian Lamon, PhD, development lead, genitourinary cancers, BMS, said in the press release.

“We would like to thank the patients who participated in this trial, as well as the investigators and site personnel for their perseverance during the conduct of this study and in delivering this important result for patients in the midst of the COVID-19 pandemic,” added Lamon.

The FDA approved cabozantinib in December 2017 for previously untreated patients with advanced RCC, based on a meaningful improvement in PFS versus sunitinib in the CABOSUN trial.²

In the phase II study, first-line treatment with cabozantinib reduced the risk of progression or death by 52% compared with sunitinib for patients with advanced RCC. The median PFS was 8.6 months with cabozantinib versus 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74; P = .0008).

The CABOSUN trial randomized 157 patients with poor- and intermediate-risk advanced RCC to receive cabozantinib at 60 mg once daily (n = 79) or sunitinib at 50 mg daily for 4 weeks on/2 weeks off (n = 78). Intermediate-risk patients accounted for 81% of the study population. Baseline characteristics were similar between the two arms.

The ORR (all partial responses) with cabozantinib was 20% compared with 9% for sunitinib. When including those with stable disease, the over disease control rate was 75% with cabozantinib versus 47% for sunitinib. A reduction in target lesion size of any magnitude was recorded for 80% of patients in the cabozantinib arm versus 50% with sunitinib.

After 30.8 months of follow-up, the median OS was 26.6 months (95% CI, 14.6-not evaluable) in the cabozantinib arm versus 21.2 months (95% CI, 16.3-27.4) in the sunitinib arm, representing a nonstatistically significant 20% reduction in the risk of death (HR, 0.80; 95% CI, 0.53-1.21; P = 0.29).

The rate of grade 3/4 adverse events (AEs) was similar between the cabozantinib and sunitinib arms, respectively (68% vs 65%). Grade 5 AEs, regardless of cause, were experienced by 4% of patients in the cabozantinib arm compared with 10% in the sunitinib group.

When compared with cabozantinib, sunitinib led to higher rates thrombocytopenia (61% vs 38%), anemia (46% vs 33%), nausea (39% vs 32%), neutropenia (35% vs 15%), and leukopenia (35% vs 12%). However, compared with sunitinib, cabozantinib was associated with more diarrhea (73% vs 55%), hypertension (67% vs 44%), liver enzyme elevation (AST, 60% vs 31%; ALT, 55% vs 28%), decreased appetite (47% vs 32%) and weight loss (32% vs 17%, dysgeusia (41% vs 29%), and palmar-plantar erythrodysesthesia (42% vs 33%).

Regarding nivolumab, the FDA approved the PD-1 inhibitor in November 2015 as a treatment for patients with metastatic RCC following prior antiangiogenic therapy, based on an extension in OS in the CheckMate-025 trial.³

In the pivotal phase III study, nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median OS. Grade 3/4 AEs were also lower with the PD-1 inhibitor compared with everolimus.

In the frontline setting, the FDA approved nivolumab in April 2018 for use in combination with ipilimumab as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.

The approval was based on the phase III CheckMate-214 trial, in which frontline treatment with the combination of nivolumab and ipilimumab reduced the risk of death by 32% compared with sunitinib for patients with metastatic RCC.⁴ The risk reduction was 37% in patients with intermediate- and poor-risk RCC, who constituted about 75% of the intent-to-treat population.

In the randomized trial, the median OS in the overall population was not reached with the combination versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95; P = .0003). In those patients with intermediate- and poor-risk RCC, the median OS was not reached in the nivolumab and ipilimumab arm and was 26.0 months in the sunitinib arm (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001). There was not a benefit for the combination versus sunitinib in those with favorable risk.

Commenting in the press release on the positive CheckMate-9ER data, Gisela Schwab, MD, president, product development and medical affairs and chief medical officer, Exelixis, stated, “Given the growing body of data showing that Cabometyx may create a more immune-permissive tumor environment that may enhance response to immune checkpoint inhibitors, we have been eagerly awaiting the results for the combination of cabozantinib and nivolumab in previously untreated renal cell carcinoma.”

Schwab added, “We’re delighted that the trial met its primary endpoint of progression-free survival as well as the secondary endpoints of overall survival and objective response rate, demonstrating consistent benefit for the combination in previously untreated renal cell carcinoma patients. We look forward to our continued collaboration with Bristol Myers Squibb as we work toward regulatory filings in the near future.”

References

1. Bristol Myers Squibb and Exelixis Announce Positive Topline Results from Pivotal Phase 3 CheckMate -9ER Trial Evaluating Opdivo® (nivolumab) in Combination with CABOMETYX® (cabozantinib) in Previously Untreated Advanced Renal Cell Carcinoma Published April 20, 2020. https://bit.ly/2RRBItE Accessed April 20, 2020.
2. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.
3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. 2015;373:1803-1813.
4. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advance or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract LBA5.

“The results from the pivotal CheckMate -9ER trial clearly demonstrate the combination of cabozantinib plus nivolumab provides a clinically meaningful benefit in the key efficacy measures of progression-free survival and overall survival for previously untreated kidney cancer patients,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, said in a press release.