Nivolumab plus Ipilimumab plus Cabozantinib Triplet Combination for Patients with Previously Untreated Advanced Renal Cell Carcinoma: Results from a Discontinued Arm of the Phase III CheckMate 9ER Trial - Beyond the Abstract

The Checkmate 9ER trial randomized participants with previously untreated advanced renal cell carcinoma (RCC) 1:1:1 between cabozantinib (cabo)/nivolumab (nivo) [doublet], cabo/ipilimumab(ipi)/nivo [triplet] versus sunitinib.1 The doublet arm had significantly improved progression-free survival (PFS) and overall survival (OS) compared to sunitinib,1 leading to FDA approval of the doublet;2 however, recruitment to the trial was discontinued after sunitinib was no longer deemed a suitable standard of care, resulting in discontinuation of the triplet arm before full accrual.3

The triplet arm accrued 55 participants out of a planned 338. Median age was 60 (range 40–84) and 34 (68%) participants were male. Karnofsky performance status was 90 or 100 in 42 participants (84%) and the remainder were Karnofsky 70 or 80. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score was “favorable” in 11 (22%), “intermediate” in 31 (62%), and “poor” in 8 participants (16%); 41 participants (82%) had undergone prior nephrectomy.4

The objective response rate (ORR) by blinded independent central review (BICR) was 44% (95% CI, 30–58.7%), with 4/55 (8%) attaining a complete response (CR). The median duration of response was 15.9 months. Median PFS by BICR was 9.9 months (95% CI, 5.7–16.8) and median OS was 37 months (95% Cl, 31.8–not reached).4

Notable adverse events (AEs) of all grades [grade ≥3] from the triplet arm were gastrointestinal symptoms such as diarrhea (54% [4%]) and nausea (32% [0%]), hand-foot syndrome (38% [14%]), mucosal inflammation (26% [2%]), fatigue (32% [2%]), hypertension (28% [8%]), decreased appetite (28% [2%]), rash (30% [4%]), pruritus (20% [0%]), hepatic and pancreatic enzyme abnormalities such as increased ALT (48% [20%]), increased AST (38% [16%]), increased lipase (28% [14%]), and increased amylase (20% [6%]), and other laboratory abnormalities such as anemia (20% [12%]), hypothyroidism (30% [0%]), and increased blood creatinine (12% [0%]).4

Treatment was discontinued due to AEs in 11/50 treated participants (22%), with 15/50 (30%) discontinuing treatment in the first six months. Thirty-five (70%) proceeded to maintenance cabo/nivo after completing 4 cycles of cabo/ipi/nivo. Median number of doses of nivo was 19 (range 1–51) and median number of doses of ipi was 4 (range 1–4). Median daily dose of cabo was 23.5 mg (range 10–40). Of the 49 patients who received cabo, 33 (67.3%) required at least one dose reduction and 43 (87.8%) required dose delays, with most adjustments due to AEs. Twenty-two (44%) received any subsequent therapy.4

The experience of the Checkmate 9ER triplet arm exemplifies the challenges of conducting clinical trials in a rapidly changing treatment landscape. Nevertheless, the results are valuable and can be indirectly compared with those of the recently presented COSMIC-313 study.5 The ORR was similar in both trials: 44% and 43%, respectively; however, the CR rate was higher in Checkmate 9ER (8% vs. 2.5%). Although this could be due to the small sample size of the triplet arm of Checkmate 9ER, the difference could also be explained by the higher prior nephrectomy rate in Checkmate 9ER (82% vs. 65%), as in situ primary RCC lesions are unlikely to achieve CR with systemic therapy.6-8 Differences in IMDC risk groups may also have contributed, as Checkmate 9ER included favorable-risk participants whereas COSMIC-313 did not; consequently, Checkmate 9ER had lower proportions of intermediate-risk (62% vs. 75%) and poor-risk (16% vs. 25%) participants. It could also be due to differences in treatment exposure due to study design (Checkmate 9ER mandated 4 cycles of cabo/ipi/nivo prior to maintenance cabo/nivo while COSMIC-313 did not); however, complete data from COSMIC-313 are still pending.1,4

It is unclear how the triplet combination compares to the doublets of cabo/nivo and ipi/nivo. As noted above, cabo/nivo is currently approved for frontline treatment after demonstrating OS benefit compared to sunitinib, with a median OS of 37.7 months vs. 34.3 months after 32 months of follow-up (HR 0.73, p = 0.0043).9 Ipi/nivo continues to demonstrate OS benefit in the intermediate/poor-risk population after 5 years of follow-up, with a median OS of 47 months compared to 26.6 months for sunitinib (HR 0.68, p < 0.0001).10 Additionally, when reviewing AE rates across trials, the triplet cohorts in Checkmate 9ER and COSMIC-313 had numerically higher hepatic AEs compared with these doublets.

The future of the triplet regimen is still to be determined. Preliminary results from COSMIC-313 showed significant PFS improvement (median PFS of cabo/ipi/nivo vs. placebo/ipi/nivo not reached vs. 11.3 months, HR 0.73, p = 0.0131);5 however, OS results are still awaited. Given the increased AEs in the cabo/ipi/nivo arm compared to the placebo/ipi/nivo arm, wide adoption of the triplet regimen will depend on demonstrated OS improvement.

Written by: Elias Chandran, MD, Nicholas Simon, MD, Giovanni Maria Iannantuono, MD, & Andrea B. Apolo, MD, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD


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