Nivolumab/Ipilimumab Prolongs Survival in Metastatic Clear Cell RCC Subsets

Treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) and a subsequent TKI was effective in patients with metastatic clear cell renal cell carcinoma (ccRCC), according to findings from the phase 2 BIONIKK trial (NCT02960906) that were presented at the 2023 Genitourinary Cancers Symposium.

The median overall survival (OS) was 34.92 months (interquartile range, 15.83-not reached [NR]) in patients who received nivolumab (HR, 1.56; 95% CI, 0.99-2.46), NR (interquartile range [IQR], 29.80-NR) in those who received nivolumab plus ipilimumab, and 45.18 months (interquartile range, 14.13-NR) in those who received a TKI (HR, 1.29; 95% CI, 0.76-2.19).¹

“Updated survival results from the BIONIKK trial confirm the high efficacy of nivolumab/ipilimumab in [immune-high and immunosuppressive tumor microenvironments (ccrcc4), as well as those with a high angiogenic signature (ccrcc2)], the high efficacy of VEGFR-TKI alone in ccrcc2 tumors, and the overall superior efficacy of nivolumab/ipilimumab over nivolumab alone,” lead study author, Yann-Alexandre Vano, MD, of the Institut du Cancer Paris CARPEM, AP-HP.Centre in France, and coauthors, wrote in a poster of the data.

Previously reported findings from BIONIKK showed that classifying renal tumors into 4 groups could allow for more accurate predictions of overall response rate (ORR), progression-free survival (PFS), and time to next treatment (TTNT). At a median follow-up of 18.0 months (interquartile range, 17.6-18.4), the ORR was 29% with nivolumab and 39% with nivolumab/ipilimumab in tumors with an immune-low tumor microenvironment (ccrcc1); 44% with nivolumab and 50% with nivolumab/ipilimumab in ccrcc4 tumors; 50% with a VEGFR-TKI and 51% with nivolumab/ipilimumab in ccrcc2 tumors; and 0% with a VEGFR-TKI and 20% with nivolumab/ipilimumab in tumors with a normal tumor microenvironment (ccrcc3).²

The multicenter, randomized, non-comparative BIONIKK trial classified patients by their tumor molecular group based on frozen tumor samples.¹ Eligible patients included those with previously untreated metastatic ccRCC who were at least 18 years of age and had an ECOG performance score (PS) of 0 to 2, no active brain metastases, and available frozen tumor tissue. By day 15 post-screening, patients were stratified by molecular groupings ccrcc1, ccrcc2, ccrcc3, and ccrcc4.

Patients with ccrcc1 and ccrcc4 tumors were randomized to receive intravenous (IV) nivolumab at 3 mg/kg every 2 weeks or IV nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles followed by 240 mg of nivolumab every 2 weeks. Patients with ccrcc2 and ccrcc3 tumors were randomized to receive the nivolumab/ipilimumab regimen or a VEGFR-TKI regimen consisting of either oral sunitinib (Sutent) at 50 mg daily for 4 weeks on and 2 weeks off or oral pazopanib (Votrient) at 800 mg daily. Patients remained on treatment until disease progression, death, or the end of the 18-month study.

BIONIKK had a primary end point of ORR and key secondary end points of PFS and OS. In total, 199 patients were randomized to receive nivolumab (n = 58), nivolumab/ipilimumab (n = 101), or a TKI (n = 40).

In the nivolumab arm, 67% (n = 39), 22% (n = 13), and 10% (n = 6) of patients had an ECOG PS of 0, 1, and 2, respectively, and 72% (n = 42) and 28% (n = 16) of patients had ccrcc1 and ccrcc4 tumors, respectively. In the nivolumab/ipilimumab arm, 77% (n = 78), 21% (n = 21), and 2% (n = 2) of patients had an ECOG PS of 0, 1, and 2, respectively, and 41% (n = 41), 18% (n = 18), 37% (n = 37), and 5% (n = 5) of patients had ccrcc1, ccrcc4, ccrcc2, and ccrcc3 tumors, respectively. In the TKI arm, 70% (n = 28), 30% (n = 12), and 0% of patients had an ECOG PS of 0, 1, and 2, respectively, and 90% (n = 36) and 10% (n = 4) of patients had ccrcc2 and ccrcc3 tumors, respectively.

In those with ccrcc1 tumors, the median OS was 45.80 months (interquartile range, 29.80-not assessed [NA]) in the nivolumab/ipilimumab arm vs 34.92 months (interquartile range, 17.54-NA) in the nivolumab arm (HR, 1.44; 95% CI, 0.79-2.61). In those with ccrcc2 tumors, the median OS was NA (interquartile range, 30.36-NA) in the nivolumab/ipilimumab arm vs NA (interquartile range, 25.83-NA) in the TKI arm (HR, 1.15; 95% CI, 0.57-2.32). In those with ccrcc3 tumors, the median OS was NA (interquartile range, 13.51-NA) in the nivolumab/ipilimumab arm vs 12.2 months (interquartile range, 7.88-18.48) in the TKI arm (HR, 3.2; 95% CI, 0.57-17.93). In those with ccrcc4 tumors, the median OS was NA (interquartile range, 31.61-NA) in the nivolumab/ipilimumab arm vs 34.36 (interquartile range, 13.75-NA) in the nivolumab arm (HR, 1.64; 95% CI, 0.59-4.54).

The updated ORR was 34.5% (n = 20), 48.5% (n = 49), and 52.5% (n = 21) in the nivolumab, nivolumab/ipilimumab and TKI arms, respectively, and the updated ORR, median PFS, and TTNT according to molecular group were consistent with previously reported findings.

In the nivolumab arm, the respective ORR, median PFS, and median TTNT were 31% (n = 13), 5 months (IQR, 2-15), and 11 months (IQR, 6-27) in those with ccrcc1 tumors and 44% (n = 7), 8 months (IQR, 2-NE), and 13 months (IQR, 5-NE) in those with ccrcc4 tumors. In the nivolumab/ipilimumab arm, those with ccrcc1, ccrcc2, ccrcc3, and ccrcc4 tumors, respectively, experienced an ORR of 44% (n = 18), 54% (n = 20), 20% (n = 1), and 55% (n = 10); the median PFS was 8 months (IQR, 3.5-29), 11 months (IQR, 6-40), 16 months (IQR, 2-NE), and 13 months (IQR, 2-NE); and the median TTNT was 13 months (IQR, 9-35), 22 months (IQR, 13-39), 17 months (IQR, 2-NE), and 29 months (IQR, 14-NE). In the TKI arm, the respective ORR, median PFS, and median TTNT were 21% (n = 58), 14 months (IQR, 5-39), and 16 months (IQR, 11-39) in those with ccrcc2 tumors and 0%, 2.4 months (IQR, 2-NE), and 4.1 months (IQR, 3-NE) in those with ccrcc3 tumors.

In total, 67% of patients (n = 133) received a second-line treatment after nivolumab (69%; n = 40), after nivolumab/ipilimumab (64%; n = 64), and after a TKI (72.5%; n = 29). Of these patients, 80% (n = 106) received a TKI in the second line, and 50% (n = 20) of patients who received a TKI in the first line received second-line nivolumab.

Of the patients who received second-line TKIs post-nivolumab, 76% (n = 28) and 24% (n = 9) of patients with ccrcc1 and ccrcc4 tumors, respectively, received axitinib (Inlyta; 16%; n = 6), cabozantinib (Cabometyx; 51%; n = 19), or sunitinib/pazopanib (32%; n = 12), respectively. Post-nivolumab/ipilimumab, 42% (n = 26), 39% (n = 24), 5% (n = 3), and 14% (n = 9) of patients with ccrcc1, ccrcc2, ccrcc3, and ccrcc4 tumors, respectively, received axitinib (11%; n = 7), cabozantinib (53%; n = 33), lenvatinib (Lenvima; 3%; n = 2), or sunitinib/pazopanib (32%; n = 20), respectively. Post-TKI, 7 patients with ccrcc2 tumors received axitinib (29%; n = 2) or cabozantinib (71%; n = 5), respectively. No patients with ccrcc3 tumors received second-line treatment post-TKI.

The median follow-up for patients who received a second-line TKI was 34 months (range, 24-38). The ORR with a second-line TKI was 27% (n = 10), 45% (n = 28), and 57% (n = 4) in the patients who had received first-line nivolumab, nivolumab/ipilimumab, and TKI, respectively. Notably, 1 patient each in the post-nivolumab/ipilimumab and post-TKI arms achieved a complete response.

The median PFS in the patients who received a second-line TKI was 8.7 months (range, 6.9-22), 11 months (range, 9.2-15), and 12 months (range, 11-NE) in those who had received first-line nivolumab, ipilimumab/nivolumab, and a TKI, respectively.

The median OS in the patients who received a TKI in the second line was 17.9 months (range, 7.5-NE), 26 months (range, 13.1-NE), and NE (range, 26.8-NE) in those who had received first-line nivolumab, ipilimumab/nivolumab, and a TKI, respectively.

Of the patients who received a second-line TKI, 54% (n = 57) received cabozantinib. In the patients who received cabozantinib who had received first-line nivolumab, nivolumab/ipilimumab, and a TKI, the ORR with cabozantinib was 21%, 45%, and 60%, respectively, with respective treatment durations of 7.0 months (interquartile range, 1.2-11.2), 11.7 months (interquartile range, 5.7-17.8), and 12.0 months (interquartile range, 11.7-24.0). The median PFS with second-line cabozantinib in the patients who received first-line nivolumab, nivolumab/ipilimumab, and a TKI was 8.3 months (interquartile range, 3.8-NE), 11 months (interquartile range, 9.2-20), and 22 months (interquartile range, 11-NE), respectively, and the median OS was 16 months (interquartile range, 9.4-NE), 23 months (interquartile range, 18-NE), and NE (interquartile range, 27-NE), respectively.

Of the patients who received a first-line TKI followed by second-line nivolumab, the ORR was 10%, the median PFS was 3.3 months (range, 2.5-17), and the median OS was 13.3 months (range, 7.7-NE).

The median PFS2, defined as the time from the initiation of line 1 to progression to line 2 or death, was 28 months (range, 10-52), 41 months (range, 18-NE), and 27 months (range, 8-NA) in the patients who received first-line nivolumab, nivolumab/ipilimumab, or a TKI, respectively. In the patients who received a second-line TKI, the median PFS2 was 23 months (range, 16-41), 27 months (range, 22-41), and 40 months (range, 38-NE) in those who received first-line nivolumab, nivolumab/ipilimumab, or a TKI, respectively.

“The BIONIKK trial will continue to explore new biomarkers of response in frontline mRCC,” the study authors concluded.

Disclosures: Dr Vano reports honoraria from Astellas Pharma, Bristol Myers Squibb, Ipsen, MSD Oncology, Novartis, Pfizer, and Roche; consulting or advisory roles with Bristol Myers Squibb and Roche; research funding from Bristol Myers Squibb (Inst) and Ipsen (Inst); and receiving travel, accommodations, and expenses from Bristol Myers Squibb, MSD Oncology, Pfizer.

References

1. Vano YA, Phan L, Simonaggio A, et al. Overall survival (OS) and efficacy results of second-line treatment in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) treated in the randomized phase II BIONIKK trial. J Clin Oncol. 2023;41(suppl 6):607. doi:10.1200/JCO.2023.41.6_suppl.607
2. Vano YA, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):612-624. doi:10.1016/S1470-2045(22)00128-0