Dataset Information

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A).

ABSTRACT:

Purpose

To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy.

Methods

Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%.

Results

One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab.

Conclusion

Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

SUBMITTER: Atkins MB

PROVIDER: S-EPMC9426835 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A).

Atkins Michael B MB Jegede Opeyemi A OA Haas Naomi B NB McDermott David F DF Bilen Mehmet A MA Stein Mark M Sosman Jeffrey A JA Alter Robert R Plimack Elizabeth R ER Ornstein Moshe M Hurwitz Michael M Peace David J DJ Signoretti Sabina S Denize Thomas T Cimadamore Alessia A Wu Catherine J CJ Braun David D Einstein David D Catalano Paul J PJ Hammers Hans H

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220420 25

<h4>Purpose</h4>To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy.<h4>Methods</h4>Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (pa ...[more]

PMID: 35442713

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Project description:BackgroundNivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.MethodsWe randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk.ResultsA total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.ConclusionsOverall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).

Project description:Background and purposeThis study aims to evaluate neutrophil-to-eosinophil ratio (NER) as a prognostic and/or predictive biomarker in metastatic clear cell renal cell carcinoma (m-ccRCC) treated with nivolumab or ipilimumab/nivolumab.Patients/materials and methodsWe performed a retrospective study on m-ccRCC patients treated with nivolumab or ipilimumab/nivolumab (2012-2022). Baseline NER was calculated and correlated with clinical outcomes: response rate (RR), progression free survival (PFS) and overall survival (OS). Corresponding transcriptomic data were analysed.ResultsWe included 201 m-ccRCC patients, 76 treated with ipilimumab/nivolumab and 125 with nivolumab. Baseline NER was statistically significantly associated with International Metastatic RCC Database Consortium (IMDC) risk groups. Increased NER was associated with shorter PFS and OS in the total patient series and nivolumab-treated patients. In patients treated with ipilimumab/nivolumab, increased NER was only statistically significantly associated with shorter OS. The impact of baseline NER on PFS and OS was independent of IMDC risk stratification. No clear correlation was found between baseline NER and RECIST response or maximal tumour shrinkage. In two additional databases, NER was also associated with PFS and OS in first-line vascular-endothelial-growth-factor-receptor tyrosine-kinase-inhibitors (VEGFR-TKIs), but not to disease-free survival in the post-nephrectomy setting. Lower NER was associated with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors.InterpretationLower baseline NER is associated with better PFS and OS, independent of IMDC risk score, in m-ccRCC patients treated with ipilimumab/nivolumab or nivolumab. It correlates with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. The predictive power of this biomarker is probably limited and insufficient for patient selection.

Project description:BackgroundThe Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.MethodsThe open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.ResultsFRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments.ConclusionsResults showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.

Project description:Combination anti-PD-(L)1/CTLA-4 blockade is approved in patients with hepatocellular carcinoma (HCC) in the first-line setting or after sorafenib, but whether this treatment has efficacy after prior anti-PD-(L)1 therapy is unknown. We performed a multicenter retrospective review of patients with advanced HCC treated with ipilimumab plus nivolumab after prior anti-PD-(L)1 therapy, excluding patients with prior anti-CTLA-4 treatment. Of the 32 patients who met our inclusion criteria, prior anti-PD-(L)1 regimens included atezolizumab plus bevacizumab (50%, n = 16), other anti-VEGF plus anti-PD-(L)1 combinations (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The median number of prior systemic therapies was 2 (range, 1-8). The objective response rate with ipilimumab plus nivolumab by RECIST 1.1 was 22% [1 complete response (3%), 6 partial response (19%), 8 stable disease (25%), 16 progressive disease (50%), and 1 not evaluable (NE) (3%)], and objective response was associated with improved progression-free survival and overall survival. Immune-related adverse events were reported in 13 patients (41%), with no new safety signals. This study demonstrates that ipilimumab plus nivolumab has efficacy in patients with HCC who have received prior anti-PD-(L)1 therapy, suggesting that failure to respond to prior PD-(L)1 blockade should not preclude treatment with salvage ipilimumab plus nivolumab. Prospective studies are needed to define the optimal sequence of therapies.SignificanceAnti-PD-(L)1 containing regimens are the preferred first-line treatment for advanced HCC, but whether salvage with PD-(L)1/CTLA-4 blockade is effective in patients who have failed prior anti-PD-(L)1 therapy is unknown. Our study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC previously treated with anti-PD-(L)1 therapy, supporting the continued use of this regimen in the late-line setting after prior anti-PD-(L)1 exposure.

Dataset Information

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A).

Purpose

Methods

Results

Conclusion

Publications

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A).

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