Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced non-clear cell renal cell carcinoma (nccRCC) (HCRN GU16-260-Cohort B).
Authors: Atkins Michael B. , Jegede Opeyemi , Haas Naomi B. , McDermott David F. , Bilen Mehmet Asim , Hawley Jessica , Sosman Jeffrey A. , Alter Robert S. , Plimack Elizabeth R. , Ornstein Moshe Chaim , Hurwitz Michael E. , Peace David J. , Signoretti Sabina , Wu Catherine J. , Catalano Paul J. , Hammers Hans J. 
Published: June 2021

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Background: The HCRN GU16-260 trial reported on the efficacy and toxicity of nivo monotherapy in treatment naïve clear cell RCC (Cohort A) and the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy (Atkins JCO 2020.38.15_suppl.5006). Limited information is available on the effects of such an approach in pts with advanced nccRCC. Methods: Eligible pts with treatment-naïve nccRCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to enrolling on Part B for correlative studies. Results: 35 pts with nccRCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 63 (range 35-84 years); 89% male. IMDC favorable 8 (23%), intermediate 18 (51%) and poor risk 9 (26%). Of the 35 pts 19 (54%) had papillary, 6 (17%) chromophobe and 10 (29%) unclassified histology. RECIST defined ORR was 5 of 35 (14.3%) [CR 2 (5.7%), PR 3 (8.6%)], SD 16 (45.7%), PD 14 (40.0%). Immune-related ORR was 8 of 35 (22.9%). RECIST ORR by histology was: papillary - 1/19 (5%); chromophobe - 1/6 (17%); unclassified - 3/10 (30%). 9 pts (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified, 1 papillary) responding. Median PFS was 4.0 (2.7, 4.3) mo. 21 pts remain alive. None of the responders have progressed or died. 28 pts (25 PD, 3 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 12 did not enroll due to symptomatic PD (2), grade 3-4 toxicity on nivo (3), or other including no biopsy tissue (7). In the 16 Part B pts, best response to nivo/ipi was: PR (1, 6%) – (unclassified/non-sarcomatoid); SD (7, 44%); PD (8, 50%). Grade 3 Treatment-related adverse events (TrAEs) were seen in 7/35 (20%) on nivo. Grade 3-5 TrAEs were seen in 7/16 (44%) on nivo/ipi with 1 pt experiencing sudden death. Correlative studies including PD-L1 status, WES and RNAseq are pending. Conclusions: Nivo monotherapy has limited activity in treatment naïve nccRCC with most responses (4 of 5) seen in pts with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi was provided in 16 of 28 (57%) pts with PD/pSD on nivo monotherapy, with 1 response observed. Clinical trial information: NCT03117309.