DATA SUPPLEMENT Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238

9529 Background: Tebentafusp (gp100 x CD3) has demonstrated an overall survival (OS) benefit in mUM. Benefit was observed in patients (pts) who achieved a RECIST v1.1 partial response (PR), stable disease (SD) and even progressive disease (PD) (Nathan 2021). In Phase (Ph) 1, some melanoma pts had SD with tumor reduction > 10% that was confirmed at ≥ 1 subsequent scan (referred to as minor response, MR). In Ph 2, an analysis of MR was pre-specified as an endpoint and presented here. Methods: 127 HLA-A*02:01+ pts with previously treated mUM received weekly intravenous tebentafusp following intra-pt dose escalation of 20mcg Week 1, 30mcg Week 2 and 68mcg Week 3+ (NCT02570308; Carvajal 2022). Radiologic assessments were performed every 8 weeks until week 40, then q12 weeks. Tumor assessment was evaluated by a blinded independent review committee per RECISTv1.1. MR was prospectively defined as RECISTv1.1 best response of SD with reduction in sum of target lesions of -10% to -29% and which was confirmed ≥ 4 weeks later. ctDNA levels were assessed using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX (Natera). Molecular response was defined as ≥ 0.5 log [68%] ctDNA reduction by week 9. Data cut off: Oct 2022. Median duration of follow-up was 46 months. Results: Of 127 pts, the clinical benefit rate of PR + SD was 50% (64/127). 25% (32/127) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 6 PR (ORR 5%) and 26 SD (20%). 8/26 SD (6% of 127) met the pre-defined threshold for MR, most (5/8) had >20% reduction. The median duration of response for PR and MR were 8.7 months and 10.6 months, respectively. The estimated percent of pts with PR and MR remaining in response at Month 20 were 20% and 33%, respectively. 3/6 PR pts were alive ≥ 3 years vs 3/8. 58% of PR + SD pts with evaluable ctDNA had a molecular response (26/45), including 2/4 PRs and 5/5 MRs. Conclusions: This Ph2 UM study prospectively confirmed that a subset of SD patients had tumor reduction over multiple scans. The frequency of minor response was similar to that of PR and had similar durability, OS and ctDNA molecular response. SD with confirmed tumor reduction is an emerging endpoint for the ImmTAC platform and will be studied in other trials (NCT05549297, NCT04262466). Clinical trial information: NCT02570308 .

386 Background: In patients with previously untreated aRCC, A + Ax combination therapy has shown superior progression-free survival (PFS) and objective response rate (ORR) vs sunitinib across all International Metastatic RCC Database Consortium (IMDC) risk groups. This study reports real-world outcomes at up to 36 months post treatment initiation in patients with aRCC receiving A + Ax in the UK. Methods: Retrospective data were collected from medical records of patients aged ≥18 years diagnosed with aRCC, who initiated A + Ax on or after August 1, 2019, via the Early Access to Medicines Scheme at 10 UK sites. Patients were followed until July 31, 2023. Primary endpoints were overall survival (OS), PFS, ORR, and best response at 36 months post A + Ax initiation. Data were analyzed descriptively. Results: 130 patients were included. Median age at baseline was 67.1 years (range, 38.5-87.0 years); 74% (n=96) were male; 69% (n=90) were White, 4% (n=5) were Asian/Asian British, and ethnicity was not recorded in 27% (n=35); 94% (n=122) had an Eastern Cooperative Oncology Group score of 0 or 1. IMDC risk status was favorable in 39% (n=51), intermediate in 40% (n=51), and poor in 19% (n=25). Median time from aRCC diagnosis to A + Ax initiation was 2.5 months (range, 0.03-115.4 months). Clear cell histology was the most prevalent (88%; n=115); 68% (n=88) had undergone nephrectomy, and 78% (n=102) had 1 or 2 metastatic sites at index. The OS rate (95% CI) at 12, 24, and 36 months was 81.5% (75.1%-88.5%), 65.3% (57.6%-74.0%), and 53% (45.2%-62.9%), respectively. The PFS rate (95% CI) at 12, 24, and 36 months was 53.1% (45.1%-62.5%), 36.4% (29.0%-45.8%), and 27% (20.3%-36.0%), respectively. Median PFS was 13.5 months (95% CI, 10.2-17.7 months). ORR (n=127) at 36 months was 62% (95% CI, 53.8%-70.6%), including a best response of complete response (CR) in 5% (n=6) and partial response (PR) in 57% (n=73); best response was stable disease in 31% (n=39) and progressive disease in 7% (n=9; best response was not recorded in 3 patients). Median duration of response was 14.9 months (95% CI, 12.0-23.5). Median time to discontinuation (TTD) of A or Ax was 11.7 months (95% CI, 9.0-17.6), and for A + Ax combined was 14.7 months (95% CI, 11.0-24.4). Adverse events (AEs) were reported in 68% (88/129) of patients, who had a total of 519 nonserious AEs due to A + Ax treatment; 13% (17/129) of patients had a total of 27 serious AEs. The most common AEs (number of patients) were diarrhea (n=49), fatigue (n=33), and oral mucositis (n=24); 9 patients discontinued A and/or Ax due to AEs, including diarrhea in 3 patients. Conclusions: In this UK-based real-world study of first-line A + Ax treatment in patients with aRCC, OS, PFS, ORR, and best response observed at 36 months were in line with findings from clinical trials, with no newly emerging AEs.

BackgroundPredictive biomarkers for immune checkpoint blockade (ICB) in the second-line (2L) treatment of metastatic renal cell carcinoma (mRCC) are lacking.MethodsPatients with histologically confirmed RCC who started nivolumab after at least four months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS).ResultsTwenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active PD1+ CD4+ T cells were enriched in non-responders (q=0.003) and associated with worse PFS on nivolumab (p=0.04). Responders showed a significant reduction in the effector CD4+T cell (TEF) fraction compared to non-responders at 3 months on nivolumab (0.40 vs 0.80, p=0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q=0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 vs 87 cells/mm2, p= 0.04).ConclusionIn this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

Axel Bex, Franck Bonnetain, Alberto Bossi, Sergio Braccarda, Ronald Bukowski, James Catto, Toni Choueiri, Simon Crabb, Tim Eisen, Mounira El Demery, John Fitzpatrick, Vincent Flamand, Peter J. Goebell, Gwendael Gravis, Nadine Houédé, Didier Jacqmin, Richard Kaplan, Bernard Malavaud, Christophe Massard, Bohuslav Melichar, Loïc Mourey, Paul Nathan, David Pasquier, Camillo Porta, Damien Pouessel, David Quinn, Alain Ravaud, Frédéric Rolland, Manuela Schmidinger, Bertrand Tombal, Diego Tosi, Elodie Vauleon, Alessandro Volpe, Pascal Wolter Conception and design (SC) Administrative support (DATECAN study group) Provision of study materials (DATECAN study group) Collection and assembly of data (RC) Data analysis and Interpretation (SC) Manuscript writing (SC) Final approval of manuscript (SC, RC)

CONTEXT:The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to significant necrosis without significant reduction in tumour size. In addition, the vascular effects of antiangiogenic therapy may occur long before there is any reduction in tumour size. OBJECTIVE:To perform a systematic review of conventional and novel imaging methods for the assessment of response to targeted agents in RCC and to discuss their use from a clinical perspective. EVIDENCE ACQUISITION:Relevant databases covering the period January 2006 to April 2013 were searched for studies reporting on the use of anatomic and functional imaging techniques to predict response to targeted therapy in RCC. Inclusion criteria were randomised trials, nonrandomised controlled studies, retrospective case series, and cohort studies. Reviews, animal and preclinical studies, case reports, and commentaries were excluded. A narrative synthesis of the evidence is presented. EVIDENCE SYNTHESIS:A total of 331 abstracts and 76 full-text articles were assessed; 34 studies met the inclusion criteria. Current methods of response assessment in RCC include anatomic methods--based on various criteria including Choi, size and attenuation CT, and morphology, attenuation, size, and structure--and functional techniques including dynamic contrast-enhanced (DCE) CT, DCE-magnetic resonance imaging, DCE-ultrasonography, positron emission tomography, and approaches utilising radiolabelled monoclonal antibodies. CONCLUSIONS:Functional imaging techniques are promising surrogate biomarkers of response in RCC and may be more appropriate than anatomic CT-based methods. By enabling quantification of tumour vascularisation, functional techniques can directly and rapidly detect the biologic effects of antiangiogenic therapies compared with the indirect detection of belated effects on tumour size by anatomic methods. However, larger prospective studies are needed to validate early results and standardise techniques.