Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM

BackgroundImmune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP).Case presentationsA 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment.ConclusionsThrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.

17 Background: ARV-110 is a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets AR. Patients (pts) with mCRPC have limited treatment (tx) options due to decreasing AR dependence of tumors upon successive therapies. Previous phase 1 data indicated clinical activity for ARV-110 in heavily pretreated pts with mCRPC and suggested enhanced activity in pts with specific molecular profiles, eg, AR T878 and H875 mutations, leading to a phase 2 expansion (ARDENT) to further characterize ARV-110 in biomarker-defined pt subgroups. We report results of the ongoing phase 1/2 study. Methods: In phase 1, pts with mCRPC and disease progression after ≥2 prior therapies (enzalutamide and/or abiraterone required) received ARV-110 orally once or twice daily (QD or BID) in sequential cohorts (3 + 3 dose escalation design). Primary objectives were to assess ARV-110 safety and select the recommended phase 2 dose (RP2D). Phase 2 pts with mCRPC and 1–2 prior novel hormonal agents (NHAs) ± chemotherapy were assigned to 3 biomarker-defined subgroups: 1) AR T878 and/or H875 mutations, 2) AR L702H mutation or AR-V7 (variants not degraded by ARV-110 in nonclinical studies), and 3) wild-type AR or other AR alterations. A fourth subgroup enrolled pts based on clinical history of less prior tx: ≤1 therapy for mCRPC, 1 NHA, and no chemotherapy. Primary objective is to assess ARV-110 antitumor activity. Results: As of Aug 26, 2021, 173 pts were enrolled (67 in phase 1; 106 in phase 2). In phase 1, ARV-110 doses ranged from 35–700 mg QD or 210–420 mg BID; 420 mg QD was selected as the RP2D based on safety, pharmacokinetics, and efficacy. Across 140 biomarker-evaluable phase 1/2 pts with ≥1 month of prostate-specific antigen (PSA) follow-up, 26 with AR T878A/S and/or H875Y mutations had best PSA declines ≥50% (PSA50) and ≥30% (PSA30) of 46% and 58%, respectively, vs 10% and 23% in 114 pts without these mutations. Of 7 RECIST-evaluable pts with AR T878A/S and/or H875Y mutations, 6 had tumor shrinkage (2 with confirmed partial responses), and 4 remain on tx. Five of 19 (26%) PSA-evaluable pts in the fourth subgroup (only 1 prior NHA; no prior chemotherapy) achieved PSA50. Overall PSA50 and PSA30 response rates were 16% and 29%, respectively. There were no grade ≥4 tx-related adverse events (TRAEs) in 113 pts treated at the RP2D. The most common any grade TRAEs at the RP2D were nausea (42%; grade 3: 1%), fatigue (27%; grade 3: 1%), vomiting (23%; grade 3: 1%), decreased appetite (19%; grade 3: 0), diarrhea (15%; grade 3: 2%), and alopecia (11%). Conclusions: ARV-110, a novel AR protein degrader, demonstrates clinical activity in a post-NHA, heavily pretreated mCRPC pt population, with greatest PSA50 activity and RECIST responses in pts with AR T878 and/or H875 mutations, likely representing a particularly ARV-110–sensitive population. ARV-110 merits further investigation in pts with mCRPC. Clinical trial information: NCT0388861.

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