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Background In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.Methods In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.Results At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.Conclusions M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

PurposeAnalysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient’s treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features.MethodsThis is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. ResultsThe presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). ConclusionsThe association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response.