Howard A. Burris’s research while affiliated with Sarah Cannon Research Institute and other places

PURPOSE To report on CheckMate 627 (ClinicalTrials.gov identifier: NCT02832167 ), a phase II adaptive basket design trial of nivolumab in uncommon advanced/metastatic tumors. METHODS Adults with previously treated advanced/metastatic malignancies received nivolumab 240 mg once every 2 weeks for eight cycles, followed by nivolumab 480 mg once every 4 weeks. The primary end point was investigator-assessed objective response rate (ORR). In addition to observed ORRs, model-adjusted ORRs were estimated via Bayesian analysis in patients who completed ≥28 weeks of follow-up, to correct for variability inherent in multitumor studies. This adaptive model allowed for borrowing of information from other tumors demonstrating similar ORR and evaluation of nivolumab treatment effect versus historical standard-of-care (SOC) controls. Nivolumab was considered to have met the criteria for ORR superiority in a group if there was ≥80% posterior probability of ORR with nivolumab exceeding ORR with historical SOC control treatment in that group. RESULTS The study included 25 tumor groups (n = 239), with 24 groups included in the Bayesian ORR analysis (efficacy was reported but not modeled in the other group that contained a mix of tumor types). The poorly differentiated neuroendocrine tumor (PD-NET) group (n = 20) met the prespecified criterion for ORR superiority with a 93% probability of the model-adjusted ORR with nivolumab (22% [95% CI, 8 to 44]) exceeding the respective historical SOC ORR of 10.0%. The observed ORR was 30.0% (95% CI, 11.9 to 54.3). There were no new safety signals for nivolumab. CONCLUSION Nivolumab showed evidence of antitumor activity in patients with advanced/metastatic PD-NET in CheckMate 627. The results of this study support the use of an adaptive basket design for identification of rare cancers responsive to immunotherapy.

Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.

mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non–small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors.

Tumor‐agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor‐agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability‐high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor‐agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody‐drug conjugate (Her2‐positive–immunohistochemistry 3+ expression) with pan‐cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue‐agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.

Background: Advances in cancer treatment have led to the rise of targeted therapies as practice-changing modalities, demonstrating significant efficacy in molecularly selected patients. However, depth of response and survival benefit is variable. Limitations in radiographic imaging create challenges in determining a clinical response. Circulating tumor DNA (ctDNA) is a promising minimally-invasive, predictive biomarker. Here we explore the utility of tumor-informed, on-treatment ctDNA dynamics for early response monitoring and prognostication in patients with HER2-positive tumors of various histologies receiving trastuzumab + pertuzumab on the phase II basket trial, MyPathway (NCT02091141). Methods: In this retrospective study, 58 patients were included based on availability of tissue comprehensive genomic profiling (CGP) results and baseline/on-treatment plasma. FoundationOne® Tracker was utilized to detect and quantify ctDNA, selecting 2-16 tumor-derived variants from tissue CGP and monitoring the corresponding patient’s plasma with multiplex PCR. ctDNA was assessed at baseline and Cycle 3 Day 1 (C3D1) of therapy. Correlations between ctDNA changes and objective response, progression-free survival (PFS) and overall survival (OS) were made using Kaplan Meier analyses and landmarked at C3D1. Patients ctDNA- at baseline and C3D1 were excluded. Results: Of the 58 patients, personalized ctDNA assays were successfully designed for 52 (89.7%) representing 14 unique tumor histologies. Of 52, 48 (92.3%) had ctDNA results available for baseline analysis with a median of 100.7 mean tumor molecules per mL (MTM/mL); 89.6% were ctDNA+ with a median of 119.5 MTM/mL. A total of 39 patients had both baseline and C3D1 results for ctDNA response analyses. On-treatment ctDNA decline >90% (N=10) was associated with longer survival compared to <90% decline (N=16) or any increase (N=13) in ctDNA (OS: NR, 9.4 months (mo); P= 0.007). CtDNA dynamics remained predictive in a disease specific analysis of colorectal cancer (N=18; OS: NR, 10.2 mo; P= 0.04). Similar results were seen when stratifying patients by baseline ctDNA level (above/below median MTM/mL) or HER2 (ERBB2) mutation vs amplification. ctDNA increase at C3D1 preceded radiographic progression by a median of 1.3 mo. In patients with stable disease, >90% decline in ctDNA was associated with longer OS compared to <90% decline or any increase (NR, 9.4 mo; P= 0.01). Conclusion: Tumor-informed ctDNA monitoring provides insight into early treatment response and survival outcomes in patients with diverse HER2 amplified or mutated tumors receiving HER2 targeted therapy. On-treatment ctDNA dynamics refine and can potentially detect response/progression ahead of standard of care response assessments, suggesting early ctDNA monitoring as a valuable complementary tool for real-time treatment response monitoring. Citation Format: Razelle Kurzrock, Merrida Childress, Wenshu Li, Anna Muse, Julia Malato, Yong Wang, Minetta Liu, Alexey Aleshin, Richard S. Wang, Julia Thierauf, Christopher J. Sweeney, John Hainsworth, Tania Szado, Amanda Young, Katja Schulze, David Spigel, Funda Meric-Bernstam, Charles Swanton, Howard A. Burris. Tumor informed circulating tumor DNA monitoring for early treatment response and survival outcomes on trastuzumab + pertuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1209.