Selected Articles from This Issue

Therapies targeting HER2 have become a standard of care (SOC) treatment for patients with HR⁺ HER2⁺ breast cancer; however, resistance can arise through multiple mechanisms. Those who progress on HER2 therapies may benefit from further treatment with a combination of cytotoxic chemotherapy and additional HER2-directed agents. Initial results from the monarcHER trial found that abemaciclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, combined with the HER2-targeting immunotherapeutic trastuzumab and the selective estrogen receptor degrader fulvestrant improved progression free survival (PFS) in patients with HR⁺ HER2⁺ advanced breast cancer (ABC) compared to chemotherapy plus trastuzumab. In this update to the phase II monarcHER trial, Tolaney and colleagues assessed overall survival (OS) in patients with HR+ HER2+ with ABC treated with abemaciclib, trastuzumab, and fulvestrant (Arm A), abemaciclib plus trastuzumab (Arm B), or SOC chemotherapy plus trastuzumab (Arm C). The authors report a median OS of 31.1 months in Arm A, 29.2 months in Arm B, and 20.7 months in Arm C. Consistent with previous findings, treatment was well-tolerated with a manageable safety profile. Additionally, an exploratory RNA-sequencing analysis found that patients with Luminal subtypes had better OS and PFS than those with non-Luminal subtypes. These results demonstrate improved OS with abemaciclib, trastuzumab, plus fulvestrant warrant further investigation.

Patients with homologous recombination deficient tumors, which can arise from mutations in BRCA1/2, may benefit from the use of PARP inhibitors such as olaparib. In early results from the phase II MEDIOLA study, olaparib plus durvalumab, a PD-1-directed monoclonal antibody, showed promising efficacy and safety in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and germline BRCA1/2 mutations (gBRCAm). In a follow-up, Drew and colleagues report extended data from a gBRCAm PSROC expansion cohort, as well as results from a non-gBRCAm PSROC doublet cohort and a non-gBRCAm PSROC triplet cohort, with the triplet cohort receiving the anti-VEGF monoclonal antibody bevacizumab in addition to olaparib and durvalumab. The treatment regimens were well tolerated, with anemia being the most common adverse event. In the gBRCAm PSROC expansion doublet cohort, the authors observed an overall response rate of 92.2%. At 24 weeks, the non-gBRCAm PSROC doublet and triplet cohorts had a disease control rate of 28.1% and 74.2%, respectively. Overall, the authors found that the combination of olaparib plus durvalumab continued to show notable efficacy in patients with gBRCAm PSROC and that the addition of bevacizumab showed promising responses in patients with non-gBRCAm PSROC, highlighting the need for additional studies in patients with non-gBRCAm ovarian cancer.

Resistance to immune checkpoint inhibitors may be overcome by enhancing antigen presentation by antigen-presenting cells (APCs) and increasing T-cell infiltration in the tumor microenvironment. The costimulatory receptor CD40 is expressed on APCs and is directly involved in T- and B-cell activation, making it an attractive target. In this phase II trial, Weiss and colleagues assess the efficacy of the CD40 monoclonal antibody sotigalimab with nivolumab, a PD-1 monoclonal antibody, in patients with advanced melanoma who progressed following PD-1 inhibitor therapy. Of 33 evaluable patients, five had confirmed partial responses (PR), yielding an overall response rate of 15%, and two PRs are ongoing at 45.9+ and 26+ months. The authors report a median duration of response of ≥26 months. The treatment regimen was manageable, with only 13% of patients experiencing a grade 3 adverse event (AE) and no AE-related sotigalimab discontinuations. The durable responses in a subset of patients combined with a favorable safety profile call for further evaluation in patients with anti-PD-1-resistant melanoma.

Overcoming chemotherapy resistance in metastatic triple-negative breast cancer (mTNBC) is an ongoing therapeutic challenge. Clinical trials investigating the addition of the PD-1-targeted monoclonal antibody pembrolizumab to standard chemotherapy regimens have had some success, yet a better understanding of resistance mechanisms is needed to inform clinical decision making. In this phase II clinical trial, Wilkerson and colleagues evaluate the efficacy and safety of a combination of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in patients with mTNBC and identify transcriptomic correlates of therapeutic response. In 30 patients, the authors report an overall response rate of 48%, with 2 complete responses (CR), 11 partial responses (PR), and 8 with stable disease. A median progression free survival of 5.8 months and a median overall survival of 13.4 months were achieved. RNA sequencing of core tissue biopsies obtained prior to treatment demonstrated that patients achieving CR and PR demonstrated increased expression of IGHG1, and that tumors with high IGHG1 levels showed enrichment of B cells and follicular helper T cells, indicating the potential use of IGHG1 as a biomarker of chemoimmunotherapeutic response. Collectively, these findings highlight the promise of CNP as a treatment strategy and warrant further studies to validate IGHG1 as a marker for lymphocytic infiltration and response to chemoimmunotherapy.