Osimertinib & Ipilimumab Combination in EGFRm NSCLC Patients

Genomics, Lung Cancer: Genomics, Lung CancerIn a recent development in the treatment of epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC), researchers reported positive results from a Phase Ib clinical trial evaluating the safety and tolerability of the combination of osimertinib and ipilimumab. The research was presented at the ESMO 2023 Congress, held in Madrid, Spain (Abstract 1335P). Osimertinib, an oral EGFR tyrosine kinase inhibitor (TKI), has proven to be a valuable option for the first-line treatment of EGFRm mNSCLC. However, combining osimertinib with PD-1/PD-L1 inhibitors has been hindered by excessive toxicity concerns. This led researchers to explore alternative combinations with immune checkpoint inhibitors, such as the CTLA-4 inhibitor ipilimumab. The decision to explore this combination stemmed from a prior Phase I trial that evaluated the use of the EGFR TKI erlotinib with ipilimumab in EGFRm mNSCLC. While the trial was terminated due to gastrointestinal dose-limiting toxicities (DLTs), it did reveal an unprecedented improvement in survival with a median overall survival of 42.3 months. Based on this observation, the researchers designed a clinical trial to investigate the combination of osimertinib with ipilimumab in EGFRm mNSCLC with a focus on the dose-escalation phase. This single-center, Phase IB trial enrolled patients who had been on a stable dose of first-line osimertinib (40 or 80 mg/day) for at least 28 days without disease progression. The trial commenced with Cohort 1 (C1), where patients received osimertinib daily along with ipilimumab at 3mg/kg every 3 weeks. A safety run was conducted with six patients, and the dose was planned to be expanded if fewer than or equal to one out of six patients experienced DLTs. However, if two or more out of six patients encountered DLTs, the study would de-escalate to Cohort 2 (C2), where patients received osimertinib daily with ipilimumab at 1mg/kg every 3 weeks. C2 would be expanded if fewer than or equal to one out of six patients experienced DLTs, and the study would be closed if two or more out of six patients experienced DLTs. The primary objective of the study was to determine the tolerability (per NCI CTCAE v5) of the osimertinib and ipilimumab combination, with key secondary endpoints including objective response rate, progression-free survival (PFS), and overall survival. Between September 2020 and March 2022, a total of 10 patients were enrolled, with four in C1 and six in C2. The majority of patients were never-smokers (80%), female (80%), and White (100%) with an ECOG performance status of 1. During the trial, three DLTs were observed, including one Grade 3 thromboembolic event and two Grade 2 cases of diarrhea, all of which occurred in C1. Common all-grade treatment-related adverse events (TRAEs) included diarrhea (60% of patients), fatigue, nail changes, and rash (40% of patients each). Grade 3-4 TRAEs were rare, with only one patient experiencing Grade 3 hepatitis, diarrhea, anorexia, and weight loss (10% of patients each). Most of the Grade 3 TRAEs were observed in C1, with one out of six patients (17%) experiencing Grade 3 weight loss in C2. As a result of these findings, the researchers chose C2's dose for further evaluation in the dose-expansion cohort, with eight additional patients accrued to date. For additional insights into the Phase Ib study, Oncology Times chatted with study presenter, Sonam Puri, MD, Assistant Professor in the Division of Oncology and Physician Leader of the Thoracic Clinical Trials Research Group at the Huntsman Cancer Institute of the University of Utah. Oncology Times: What patient characteristics or EGFR mutation status might influence the response to osimertinib and ipilimumab, and how should these factors be considered in clinical decision-making? Puri: “Historically, lung cancer patients harboring EGFR mutations are not considered good candidates for immunotherapy (IO) as they have a suppressed immune tumor microenvironment. In addition, IO-based therapies in combination with tyrosine kinase inhibitors have been associated with higher adverse events in this population. However, the majority of the data supporting this is related to the use of either single-agent or combination therapies with anti-PD-1/PD-L1 drugs. “We conducted an early-phase clinical trial at HCI evaluating the combination of EGFR TKIs erlotinib and CTLA-4 inhibitor ipilimumab. The trial was closed early due to a higher-than-expected number of gastrointestinal toxicities, but we saw an unprecedented improvement in survival among 11 patients with EGFR mutations who were enrolled in the study with a median PFS of 27.8 months and median OS that was not reachable with a follow-up of ~3 years. This signals toward a population of EGFR patients that can derive additional benefit from incorporation of a short course of CTLA-4 therapy, and it was the driving force behind the design of the current study that is evaluating the combination of EGFR TKI osimertinib and ipilimumab in a similar population. “Currently, the sample size included in the present analysis (N=10) precludes us from conducting a more thorough evaluation of the clinical, pathological, or treatment-related factors that would ultimately help us define the population of EFGR patients that are most likely to benefit from the addition of CTLA-4 inhibitors. However, the serial blood collection and robust correlative analysis planned as part of the current study would help us address this question in the near future.” Oncology Times: What are the next steps for evaluating the osimertinib and ipilimumab combination, especially in terms of dose expansion? How might these findings impact the future of treatment options for EGFRm NSCLC patients? Puri: “Our study is currently in dose expansion where we are further assessing the safety of osimertinib in combination with ipilimumab at the dose of 1 mg/kg every 3 weeks for four doses. A total of 17 patients have been enrolled to date at the current dose. If our final analysis confirms the safety of this combination, we plan to conduct a follow-up study to evaluate the efficacy of the combination.” Dibash Kumar Das is a contributing writer. Discover More Genomics Research Oncologists' Guide to Genomics highlights the latest trends in genomics and molecular diagnostics for oncology. 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