1335P - Phase Ib study to evaluate the safety and tolerability of osimertinib with ipilimumab in EGFRm NSCLC

Background

Osimertinib (Osi) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) indicated in the 1^stline treatment of EGFR mutated(m) metastatic NSCLC (mNSCLC). Although the combination of Osi with PD-1/PD-L1 inhibitors is prohibitive due to excessive toxicity, combinations with other immune checkpoint inhibitors, such as CTLA4 inhibitor Ipilimumab (Ipi), remain largely unexplored. In a phase 1 trial, we evaluated the combination of EGFR TKI erlotinib and Ipi in EGFRm mNSCLC. The study was closed due to gastrointestinal dose-limiting toxicities (DLTs), but we observed unprecedented improvement in survival (median OS 42.3m). Based on this observation, we designed a phase 1 trial of Osi with Ipi in EGFRm mNSCLC. Here we present results from the dose escalation phase.

Methods

This is a single-center, phase 1B trial. Eligible pts required a stable dose of 1^st line Osi (40 or 80mg/day) for >/= 28 days w/o disease progression. The trial was initiated with cohort1(C1), Osi daily + Ipi 3mg/kg/3 wk with a safety run of 6 pts and planned expansion at this dose if /= 2/6 pts experience DLTs. C2 would be expanded if /= 2/6 pts experience DLTs. The study's primary objective was to determine the tolerability (NCI CTCAEv5) of Osi + Ipi. Key secondary endpoints are ORR, PFS, and OS.

Results

10 pts (4 C1;6 C2) were enrolled between 9/2020-3/2022. The majority of pts were never smoker, female 80%, white 100% with an ECOG of 1. 3 DLTs (1 G3 thromboembolic event, 2 G2 diarrhea) were observed in the 2/4 pts in C1, hence de-escalation C2 enrolled 6 additional pts. Most common all-grade TRAEs were diarrhea in 60% (6/10), fatigue, nail changes and rash (40%, 4/10 pts) each. G3-4 TRAEs were infrequently observed with G3 hepatitis, diarrhea, anorexia, and weight loss in 10% (1/10) pts each. Most G3 TRAEs were observed in C1. 1/6 pts (17%) experienced G3 weight loss in C2. C2 dose was selected for dose expansion (8 additional pts accrued to date).

Conclusions

In EGFRm NSCLC pts the combination of Osi with Ipi (1mg/kg/3wk) was safe and tolerable. This dose is currently undergoing additional evaluation in the dose expansion cohort.

Clinical trial identification

NCT04141644.

Editorial acknowledgement

Legal entity responsible for the study

The Huntsman Cancer Institute at the University of Utah.

Funding

Bristol Myers Squib.

Disclosure

S. Puri: Financial Interests, Personal, Advisory Board: Pfizer, Jazz Pharmaceuticals, AstraZeneca, G1 Therapeutics. S. Patel: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Funding: AstraZeneca. All other authors have declared no conflicts of interest.