UCLA l-08: A phase ib/II study of combined HER inhibition adding necitumumab and trastuzumab to osimertinib in patients with refractory EGFR-mutated lung cancer

e21165 Background: Patients (pts) with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR with HER2 blockade results in complete and long-term reversal of osimertinib resistance in preclinical models. Methods: This is an investigator-initiated, single arm, open label phase 1b/2 study to identify the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the combination of osimertinib, necitumumab, and trastuzumab (ONT) in adults with histologically confirmed, metastatic NSCLC with an activating and sensitizing EGFR mutation who have progressed on osimertinib as their most recent treatment. Study pts receive daily oral osimertinib in conjunction with necitumumab and trastuzumab intravenously every other week. In phase 1b, a 3+3 dose-escalation design is used to determine the RP2D (Table 1). In phase 2, if ≥ 2 responses are seen out of 10 pts treated at the RP2D, an additional 10 pts will be accrued. Patient reported outcomes (PRO-CTCAE) and quality of life (FACT-L) data are collected prospectively. Efficacy is assessed as objective response rate (ORR) based on RECIST 1.1 criteria. Results: 22 pts (median age = 63; range = 40-82) have been enrolled and treated. The most commonly observed treatment-related AEs seen at any DL included acneiform rash (63.6%), headache (45.5%), nausea (40.9%), dry skin (36.4%), diarrhea (31.8%), paronychia (27.3%), oral mucositis (27.3%), vomiting (22.7%), fatigue (18.2%), chills (18.2%), and anorexia (18.2%). Grade 3 treatment-related toxicities were acneiform rash (22.7%), diarrhea (4.5%), decreased lymphocyte count (4.5%) and hypertension (4.5%). There were no treatment-related Grade ≥ 4 AEs. 12 evaluable pts were enrolled in phase 1b [3 at Dose Level (DL) 1, 3 at DL 2, and 6 at DL 3]; 3 non-evaluable pts were replaced. Pts treated at DL 1 and DL 2 had no dose-limiting toxicities (DLTs) and 1/6 pts at DL 3 had a DLT (persistent grade 3 rash). Due to grade 2 and 3 rash and paronychiae occurring after cycle 1 at DL 3, DL2 was determined to be the RP2D.The proportion of evaluable phase 1b pts achieving partial response or stable disease was 58.3% (7/12). Seven pts have been enrolled at DL2. Conclusions: ONT toxicities are manageable, and the combination has promising preliminary efficacy in refractory EGFR-mutated metastatic NSCLC. Evaluation of phase 2, stage 1 is expected to be completed by April 2023 and will be reported at the meeting. Clinical trial information: NCT04285671 . [Table: see text]