329P - ORCHARD: Osimertinib + necitumumab in patients (pts) with advanced NSCLC whose disease progressed on first-line (1L) osimertinib

Background

Osimertinib is a 3^rd generation, irreversible, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with CNS activity; it is the preferred 1L treatment in pts with EGFR-TKI-sensitising (EGFRm) advanced NSCLC. However, pts on 1L osimertinib may develop treatment resistance, commonly by secondary EGFR alterations. The ongoing Phase II ORCHARD platform study (NCT03944772) aims to characterise these resistance mechanisms and identify novel 2L combinations. Preclinical data demonstrated antitumour activity when combining osimertinib with an anti-EGFR monoclonal antibody (mAb). Here we report an interim analysis of safety and efficacy of osimertinib + necitumumab, a mAb that blocks the ligand binding site of EGFR, in pts with EGFRm advanced NSCLC and a secondary EGFR alteration post 1L osimertinib.

Methods

Pts with a secondary alteration in EGFR (amplification, L718 or G724 mutation, exon 20 insertion) determined by next generation sequencing on tissue collected post disease progression on 1L osimertinib, received osimertinib (80 mg, orally, once daily) + necitumumab (800 mg intravenously on Day 1 + 8 of a 3-week cycle). Primary endpoint: objective response rate (ORR); other endpoints: safety. Futility criterion was defined as <10% chance ORR is ≥45%. Data cutoff (DCO): 11 Feb 2022.

Results

Sixteen pts were treated (56% ≥65 years, 63% male, 63% white, 61% never smokers). At DCO, 11 pts (69%) had discontinued treatment and 13 were evaluable for confirmed response. ORR was 15% (n=2 confirmed partial responses, 80% CI 4.2, 36.0). Stable disease was reported in 5 pts (39%) and progressive disease in 5 pts (39%); 1 pt (8%) was non-evaluable. Recruitment was closed as futility criteria were met. Overall, 7/16 (44%) had one or more Grade ≥3 adverse event (AE); 5 (31%) had serious AEs, 2 (13%) had an AE with an outcome of death, 1 was possibly related to necitumumab. No cases of interstitial lung disease seen.

Conclusions

Osimertinib + necitumumab showed no new safety signals in this population; however, futility criterion was met and recruitment was closed. These results suggest that this combination may not have the requisite clinical activity for further clinical development in this pt population.

Clinical trial identification

NCT03944772.

Editorial acknowledgement

The authors would like to acknowledge Annie Mellings, MSc, of Ashfield MedComms, an Inizio company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Legal entity responsible for the study

AstraZeneca.

Funding

This study (NCT03944772) was funded and sponsored by AstraZeneca. Necitumumab was provided by the manufacturer Eli Lilly for inclusion in this study.

Disclosure

J.W. Riess: Financial Interests, Institutional, Research Grant: Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Revolution Medicines; Financial Interests, Personal, Advisory Role, Consultation fees: Novartis, Blueprint; Financial Interests, Personal, Advisory Board: BeiGene, Daiichi Sankyo, EMD Serano, Jazz Pharmaceuticals, Janssen, Turning Point, Bristol Myers Squibb, Roche/Genentech, Boehringer Ingelheim, Regeneron. J.A. De Langen: Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, Roche, Lilly, MSD; Financial Interests, Personal, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, MSD. Z. Piotrowska: Financial Interests, Personal, Research Grant: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan, Daiichi Sankyo, AbbVie, Janssen, Blueprint; Financial Interests, Personal, Advisory Role, Consulting fees: Janssen, AstraZeneca, Eli Lilly, Takeda, Daiichi Sankyo, Cullinan, C4 Therapeutics, Jazz, Blueprint. S.B. Goldberg: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Blueprint Medicine, Sanofi Genzyme, Daiichi Sankyo, Regeneron, Takeda; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Mirati Therapeutics. J.W. Goldman: Financial Interests, Personal, Other, Honoraria: AstraZeneca, BMS, Genentech, Pfizer; Financial Interests, Institutional, Research Grant: Advaxis, Array, AstraZeneca, BMS, Eli Lilly, Genentech/Roche, G1 Therapeutics, Merck, Pfizer; Financial Interests, Personal, Other, Travel support: AstraZeneca. I. Okamoto: Financial Interests, Personal, Advisory Role: AstraZeneca, Chugai Pharma, AbbVie; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, MSD Oncology, Bristol Myers Squibb, Chugai Pharma, Pfizer; Financial Interests, Personal, Research Grant: Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, MSD Oncology, Astellas Pharma, Bristol Myers Squibb, Chugai Pharma, AbbVie. S. Ponce Aix: Financial Interests, Personal, Research Grant: Roche, MSD; Financial Interests, Personal, Other, Lectures: Roche, MSD, BMS, AstraZeneca, Pfizer. S. Teraoka: Financial Interests, Personal, Advisory Role: Pfizer Inc.; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma, Novartis, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical Co.,Ltd. H. Ambrose, J. Maidment, B. Merchan Ruiz: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. K.H. Tang, N. Hewson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Cosaert: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Project Lead: Orchard, Hudson. H.A. Yu: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Janssen, Blueprint Medicine, C4 Therapeutics, Daiichi, Black Diamond, Cullinan; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Lilly, Cullinan, Novartis, Daiichi, Janssen, Blueprint, ERASCA.