The Nail in the Coffin?: Examining the KEYNOTE-789 Clinical Trial’s Impact

Abstract

Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.

Keywords:

• EGFR
• post-osimertinib
• chemo-immunotherapy
• targeted therapy

Abbreviations

AE, adverse effect; ALK, anaplastic lymphoma kinase; BICR, Blinded Independent Central Review; DOR, duration of response; EGFR, epidermal growth factor receptor; ICIs, immune checkpoint inhibitors; IO, immunotherapy; NSCLC, non-small cell lung cancer; OS, overall survival; ORR, objective response rate; PD-L1, programmed cell death ligand-1; PD-1, programmed cell death protein-1; PFS, progression-free survival; TMB, tumor mutation burden; TME, immunosuppressive tumor microenvironment; TPS, tumor proportion score; TK, tyrosine kinase; TKI, tyrosine kinase inhibitors; VEGF, Vascular endothelial growth factor.

Ethics Statement

This work is a commentary utilizing published de-identified clinical trial results and is considered exempt from IRB approval.

Disclosure

There are no direct conflicts of interest to disclose. Dr Arter has no potential conflicts to disclose. Dr Nagasaka has received consulting fees from Caris Life Sciences, honoraria from AstraZeneca, Daiichi Sankyo, Novartis, Lilly, Pfizer, EMD Serono, Genentech, Mirati, Regeneron, Takeda, Janssen, Blueprint Medicine and travel support from AnHeart Therapeutics.

Additional information

Funding

No funding was received for this project.