ATTLAS, IMpower151 and ORIENT-31: Dusting off IMpower150 for Post-Osimertinib in -Mutated NSCLC?

Treatment strategies for post-epidermal growth factor receptor () tyrosine kinase inhibitor (TKI) therapy in -mutant non-small cell lung cancer (NSCLC) is an ongoing challenge. Previously, the IMPRESS trial comparing platinum doublet chemotherapy with or without -TKI did not demonstrate any progression-free survival (PFS) benefit. The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with -mutant NSCLC who progressed on first-generation -TKIs. Given the retrospective nature of the analysis, the IMpower150 regimen is not approved in the US for post--TKI treatment. Currently, osimertinib or other third-generation (3G) -TKIs is the first-line standard of care for advanced -mutant NSCLC. MARIPOSA-2 provided the first randomized trial post-osimertinib in -mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab). The IMpower150 and MARIPOSA-2 quad regimens differ in the principle of whether to continue or even "double-down" on inhibition. Recently, three prospective randomized trials conducted in Asia offered promising results, showing that a quad regimen of doublet platinum chemotherapy plus anti-angiogenesis agent and ICI may be as efficacious as MARIPOSA-2 with a lower rate of toxicities and accounting for the PFS difference if 1L chemotherapy plus osimertinib instead of osimertinib monotherapy. In particular, the median PFS achieved by the quad regimens of ATTLAS and IMpower151 is 8.5 months. However, only 8.2% and 17.9% of the -mutant NSCLC patients who received the quad regimens progressed on 3G -TKI, respectively. Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non- containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G -TKI) progression, are urgently needed.