Comparative Efficacy of Targeted Therapy Combinations in Advanced Lung Adenocarcinoma

Abstract

Advanced lung adenocarcinoma is now routinely subdivided by driver mutation, and for each major driver the therapeutic question has shifted from whether a targeted agent works to whether combining it with a second agent, or replacing it with a chemotherapy-free doublet, outperforms an already-effective targeted monotherapy. This article synthesizes the pivotal randomized trial literature addressing that comparative-efficacy question for EGFR-, ALK-, and KRAS G12C-mutant advanced lung adenocarcinoma. In EGFR-mutated disease, adding chemotherapy to osimertinib (FLAURA2) and replacing osimertinib with amivantamab plus lazertinib (MARIPOSA) each extended progression-free survival by a comparable margin in the first-line setting, amivantamab-containing regimens extended progression-free survival after osimertinib progression (MARIPOSA-2), and amivantamab plus chemotherapy established a new standard for the chemotherapy-reliant exon 20 insertion subtype (PAPILLON); by contrast, adding bevacizumab to first-line osimertinib (WJOG9717L) did not significantly improve progression-free survival over osimertinib alone. In ALK-positive disease, next-generation inhibitors substantially outperformed first-generation crizotinib (ALTA-1L, CROWN), and in KRAS G12C-mutant disease, two independently developed inhibitors each reported a real but comparatively modest progression-free survival advantage over docetaxel (KRYSTAL-12, CodeBreaK 200). We give particular weight to trials with a negative or modest result alongside the positive ones, since a synthesis built only from favorable comparisons would misrepresent how uneven this evidence base actually is. Read together, the evidence supports several specific combination or next-generation-monotherapy strategies as genuine, reproducible advances over targeted monotherapy, while leaving head-to-head comparison between leading first-line strategies, biomarker-guided selection among post-progression options, and a fuller accounting of comparative toxicity as the field's central open problems.