First-generation reversible TKIs (gefitinib, erlotinib) and second-generation irreversible pan-HER inhibitors (afatinib, dacomitinib) established the proof-of-concept for targeted therapy in EGFR-mutant NSCLC. While effective initially, all are limited by the emergence of the T790M gatekeeper mutation as the dominant resistance mechanism.

Osimertinib is a third-generation, irreversible, mutant-selective EGFR TKI that targets both sensitizing mutations and the T790M resistance mutation. The landmark FLAURA trial established osimertinib as the standard first-line therapy, and adjuvant osimertinib (ADAURA trial) has demonstrated significant disease-free survival benefit in resected EGFR-mutant NSCLC [3].

Despite its efficacy, acquired resistance is inevitable, arising through EGFR-dependent mechanisms (notably the C797S mutation, ~30% of cases) and EGFR-independent bypass pathways including MET amplification (~25%), HER2 amplification, and histologic transformation [4].

To address C797S-mediated resistance, fourth-generation EGFR TKIs are under active development. Candidates including BDTX-1535, JIN-A02, and HS-10504 are designed to target triple-mutant EGFR (Del19/T790M/C797S or L858R/T790M/C797S) and have entered early-phase clinical trials [5].

Combination strategies pairing osimertinib with MET inhibitors (capmatinib, tepotinib) are also being evaluated to preempt or overcome off-target resistance mediated by MET amplification [6].

ALK rearrangements occur in ~3–5% of NSCLC. Sequential ALK TKI therapy has transformed outcomes: first-generation crizotinib was followed by second-generation agents (alectinib, brigatinib, ceritinib), and now the third-generation macrocyclic inhibitor lorlatinib has emerged as the preferred first-line option.

ROS1 fusions (~1–2% of NSCLC) are targetable by crizotinib, entrectinib, and the next-generation agent repotrectinib (FDA-approved 2023), which overcomes the common ROS1 G2032R resistance mutation. Lorlatinib has also shown durable activity in TKI-naïve ROS1-positive NSCLC (ORR 73%, median PFS 53.6 months in a phase 2 trial) [8].

RET fusions (~1–2%) are now effectively targeted by the selective inhibitors selpercatinib and pralsetinib. The LIBRETTO-431 phase 3 trial established selpercatinib as superior to chemotherapy in treatment-naïve RET fusion-positive NSCLC [9].

NTRK fusions (~0.2%) respond to the CNS-active inhibitors larotrectinib and entrectinib, with entrectinib demonstrating an ORR of 62.7% and median PFS of 28.0 months in NTRK-positive NSCLC [10].

BRAF V600E mutations (~2%) are addressed by the dual BRAF/MEK inhibitor combinations dabrafenib + trametinib (approved 2017) and, more recently, encorafenib + binimetinib (FDA-approved October 2023 based on the PHAROS trial) [11].

MET exon 14 skipping mutations (~3%) are targeted by the selective MET inhibitors capmatinib and tepotinib, both FDA-approved.

Sotorasib (FDA-approved May 2021) and adagrasib (FDA-approved December 2022) are the first two approved KRAS G12C inhibitors. In the phase 3 CodeBreaK 200 trial, sotorasib demonstrated significantly longer PFS versus docetaxel (5.6 vs. 4.5 months; HR 0.66; p=0.0017) [13]. Adagrasib showed an ORR of 42.9% and median PFS of 6.5 months in the KRYSTAL-1 phase 2 cohort, with notable intracranial activity (33.3% ORR in CNS metastases) [14].

Divarasib (GDC-6036) demonstrated an ORR of 53.4% and median PFS of 13.1 months in phase 1 expansion, with 5–20-fold greater potency than first-generation agents in preclinical models [15]. Novel "ON-state" inhibitors targeting the active GTP-bound KRAS conformation, pan-RAS inhibitors, and SOS1 inhibitor combinations are in early clinical development to overcome intrinsic and acquired resistance, which is frequently mediated by co-mutations in STK11 and KEAP1 [16].