Personalized therapy for non-small cell lung cancer (NSCLC) has been revolutionized by comprehensive molecular testing, particularly next-generation sequencing (NGS), which identifies driver mutations and facilitates the delivery of targeted therapies. These strategies have demonstrated meaningful improvements in overall survival (OS) by enabling individualized treatment plans based on molecular profiling.
Targeting MET Alterations in NSCLC
MET alterations, including MET exon 14 skipping mutations and amplifications, are significant therapeutic targets in NSCLC, occurring in approximately 3% to 4% of patients. MET tyrosine kinase inhibitors (TKIs) such as crizotinib, capmatinib, and tepotinib have shown efficacy in patients with these mutations. For instance, the PROFILE 1001 trial (NCT00585195) revealed that crizotinib achieved an objective response rate (ORR) of 32% with a median duration of response (mDOR) of 9.1 months and a median progression-free survival (mPFS) of 7.3 months. Capmatinib, in the GEOMETRY Mono-1 trial (NCT02414139), demonstrated an ORR of 67% in the first-line setting (mDOR, 12.6 months; PFS, 12.3 months; OS, 20.8 months) and 44% in the second-line setting (mDOR, 9.7 months; PFS, 5.5 months). Tepotinib, evaluated in the VISION trial (NCT02864992), showed an ORR of 54% in treatment-naive patients and 44% in previously treated patients, with an mDOR of 11.1 months and mPFS of 10.4 and 11.0 months in the first and second lines, respectively.
RET Fusion-Targeted Therapy
RET fusions, present in 1% to 2% of NSCLC cases, are another key therapeutic target. Selective RET inhibitors like selpercatinib and pralsetinib have demonstrated significant efficacy in clinical trials. The LIBRETTO-001 trial (NCT03157128) showed that selpercatinib resulted in an ORR of 84% in treatment-naive patients and 61% in those previously treated with platinum-based chemotherapy. In the phase 3 LIBRETTO-431 trial (NCT04194944), first-line selpercatinib improved PFS (24.8 vs 11.2 months; HR, 0.46; P < .001), ORR (84% vs 65%), and DOR (24.2 vs 11.5 months) compared to chemotherapy plus pembrolizumab. Pralsetinib, in the ARROW trial (NCT03037385), demonstrated an ORR of 72% in treatment-naive patients and 59% in patients previously treated with platinum-based chemotherapy, with an mDOR not reached in treatment-naive patients and 22.3 months in previously treated patients.
Targeting KRAS Mutations
KRAS mutations, particularly KRAS G12C, are common in NSCLC, and the development of selective KRAS G12C inhibitors sotorasib and adagrasib has marked a significant advancement. In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib resulted in an ORR of 37.1% with a median PFS and OS of 6.8 and 12.5 months, respectively, in previously treated patients. The phase 3 CodeBreaK 200 trial (NCT04303780) compared sotorasib with docetaxel, demonstrating a superior ORR of 28% versus 13% and a longer mPFS of 5.6 versus 4.5 months (HR, 0.66; P = .0017) with sotorasib. Adagrasib, evaluated in the phase 1/2 KRYSTAL-1 trial (NCT03785249), showed an ORR of 42.9% with an mPFS of 6.5 months and an OS of 12.6 months in previously treated patients. In the KRYSTAL-12 trial (NCT04685135), adagrasib was compared with docetaxel, showing a significantly longer PFS (5.49 vs 3.84 months; HR, 0.58; P < .0001) and higher ORR (32% vs 9%; OR 4.68; P < .0001) with adagrasib.
