Targeting the Uncommon Mutations:

The ambit of potentially targetable oncogenic drivers in NSCLC expanded in the 2010s, and, in addition to EGFR and ALK, there are seven others (listed alphabetically below). However, in contrast with EGFR/ALK, targeted drugs for these molecular subgroups have largely been evaluated/approved after phase I/II trials and in the relapse setting.

1. BRAF mutations: Dabrafenib+trametinib is approved for BRAF V600E mutation-positive NSCLC with similar ORRs (63%) in pretreated (mPFS, 7 months) and treatment-naïve (mPFS, 10.9 months) patients (NCT01336634). Vemurafenib (NCT01524978; NCT02304809) showed inferior efficacy.
2. HER2 (ErbB2) mutations: Trastuzumab deruxtecan (n=91, ORR 55%, mPFS 2 months; NCT02675829; under priority review by the FDA at the time of publication) and Pyrotinib (n=60, ORR 30%, mPFS 6.9 months; NCT03505710; available only in China) have shown ‘promising’ activity.
3. KRAS G12C mutations: Sotorasib (CodeBreaK100[NCT03600883]), approved by the FDA and the EMA as a second-line therapy, is associated with an ORR of 32%, a mPFS of 6.3 months and OS of 4 months. Adagrasib (KRYSTAL-1 [NCT03785249]) has also received FDA ‘breakthrough therapy designation’.
4. MET exon 14 skipping: Capmatinib (GEOMETRY Mono-1 [NCT02414139]) showed a higher ORR for treatment-naïve patients (68% versus 41% pretreated), while Tepotinib responses (VISION [NCT02864992]) were similar (44% treatment-naïve, 48% pre- treated) for MET exon 14 ‘skipping’
5. NTRK (Neurotrophic tyrosine receptor kinase) fusions/rearrangements;
   Given its rarity, efficacy was demonstrated by pooled analysis of three phase I/II trials involving pretreated and treatment-naïve patients with NTRK fusion-positive solid tumours for both Entrectinib (ORR 70%) (STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267] and ALKA-372-001 [EudraCT:2012- 000148-88]) and Larotrectinib (ORR 75%) (NCT02122913, NCT02637687, NCT02576431).
6. RET fusions/rearrangements:Selpercatinib(RR64%;LIBRETTO-001 [NCT03157128]) and pralsetinib (ORR 61%; ARROW [NCT03037385]) are effective for RET-rearranged lung and thyroid
7. ROS1 fusions/rearrangements: Similar to the ALK timeline, Crizotinib was the first ROS1 inhibitor to be approved (phase I trial: PROFILE 1001 [NCT00585195]; ORR 72%, mPFS 19 months), with identical outcomes in another, phase II trial (NCT01945021). Unlike ALK, ceritinib effectiveness was primarily for Crizotinib-naïve patients (NCT01964157). Lorlatinib efficacy was also more pronounced for Crizotinib- naïve than Crizotinib-pretreated patients (ORR 62% ver- sus 35%; mPFS 21 versus 5 months; NCT01970865). Entrectinib approval was based on pooled analysis of STARTRK-1, STARTRK-2 and ALKA-372-001 trials (ORR 67%, mPFS 16 months).