Table 1.
Clinical Trials for the Treatment of Advanced NSCLC with Targetable Oncogenic Drivers and Targeted Therapies Recommended by NCCN, or Approved by FDA or EMA
| Targetable Driver genes | Incidence | Targeted Agent | Clinical Trials | Phase | Patients Included | Results | Approved or Recommended by |
|---|---|---|---|---|---|---|---|
| ROS1 rearrangements | 1–2% | Crizotinib11 | PROFILE 1001 (NCT00585195) | I | ROS1-rearranged NSCLC | n=50, ORR 72%, mPFS 19.2 mo | NCCN, FDA, EMA |
| Ceritinib23 | NCT01964157 | II | ROS1-rearranged NSCLC | n=32, ORR 62%, DCR 81%, mPFS 9.3 mo for all pts, 19.3 mo for crizotinib-naïve pts | NCCN | ||
| Entrectinib (RXDX-101)26 | ALKA-372-001 (EudraCT 2012–0001), STARTRK-1 (NCT02097810), STARTRK-2 (NCT02568267) | I/II | ROS1-rearranged NSCLC | n=53, ORR 77.4% (intracranial ORR, 73.9%), mDOR 24.6 mo, mPFS 19.0 mo (without CNS metastases: 26.3 mo; with CNS metastases: 13.6 mo) | NCCN, FDA | ||
| Lorlatinib31 | NCT01970865 | II | ROS1-rearranged NSCLC | n=47, ORR 36.2%, mPFS 9.6 mo | NCCN | ||
| DS-6051b32 | NCT02675491 | I | Advanced solid malignant tumors harboring either ROS1 or NTRK fusion. | n=15, ORR 58.3% in pts with target lesions, 66.7% in crizotinib-naïve pts, DCR 100%. | |||
| DS-6051b | NCT02279433 | I/Ib | Solid tumors harboring ROS1 or NTRK1, NTRK2, or NTRK3 rearrangements | Ongoing | |||
| Repotrectinib (TPX-0005)33 | TRIDENT-1 (NCT03093116) | I/II | Solid malignancies harboring ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangements | n=11, ORR 82% for TKI-naive pts, n=18, ORR 39% for pts pretreated with one TKI. | |||
| RET rearrangements | 1–2% | Vandetanib48 | NCT01823068 | II | RET-rearranged NSCLC | n=18, ORR 18%, mPFS 4.5 mo, mOS 11.6 mo | NCCN* |
| Vandetanib46 | UMIN000010095 | II | RET-rearranged NSCLC | n=19, ORR 53%, mPFS 4.7 mo, mOS 11.1 mo | NCCN* | ||
| Cabozantinib45 | NCT01639508 | II | RET-rearranged NSCLC | n=26, ORR 28%, mPFS 5.5 mo, mOS 9.9 mo | NCCN* | ||
| Lenvatinib47 | NCT01877083 | II | RET-rearranged NSCLC | n=25, ORR 16%, mPFS 7.3 mo | |||
| Alectinib | NCT03131206 | I/II | RET-rearranged NSCLC | Ongoing | |||
| Selpercatinib (LOXO-292)51 | LIBRETTO-001 (NCT03157128) | I/II | RET-rearranged NSCLC | n=30, ORR 77% | FDA | ||
| Selpercatinib (LOXO-292)52 | LIBRETTO-001 (NCT03157128) | I/II | RET-rearranged NSCLC | n=105, ORR 68%, CNS ORR 91%, mDOR 20.3 mo, mPFS 18.4 mo for pre-treated pts. n=34, ORR 85%, mDOR, mPFS were not reached for treatment-naive pts. | FDA | ||
| BLU-66754 | NCT03037385 | I | RET-rearranged NSCLC | n=11, ORR 45% | |||
| MET exon 14 skipping mutation | 3% | Crizotinib62 | PROFILE 1001 | I | MET exon 14 skipping mutant NSCLC | n=65, ORR 32%, mPFS 7.3 mo, mOS 20.5 mo | NCCN*, FDA |
| Capmatinib (INC280)67 | GEOMETRY mono-1 (NCT02414139) | II | MET exon 14 mutant or MET amplified NSCLC | n=69, ORR 40.6%, mPFS 5.4 mo for pretreated pts. n=28, ORR 67.9%, mPFS 9.7 mo for treatment-naïve pts | FDA | ||
| Tepotinib68 | NCT02864992 | II | MET exon 14 skipping mutant NSCLC | n=41, ORR 35% | FDA | ||
| Savolitinib69 | NCT02897479 | II | MET exon 14 skipping mutant PSC or other types of NSCLC | n=31, ORR 51.6%, mPFS was not reached. | |||
| MET amplification | 1–5% | Tepotinib + gefitinib70 | NCT01982955 | Ib/II | MET amplified NSCLC | n=12, ORR 66.7%, mPFS 21.2 mo | |
| Tepotinib + gefitinib70 | NCT01982955 | Ib/II | High MET-expressing NSCLC | n=19, ORR 33.3%, mPFS 8.3 mo | |||
| Savolitinib + osimertinib71 | TATTON (NCT02143466) | Ib | EGFR-mutant NSCLC that had developed resistance to first- or second-generation EGFR-TKI through MET gene amplification | n=46, ORR 52%, mDOR 7.1 mo | |||
| Savolitinib + osimertinib71 | TATTON (NCT02143466) | Ib | EGFR-mutant NSCLC that had developed resistance to third-generation EGFR-TKI through MET gene amplification | n=48, ORR 28%, mDOR 9.7 mo | |||
| Savolitinib + osimertinib | SAVANNAH (NCT03778229) | II | EGFRm+ MET+, NSCLC progressed following osimertinib treatment | Ongoing | |||
| BRAF mutation | 2–4% | Dabrafenib77 | NCT01336634 | II | Treated and untreated BRAFV600E+ NSCLC | n=78, ORR 33%, mPFS 5.5 mo, mOS of 12.7 mo | |
| Dabrafenib + trametinib78 | NCT01336634 | II | Untreated BRAFV600E+ NSCLC | n=36, ORR 64%, mPFS 10.9 mo, mOS 24.6 mo | NCCN, FDA, EMA | ||
| Dabrafenib + trametinib79 | NCT01336634 | II | Chemotherapy-pretreated BRAFV600E+ NSCLC | n=57, ORR 63%, mPFS 10.2 mo, mOS 18.2 mo | NCCN, FDA, EMA | ||
| NTRK rearrangements | 3–4% | Larotrectinib (LOXO-101)92 | NCT02576431 | II | NTRK fusion-positive solid tumors | n=55, ORR 75% regardless of tumor type, mDOR and mPFS were not reached. | NCCN, FDA, EMA |
| LOXO-195 | NCT03215511 | I/II | NTRK fusion cancers treated with a prior TRK inhibitor | Ongoing | |||
| Entrectinib (RXDX-101)96 | ALKA-372-001 (EudraCT 2012–0001), STARTRK-1 (NCT02097810), STARTRK-2 (NCT02568267) | I/II | NTRK fusion-positive solid tumors | n=54, ORR 57.4%, mPFS 11.2 mo, mOS 20.9 mo | NCCN, FDA, EMA | ||
| HER2 mutation | 2–4% | Afatinib102 | A retrospective international multicentre study | HER2-mutant lung adenocarcinomas | n=27, mTTF 3 mo, mDOR 6 mo, OS 23 mo | ||
| Afatinib103 | Supported by Boehringer Ingelheim. No grant number is applicable. | Heavily pretreated exon 20 ins NSCLC | n=10, mTTF 9.6 mo, ORR 33%, DCR 100% | ||||
| Trastuzumab in combination with chemotherapy or ado-trastuzumab emtansine (T-DM1)101 | A retrospective study | HER2-mutant NSCLC | n= 58, ORR 50.9%, mPFS 4.8 mo, mOS 13.3 mo. | ||||
| Neratinib, lapatinib or afatinib101 | A retrospective study | HER2-mutant NSCLC | n= 29, ORR 7.4%, mPFS 3.4 mo, mOS 6.5 mo. | ||||
| Ado-trastuzumab emtansine (T-DM1)104 | NCT02675829 | II | HER2-mutant NSCLC | n=18, ORR 44%, mPFS 5 mo | NCCN* | ||
| Poziotinib106 | NCT03066206 | II | HER2 exon 20 ins NSCLC | n=12, mPFS 5.1 mo | |||
| Trastuzumab deruxtecan (DS-8201a)107 | NCT03505710 | II | HER2-overexpressing or mutated, unresectable, and/or metastatic NSCLC | Ongoing | |||
| EGFR exon 20 ins | 1.80% | Poziotinib106 | NCT03066206 | II | EGFR or HER2 exon 20 ins NSCLC | n=44, ORR 55%, mPFS 5.5 mo | |
| Poziotinib114 | NCT03318939 | II | EGFR or HER2 exon 20 ins NSCLC | n=30, ORR 40%, mDOR 6.6 mo | |||
| TAK-788115 | NCT02716116 | I/II | EGFR exon 20 insertion NSCLC | n=28, ORR 43%, mPFS 7.3 mo | |||
| FGFR1 amplification | 20% squamous-NSCLC | Nintedanib133 | NCT01948141 | II | FGFR1-amplified pretreated squamous-NSCLC | n=6, 6-month PFS was observed within the entire 6 pts | |
| Dovitinib | NCT01861197 | II | FGFR1-amplified pretreated squamous-NSCLC | Ongoing | |||
| BGJ398134 | NCT01004224 | I | FGFR1-amplified squamous-NSCLC | n=36, ORR 11.1%, DCR 50% | |||
| Erdafitinib (JNJ-42756493) | NCT02699606 | IIa | Asian participants with various malignant tumors, including NSCLC | Ongoing | |||
| PIK3CA mutation or amplification | 2–5% | Pictilisib (GDC-0941) + cytotoxic chemotherapy | NCT00974584 | Ib | Advanced NSCLC | Completed, results have not yet been released | |
| Pictilisib (GDC-0941) + cytotoxic chemotherapy | NCT01493843 | II | Previously untreated NSCLC | Completed, results have not yet been released | |||
| Pilaralisib (SAR245408, XL147) + carboplatin/paclitaxel | NCT00756847 | I | Adults with solid tumors | Completed, results have not yet been released | |||
| DDR2 mutation | 4% | Dasatinib152 | NCT01514864 | II | Advanced cancers harboring DDR2 mutation or inactivating BRAF mutation | Terminated due to lack of efficacy | |
| Dasatinib + crizotinib | NCT01744652 | II | Advanced cancer | Ongoing | |||
Note: *Available targeted agents with activity against corresponding driver event in lung cancer.
Abbreviations: NSCLC, non-small cell lung cancer; mPFS, median progression-free survival; ORR, objective response rates; mo, months; pts, patients; mDOR, median duration of response; mTTF, median time-to-treatment failure; CNS, central nervous system; NCCN, National Comprehensive Cancer Network; FDA, the US Food and Drug Administration; EMA, European Medicines Agency; ins, insertion.