Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer
Abstract
Simple Summary
Abstract
1. Background
2. EGFR
3. EGFR TKI in Combination with Other Targeted Agents
4. EGFR Exon 20 Insertions
5. ALK Rearrangements
6. ROS1
7. KRAS
8. RAF/MEK
9. ERK 1/2
10. HER2
11. MET
12. AXL
13. IL1RAP
14. NRF2
15. ACSS2
16. FGFR
17. Squamous Cell Carcinoma
18. FOLR1/PSMA
19. ATR
20. NSD3
21. PI3K Pathway
22. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug Name | Mechanism of Action | Clinical Trial | Phase | Study Design | Target Group | Status | Preliminary Result |
---|---|---|---|---|---|---|---|
Lazertinib | EGFR TKI | NCT03046992 | I/II | Monotherapy | EGFR T790M+ NSCLC progressed after TKI | Active, not recruiting | n = 127, ORR 54% |
NCT03046992, additional cohort C | I/II | Monotherapy | First-line therapy in EGFRm + NSCLC | Active, not recruiting | n = 43, ORR 70%, mPFS 24.6mo | ||
NCT04248829 (LASER301) | III | Monotherapy | First-line treatment in advanced EGFRm + NSCLC | Active, not recruiting | |||
Amivantamab | EGFR-MET bispecific antibody | NCT04077463 (CHRYSALIS-2) | I | Combination with lazertnib | EGFRm+ NSCLC progressed after TKI | Recruiting | n = 116, ORR 32% |
NCT02609776 (CHRYSALIS) | I | Combination with lazertnib | First-line treatment in advanced EGFRm + NSCLC | Recruiting | n = 20, ORR 100% | ||
NCT04487080 (MARIPOSA) | III | Combination with lazertnib | First-line treatment in advanced EGFRm + NSCLC | Active, not recruiting | |||
Aumolertinib | Third generation EGFR TKI | NCT02981108 (APOLLO) | I/II | Monotherapy | EGFR T790M + NSCLC progressed after TKI | Active, not recruiting | n = 244, ORR 68.9%, mPFS 12.4mo |
ChiCTR2100044216 | I/II | Combination with icotinib | First-line therapy in EGFRm + NSCLC with brain metastasis | n = 12, ORR 100% | |||
BLU-945 | EGFR TKI | NCT04862780 (SYMPHONY) | I/II | Monotherapy, or combination with osimertinib | EGFRm + NSCLC progressed after TKI | Recruiting | |
BBT-176 | Fourth generation EGFR TKI against C797S mutation | NCT04820023 | I/II | Monotherapy | EGFRm + NSCLC progressed after TKI | Recruiting | |
BLU-701 | EGFR TKI against C797S mutation | NCT05153408 (HARMONY) | I/II | Monotherapy, or combination with osimertinib or chemotherapy | EGFRm + NSCLC progressed after TKI | Recruiting | |
Necitumumab | EGFR monoclonal antibody | NCT02496663 | I | Combination with osimertinib | EGFRm + NSCLC progressed after TKI | Active, not recruiting | n = 101, ORR 19% |
Sunvozertinib | EGFR ex20ins inhibitor | NCT03974022 and CTR20192097 (WU-KONG1 and 2) | I/II | Monotherapy | EGFR ex20ins + NSCLC progressed after platinum-based chemotherapy | Recruiting | n = 119, ORR 52.4% |
CTR20211009 (WU-KONG6) | II | Monotherapy | EGFR ex20ins + NSCLC progressed after platinum-based chemotherapy | n = 97, ORR 59.8% | |||
CLN-081 | EGFR ex20ins inhibitor | NCT04036682 | I/II | Monotherapy | EGFR ex20ins + NSCLC progressed after prior therapy | Recruiting | At optimal dose, n = 39, ORR 41%, mPFS 12mo |
BLU-451 | EGFR ex20ins inhibitor | NCT05241873 | I/II | Monotherapy | EGFR ex20ins + NSCLC progressed after platinum-based chemotherapy | Recruiting |
Drug Name | Mechanism of Action | Clinical Trial | Phase | Study Design | Target Group | Status | Preliminary Result |
---|---|---|---|---|---|---|---|
Patritumab deruxtecan | Anti-HER3 antibody-drug conjugate | NCT03260491 | I | Monotherapy | EGFRm + NSCLC progressed after TKI | Recruiting | n = 57, ORR 39%, mPFS 8.2mo |
NCT03260491, cohort 2 | I | Monotherapy | EGFR wild-type NSCLC progressed after chemotherapy +/− immunotherapy | Recruiting | n = 47, ORR 28%, mPFS 5.4mo | ||
NCT04619004 (HERTHENA-Lung01) | II | Monotherapy | EGFRm + NSCLC progressed after TKI | Recruiting | |||
Anlotinib | Multi-targeting TKI | NCT04770688 | I/II | Combination with osimertinib | First-line therapy in EGFRm + NSCLC | Recruiting | n = 25, ORR 65.2%, DCR 95.7% |
Alisertib | Aurora kinase inhibitor | NCT04479306 | I | Combination with osimertinib | EGFRm + NSCLC progressed after TKI | Active, not recruiting | No meaningful clinical efficacy |
Sapanisertib | mTOR inhibitor | NCT04479306 | I | Combination with osimertinib | EGFRm + NSCLC progressed after TKI | Active, not recruiting | ORR 12.5%, DCR 68.7%, mPFS 4.6mo |
Necitumumab and trastuzumab | HER2 monoclonal antibody | NCT04285671 | I/II | Combination with osimertinib | EGFRm + NSCLC progressed after osimertinib | Recruiting | 5 of 10 patients achieved tumor size reduction |
Repotrectinib | ROS1/TRK/ALK Inhibitor | NCT04772235 | I | Combination with osimertinib | Advanced EGFRm+ NSCLC | Recruiting | |
SAF-189s | ALK inhibitor | NCT04237805 | I/II | Monotherapy | ALK-altered NSCLC with/without prior ALK inhibitor | Recruiting | ORR 92.3% and 65.4% in ALKi-naive and ALKi-pretreated, respectively |
APG-2449 | ALK/ROS1/FAK TKI | NCT03917043 | I | Monotherapy | ALK-altered NSCLC with/without prior therapy | Recruiting | 4 of 14 patients resistant to 2nd-gen TKIs achieved PR |
Taletrectinib | ROS1 inhibitor | NCT04395677 | II | Monotherapy | ROS1-positive, TKI-naïve, NSCLC | Recruiting | n = 40, ORR of 90% |
NVL-520 | ROS1 inhibitor | NCT05118789 (ARROS-1) | I/II | Monotherapy | ROS1-positive solid tumors, progressed after ROS1 TKI | Recruiting | n = 21, ORR of 48% |
GDC-6036 | KRAS G12C inhibitor | NCT04449874 | I | Monotherapy | KRAS G12C + NSCLC, progressed after prior therapy | Recruiting | n = 57, ORR 53% |
NCT03178552 (BFAST), cohort G | II/III | Monotherapy | KRAS G12C + NSCLC, progressed after prior therapy | Recruiting | |||
D-1553 | KRAS G12C inhibitor | NCT05383898 | I/II | Monotherapy | KRAS G12C + NSCLC, progressed after prior therapy | Recruiting | n = 79, ORR 37.8%, mPFS 7.6mo |
ASTX029 | ERK inhibitor | NCT03520075 | I/II | Monotherapy | advanced solid tumors refractory to available therapies | Recruiting | 3 of 12 NSCLC patients achieved durable PR |
VS-6766 | Dual MEK and RAF inhibitor | NCT02407509 | I | Monotherapy or combination with everolimus | Advanced solid tumors or multiple myeloma harboring RAS-RAF-MEK pathway mutations | Recruiting | In monotherapy cohort, 3 of 10 KRASm+ NSCLC achieved PR; in combination cohort, 2 patients with G12D+ had PFS 35.8mo and 41.8mo |
NCT03875820 (FRAME) | I | Combination with defactinib | RAS or RAF mutant advanced solid tumors refractory to conventional treatment | Recruiting | ORR 15%, DCR 65% | ||
NCT04620330 (RAMP 202) | III | Monotherapy or combination with defactinib | KRAS or BRAF mutant NSCLC progressed after prior therapy | Recruiting | |||
NCT05074810 (RAMP 203) | I/II | Combination with sotoracib | KRAS G12C+ NSCLC with/without prior G12C inhibitors | Recruiting | |||
Trastuzumab deruxtecan (T-DXd) | Anti-HER2 antibody-drug conjugate | NCT05048797 (DESTINY-Lung04) | III | Monotherapy | First-line therapy for HER2m + advanced NSCLC | Recruiting | |
BI 1810631 | Selective HER2 inhibitor | NCT04886804 | I | Monotherapy | HER2-altered advanced solid tumors progressed after available therapies | Recruiting | |
Telisotuzumab vedotin | Anti-MET antibody-drug conjugate | NCT03539536 (LUMINOSITY) | II | Monotherapy | Advanced MET-overexpressing NSCLC received less than two prior therapies | Recruiting | n = 122, ORR 36.5% in non-squamous EGFR wild-type cohort |
REGN5093-M114 | Anti-MET antibody-drug conjugate | NCT04982224 | I/II | Monotherapy | Advanced MET-overexpressing NSCLC progressed after current therapies | Recruiting | |
BGB324 (bemcentinib) | Selective AXL inhibitor | NCT05469178 | I/II | Combination of with chemo-immunotherapy | First-line therapy for non-squamous NSCLC with STK11 mutation | Not yet recruiting | |
NCT02922777 | I | Combination with docetaxel | Advanced NSCLC progressed after prior therapy | Active, not recruiting | n = 21, PR 27% | ||
Nadunolimab (CAN04) | Anti-1L1RAP antibody | NCT03267316 (CANFOUR) | I/II | Combination with cisplatin and gemcitabine | Advanced NSCLC treatment-naïve or progressed after pembrolizumab | Recruiting | n = 33, ORR 53%, PFS 6.8mo |
Telaglenastat (CB-839) | Glutaminase inhibitor | NCT04250545 | I | Combination with mTOR inhibitor sapanisertib | Advanced NSCLC progressed after prior therapy | Suspended (pending dose update) | 5 of 8 patients had tumor shrinkage |
MTB-9655 | ACSS2 inhibitor | NCT04990739 | I | Monotherapy | Advanced solid tumors failed standard treatment | Recruiting | |
Pemigatinib | FGFR1-3 inhibitor | NCT05253807 | II | Monotherapy | Advanced FGFR + NSCLC progressed after available therapies | Recruiting | |
Futibatinib | FGFR1-4 inhibitor | NCT04965818 | I/II | Combination with MEKi binimetinib | Advanced solid tumors failed standard treatment | Active, not re-cruiting |
Drug Name | Mechanism of Action | Clinical Trial | Phase | Study Design | Target Group | Status | Preliminary Result |
---|---|---|---|---|---|---|---|
CBP-1018 | FOLR1 and PSMA bi-ligand drug conjugate | NCT04928612 | I | Monotherapy | LSCC and other solid tumor patients with relapse on prior lines of therapy | Recruiting | |
Berzosertib | ATR inhibitor | NCT04216316 | I/II | Combination with carboplatin, gemcitabine, and pembrolizumab | LSCC patients that are chemotherapy-naive | Recruiting | |
Rogaritinib | Pan-FGFR inhibitor | NCT03762122 | II | Monotherapy | Advanced and pretreated LSCC with FGFR1-3 mRNA overexpression | Terminated | mPFS 1.6mo mOS 3.5mo |
ZEN003694 | BET inhibitor | NCT05607108 | II | Monotherapy | Recurrent or metastatic LSCC with NSD3 amplification | Recruiting | |
Copanlisib | Pan-class I PI3K inhibitor | NCT03735628 | I/II | Combination with nivolumab | Advanced solid tumors | Active, recruiting phase completed | Disease control rate: 75% |
Gedatolisib | PI3K/mTOR inhibitor | NCT03065062 | I | Combination with palbociclib | Advanced LSCC and other solid tumors | Recruiting |
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Li, S.; de Camargo Correia, G.S.; Wang, J.; Manochakian, R.; Zhao, Y.; Lou, Y. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers 2023, 15, 2899. https://doi.org/10.3390/cancers15112899
Li S, de Camargo Correia GS, Wang J, Manochakian R, Zhao Y, Lou Y. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers. 2023; 15(11):2899. https://doi.org/10.3390/cancers15112899
Chicago/Turabian StyleLi, Shenduo, Guilherme Sacchi de Camargo Correia, Jing Wang, Rami Manochakian, Yujie Zhao, and Yanyan Lou. 2023. "Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer" Cancers 15, no. 11: 2899. https://doi.org/10.3390/cancers15112899
APA StyleLi, S., de Camargo Correia, G. S., Wang, J., Manochakian, R., Zhao, Y., & Lou, Y. (2023). Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers, 15(11), 2899. https://doi.org/10.3390/cancers15112899