Submitted:
04 November 2025
Posted:
04 November 2025
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Abstract
Keywords:
1. Introduction
2. Zipalertinib—Preclinical Data
3. Zipalertinib—Clinical Development Status
3.1. REZILIENT 1 Trial
3.2. REZILIENT 2 Trial
3.3. REZILIENT 3 Trial
3.4. REZILIENT 4 Trial
4. Future Directions
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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| Compound | Targets | Comments (References) |
|---|---|---|
| Poziotinib | Exon 20 insertions, HER-2/neu |
Approved denied by FDA [23] |
| Mobocertinib | Exon 20 insertions, L858R, del18, L861R | FDA approval voluntarily withdrawn (no PFS benefit in the EXCLAIM-2 phase III trial) [24] |
| Sunvozertinib | Exon 20 insertions, L858R, del19, T790M, G719A, L861Q | Second-line: Approval by FDA, phase III ongoing in first-line |
| Firmonertinib | Exon 20 insertions, L858R, del19, T790M, G719X, S768I, L861Q | Approval in China [25], phase II/III trials ongoing |
|
Silevertinib (formerly BDTX-1535) |
Active against almost all common and uncommon mutations; weaker activity against exon 20 insertions | Phase II ongoing [26] |
| STX-721 | Exon 20 insertions, L858R, del19, HER2 A775_G776insYVMA (exon 20) | STX-721 demonstrated exon 20 insertion potency and selectivity relative to wild-type (WT) EGFR that surpassed all other tested clinical-phase benchmark EGFR inhibitors suggesting that STX-721 may be less prone to WT EGFR–driven adverse events that have limited the efficacy of other exon 20 insertion inhibitors. Phase II ongoing [27] |
| Zipalertinib | Most EGFR mutation (except C797S), exon 20 insertions | Phase III ongoing |
| Amivantamab | EGFR amplifications, L858R, del19, T790M, G796S, exon 20 insertions, c-MET (monoclonal antibody) |
Approved by FDA and EMA |
| Trial Name | Design (NCT number) | Status |
|---|---|---|
| REZILIENT 1 | Phase I/II open-label trial in NSCLC patients harbouring exon20ins previously being treated with platinum-based chemotherapy (with or without exon20ins-targeted therapies) PEs: ORR and DoR (NCT04036682) |
Recruitment completed. N = 244 [28] |
| REZILIENT 2 | Multicentre cohort trial (phase IIB): Cohort A: prior exon20ins treatment Cohort B: first-line exon20ins treatment Cohort C: active brain metastases (exon20ins, uncommon mutations) Cohort D: uncommon mutations (NCT05967689) |
Recruitment ongoing (N = 224 in all cohorts; cohorts A and B closed) |
| REZILIENT 3 | Randomized phase III trial in advanced or metastatic first-line NSCLC patients harbouring exon20ins: platinum/pemetrexed chemotherapy and zipalertinib (4 cycles) followed by zipalertinib plus pemetrexed versus platinum/pemetrexed followed by pemetrexed plus placebo maintenance therapy. PE: mPFS (NCT05973773) |
Recruitment ongoing (N = 266 planned) |
| REZILIENT 4 | Adjuvant randomized phase III trial in NSCLC patients (stage IB-IIIA) harbouring exon 20ins and/or uncommon mutations: Platinum-based chemotherapy and zipalertinib (after tumour resection, 4 cycles) followed by zipalertinib monotherapy versus platinum-based chemotherapy (after tumour resection, 4 cycles) followed by placebo. PE: DFS after 3 years. (NCT07128199) |
Recruiting ongoing (N = 360 planned) |
| Drug | N | TL | Mutations | Results | Reference |
|---|---|---|---|---|---|
| Mobocertinib | 40 | second-line (after platinum) |
Exon20ins | ORR 18% mPFS: 3.7 months |
Jänne et al. 2024 [31] |
| Firmonertinib | 13 | first-line | PACC mutations | ORR (240 mg): 46.2% | Le et al. 2024 [32] |
| Sunvozertinib | 21 | second-line (after platinum) |
Exon20ins | ORR: 52.4% | Yang et al. 2025 [17] |
| Zipalertinib | 16 | no limit (range: 1-12) |
Exon20ins, uncommon mutations |
ORR: 31.3% iDCR: 68.8% DoR: 8.1 months |
Yu et al. 2025 [30] |
| Drug | Study | Design | Results | References |
|---|---|---|---|---|
| Firmonertinib | FAVOUR (NCT04858958): completed (China only) |
Phase Ib Part A: 1L (240 mg, N = 30), Part B: 2L (240 vs. 160 mg, N = 49) |
ORR 1L: 78.6% ORR 2L (240 mg): 46.2% ORR 2L (160 mg): 38.5% |
Han et al. 2023 [39] |
| Firmonertinib | FURVENT (NCT05607550): ongoing (mainly USA and China) |
Phase III (1L) Firmonertinib vs. platinum-based chemotherapy (N = 398), PE: mPFS, SE: mOS |
Study is active, but not recruiting patients, primary completion expected Q3/2025 | www.clincialtrials.gov |
| Sunvozertinib | WU-KONG 1B (NCT03974022): completed (mainly China and EU) |
Phase II (2L) 200 mg (part A) vs. 300 mg (part B) |
ORR 46% (2L) ORR 41.7% in amivantamab-pretreated patients FDA approval |
Yang et al. 2025 [17] |
| Sunvozertinib | WU-KONG 15* (part of WU-KONG 1) (NCT05559645): completed (China only) |
Phase II (1L and 2L) N = 28 in 1L (of note: only 1 site in China recruited patients) |
ORR 73.1% (1L) | Yang et al. 2023 [40] |
| Sunvozertinib | WU-KONG 28 (NCT05668988): ongoing (mainly China and EU) |
Phase III (1L) Sunvozertinib vs. platinum-based chemotherapy (N = 320) PE: mPFS, SE: mOS |
Study is recruiting patients, completion expected Q1/2026 | www.clincialtrials.gov |
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