Sunvozertinib redraws the map in EGFR ex20ins mutant non-small cell lung cancer

Epidermal growth factor receptor exon20 insertions (EGFR ex20ins) mutations occur in ~10% of EGFR-mutant non-small cell lung cancer (NSCLC) and are now recognized as a distinct molecular subtype per MD Anderson’s structural-function based classification (1,2). EGFR ex20ins mutations typically occur in the loop region between the αC-helix and β4 strand of the kinase domain, causing structural rearrangements that stabilize the active conformation of the receptor. These insertions sterically hinder the binding of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) by narrowing the ATP-binding pocket, while simultaneously increasing ATP affinity, thereby conferring intrinsic resistance to gefitinib and afatinib (3). Third-generation EGFR-TKI, osimertinib, demonstrated a modest objective response rate (ORR) of 25% (5/20) and a median progression-free survival (mPFS) of 9.7 months in pretreated advanced NSCLC patients with EGFR ex20ins mutations in the ECOG-ACRIN 5162 study (4). In addition, the development of selective EGFR inhibitors, specifically mobocertinib, which was structurally optimized based on osimertinib to overcome the unique challenges posed by exon 20 insertions—ultimately ended in setbacks (5). Moreover, patients with EGFR ex20ins mutations exhibit a more compromised tumor immune microenvironment compared to those with classical EGFR mutations. This inhibitory milieu contributes to their general refractoriness to immune checkpoint inhibitor (6). As a result, EGFR ex20ins NSCLC were associated with poor outcomes when treated with chemotherapy, immunotherapy, or conventional EGFR-TKIs, representing a persistent unmet need in precision oncology.

Based on the phase 1 CHRYSALIS trial, amivantamab, an EGFR-MET bispecific antibody, was approved for advanced EGFR ex20ins NSCLC after progression on chemotherapy, showing a 40% ORR and 11.1-month median duration of response (mDoR) (7). This led to a phase 3, international, randomized study evaluating first-line amivantamab plus chemotherapy vs. chemotherapy alone in 308 previously untreated EGFR ex20ins NSCLC patients (PAPILLON study). The trial met its primary endpoint, with independent central review (ICR) showing significantly PFS in the combination group [median 11.4 vs. 6.7 months; hazard ratio (HR) =0.40, 95% confidence interval (CI): 0.30–0.53, P<0.001]. ORRs were 73% vs. 47% (P<0.001). Interim overall survival (OS) showed a favorable trend (HR =0.67, 95% CI: 0.42–1.09). Safety was manageable, with predominant toxicities being reversible hematologic and EGFR-related events; only 7% discontinued amivantamab (8). These results support amivantamab-chemotherapy as a new first-line standard for EGFR ex20ins NSCLC, now included in National Comprehensive Cancer Network (NCCN) guidelines. Nevertheless, the search for selective TKI for EGFR ex20ins never stopped. Sunvozertinib (DZD9008) has emerged as a promising oral, irreversible, and highly selective inhibitor of EGFR ex20ins. Sunvozertinib was designed by replacing the rigid methylindole of osimertinib with a more flexible anilinophenyl moiety at the C-4 position of the pyrimidine ring, enhancing its adaptability to accommodate diverse EGFR exon20ins with varying ATP-binding pocket sizes. The pooled analysis of the initial phase I component of the WU-KONG1 study (NCT03974022) and WU-KONG2 (CTR20192097) provided the first human evidence of sunvozertinib’s antitumor activity. Sunvozertinib showed a confirmed ORR of 37.5% across diverse insertion subtypes. Sunvozertinib also exhibited clinical activity in heavily pretreated patients who had failed prior therapies like poziotinib or amivantamab. Despite limited efficacy in poziotinib-resistant patients [1 stable disease (SD) and 1 progressive disease (PD) in 2 patients], it induced robust responses in amivantamab-resistant patients, with 3 partial response (PR) and 1 SD among 4 patients (9). Subsequently, a single-arm, multicenter phase 2 Wu-kong6 study evaluated sunvozertinib (300 mg once daily) in 104 patients with pretreated, locally advanced or metastatic EGFR exon20ins-mutated NSCLC progressed on chemotherapy across 37 Chinese centers. Among 97 efficacy-evaluable patients, the confirmed ORR by Independent Review Committee (IRC) was 61% (95% CI: 50–71%). It’s worth noticing 14 out 26 patients (ORR =54%) who had previously been treated with EGFR-TKI responded to sunvozertinib, and 2 out of 3 patients (ORR =68%) reached PR with sunvozertinib after amivantamab progression. In addition, tumor response was observed regardless of ex20ins mutation subtypes. Albeit its marked efficacy, with a median follow-up of 7.6 months, interstitial lung disease (ILD) was observed in 6 (6%) of participants, higher than the rate of ILD reported in conventional EGFR-TKI (3.3% for osimertinib, 2.1% for furmonertinib), highlighting the safety concerns regarding accumulated ILD event with extended follow-up. Other adverse events (AEs) ≥3 grade was manageable including increased blood creatine phosphokinase (17%), diarrhea (8%), and anemia (6%) (10). Based on the aforementioned studies, sunvozertinib was granted its first approved indication in China on August 22, 2023 for locally advanced or metastatic NSCLC harboring EGFR exon20ins mutation progressed on prior platinum-based chemotherapy.

These findings positioned sunvozertinib among the most active agents in this molecular subset, alongside amivantamab. However, questions remained regarding ethnicity differences and optimal dosing, particularly whether lower doses might improve tolerability without compromising efficacy. The questions were addressed in the WU-KONG1b trial. The phase 2, randomized, dose-comparison WU-KONG1b study, marks a crucial step in refining the therapeutic window of sunvozertinib and demonstrated its efficacy in a global population beyond Chinese patients with EGFR ex20ins mutations. This trial enrolled 202 patients with platinum-pretreated EGFR ex20ins NSCLC, 184 patients were randomly assigned to receive either 200 mg (-rand) or 300 mg (-rand) of sunvozertinib daily, other 18 patients received 300 mg sunvozertinib without randomization. The primary endpoint was IRC-assessed confirmed ORR; secondary endpoints included DoR, PFS and safety.

The results demonstrated comparable efficacy between the 200 and 300 mg doses in patients with EGFR ex20ins outside China, with a confirmed ORR of 45.9% in the 200 mg randomized (-rand) arm and 45.8% in the combined 300 mg group (-all). However, the 300 mg-rand once-daily dose was associated with a higher confirmed ORR than the 200 mg-rand dose in multiple subgroups, including non-Asian patients (43.3% vs. 33.3%), patients from non-Asian countries/regions (44.1% vs. 33.3%), patients with baseline brain metastases (52.4% vs. 28.6%), and those previously treated with amivantamab (41.7% vs. 25.0%). Post hoc intracranial response assessment by IRC per RECIST 1.1 showed confirmed ORRs of 0% (200 mg, n=5) and 40% (300 mg, n=10) in patients with measurable intracranial lesions. For safety profile, the 200 mg-rand dose was associated with lower rates of common grade ≥3 treatment related adverse events (TRAEs) compared to the 300 mg-rand dose: diarrhea (2.2% vs. 18.0%), increased blood CPK (6.6% vs. 12.6%), and anemia (4.4% vs. 6.3%). Notably, no cases of ILD, pneumonitis, or pneumonia were reported in the 200 mg cohort, whereas the 300 mg cohort reported incidences of 1.8% for each of these AEs. As revealed by the relative dose intensities (RDI) data which suggest a notable dose-dependent effect on treatment tolerability. The 200 mg dose was well-tolerated with nearly perfect compliance (99.3% RDI), whereas the 300 mg dose was associated with more frequent dose reductions or interruptions, resulting in a lower RDI (84.4%) (11). These findings affirm that the 200 mg once-daily regimen delivers the optimal risk-benefit balance. It maintains robust efficacy while significantly improving tolerability, most notably by eliminating the risk of ILD observed at the higher dose. This compelling safety advantage supports its designation as the alternative dose for further development. Based on the WU-KONG1b trial, sunvozertinib received U.S. Food and Drug Administration (FDA) approval on July 2, 2025, for the second-line treatment of EGFR exon20ins mutant NSCLC.

The accompanying biomarker analysis by Xu et al., which explores circulating tumor DNA (ctDNA) dynamics and resistance mechanisms, offers critical insights into response prediction, early efficacy assessment, and post-progression biology. Using next-generation sequencing (NGS) of plasma samples collected from (WU-KONG1A), WU-KONG2 and WU-KONG6 at baseline, during treatment, and at disease progression, the study revealed a numerically higher ORR (68% vs. 45.8%) and statistical significantly longer PFS (7.4 vs. 5.5 months) in patients with baseline negative ctNDA EGFR ex20ins compared with ctDNA positive ones. Furthermore, longitudinal blood sampling of 12 patients after disease progression identified acquired EGFR C797S as a candidate on-target resistance mechanism to sunvozertinib. Off-target alterations were also detected in downstream pathways, including mutations in KRAS, PIK3CA, and JAK2 (12). This implies ctDNA can be used a predictive marker for the efficacy of sunvozertinib and a definitive tool for characterizing the resistance mechanism landscape.

To date, the first-line treatment landscape for EGFR ex20ins mutations is evolving, with several meaningful advances having been made (Table 1) (13). The phase 3 WU‑KONG28 trial has successfully demonstrated the superiority of sunvozertinib over traditional platinum‑based chemotherapy as first‑line therapy for EGFR exon20ins NSCLC, with a significant progression‑free survival benefit (HR 0.65). The results were reported as a late‑breaking abstract oral presentation at the 2026 ASCO Annual Meeting on May 29, 2026. This confirmatory study thereby fulfills the postapproval requirement and paves the way for full regulatory approval and a broader firstline indication. Furmonertinib, a third-generation EGFR-TKI approved by the National Medical Products Administration (NMPA) of China, also showed efficacy in patients with EGFR ex20ins. On July 24, 2025, it received conditional approval in China for this indication, based on a surrogate endpoint from a single-arm trial. In the phase Ib FAVOUR study, the ORR was 78.6% in treatment-naïve patients receiving the 240 mg dose of furmonertinib. Among previously treated patients, the confirmed ORR was 38.5% and 46.2% in the 160 and 240 mg dose groups, respectively (14). A real-world study demonstrated the efficacy of 240 mg furmonertinib in treating 13 prior treated, and 8 treatment naïve patients with EGFR ex20ins in a single center of China, with ORR of 52.40% (11/21), time to treatment failure (TTF) of 10.78 months, and OS of 21.67 months (15). However, as the safety profile of the 240 mg dose is based on a limited patient population, drawing definitive conclusions about its safety requires further investigation. The conditional approval of furmonertinib evokes the mobocertinib EXCLAIM-2 study, a similarly designed first-line trial that pitted the targeted agent against chemotherapy. The failure of EXCLAIM-2, which led to mobocertinib’s withdrawal, serves as a cautionary tale, highlighting the high stakes for clinical development programs and regulatory submission strategies. The Phase 3 FURMO-004 study, comparing furmonertinib vs. chemotherapy as first-line treatment for EGFR ex20ins-mutant advanced NSCLC, is currently underway (16). It should be noted that in the WU-KONG28 and FURMO-004 studies, the control arm was not designed to include chemotherapy plus a programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor, even though this combination has been widely adopted as the standard of care in the first-line setting. The lack of a chemo-immunotherapy comparator limits the ability to position sunvozertinib or furmonertinib against the current standard, potentially hindering real-world adoption. In contrast to the WU-KONG28 and FURMO-004 studies, the phase 3 trial of andamertinib (17), a small-molecule TKI approved for the EGFR exon20ins indication on May 22, 2025 by NMPA, employed a control arm that included chemotherapy plus the PD-1 inhibitor sintilimab. This design may pose a competitive challenge to sunvozertinib or furmonertinib, as regulators may view the control arms of WU-KONG28 or FURMO-004 as outdated, potentially affecting full approval or requiring additional post-marketing studies. For future trial design, control arms must reflect the evolving standard of care. In addition, two other small-molecule TKIs, zipalertinib (18) and YK-029A (19), have also initiated phase 3 trials comparing with chemotherapy alone as a first-line treatment for EGFR exon20ins-mutant NSCLC. Another agent under development, STX-721, developed by Scorpion Therapeutics Inc., is a small-molecule inhibitor targeting HER2 and EGFR ex20ins mutations. It acts as a potent and irreversible inhibitor against the majority of these mutants, demonstrating high selectivity for mutant over wild-type forms both in vitro and in vivo in preclinical study (20,21). STX-721 is currently under evaluation in phase 1/2 clinical trials for the treatment of NSCLC driven by EGFR/HER2 ex20ins alterations (22). In parallel, BEBT-109, another EGFR exon20ins-targeting TKI, has also shown promising activity. In its phase 1 study, this agent demonstrated an ORR of 44.4% (8 of 18) with a favorable safety and tolerability profile (23). Accordingly, a phase 2 trial (CTR20213409) is currently ongoing for the treatment of patients with EGFR exon20ins-mutant NSCLC in the later-line setting. Complementing the pursuit of novel TKIs, combination therapy offers an alternative for EGFR ex20ins-mutant NSCLC. The afatinib-cetuximab regimen, evaluated in a phase 2 trial, yielded an 18-week disease control rate (DCR) of 54% and a confirmed ORR of 32%, proving clinically active despite a high rate of manageable grade 3 AEs (54%) (24). In a similar context, a novel humanized EGFR antibody, JMT101 (25), in combination with osimertinib, has entered phase 3 clinical development as a first-line treatment for EGFR exon20ins-mutant NSCLC. Additionally, several antibody-drug conjugates (ADCs) and bispecific antibodies are under development, including SYS6010 (an EGFR-targeting ADC), BL-B01D1 (an EGFR/HER3 bispecific ADC) (26), and SKB571 (an EGFR/c-MET bispecific ADC) (Table 2). These emerging agents hold promise as future therapeutic modalities for EGFR exon20ins-mutant NSCLC. Faced with a constrained landscape of treatment options, primarily between Amivantamab and Sunvozertinib, understanding patient preferences becomes vital. Research shows that while EGFR ex20ins patients prioritize DCR above all, they are willing to make significant trade-offs, sacrificing 5.4–12.7% DCR to reduce severe AE risks by 10% or up to 11.7% DCR for a preferable regimen. This highlights the imperative to balance efficacy, safety, and convenience in clinical development and practice (27).

Conclusions

Sunvozertinib represents a major advance in the treatment of EGFR ex20ins NSCLC. Data from the WU-KONG program, particularly the phase 2 WU-KONG6, WU-KONG1b and phase 3 Wukong28 trials, confirm its high response rates, durable clinical benefit, and favorable safety profile. These advances herald a new era in treating patients with EGFR ex20ins NSCLC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0027/prf

Funding: This study is supported by Key Project of Chongqing Science and Health Joint Medicine (No. 2024ZDXM028).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0027/coif). Y.X. serves as an unpaid Section Editor of AME Clinical Trials Review from August 2025 to July 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Yasuda H, Park E, Yun CH, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177. [Crossref] [PubMed]
2. Robichaux JP, Le X, Vijayan RSK, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 2021;597:732-7. [Crossref] [PubMed]
3. Zhao S, Fang W, Pan H, et al. Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung Adenocarcinoma. J Thorac Oncol 2020;15:962-72. [Crossref] [PubMed]
4. Piotrowska Z, Wang Y, Sequist LV, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2020;38:abstr 9513.
5. Jänne PA, Wang BC, Cho BC, et al. First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial. J Clin Oncol 2025;43:1553-63. [Crossref] [PubMed]
6. Liu KJ, Li HR, Tan QQ, et al. Tumor immune microenvironment of NSCLC with EGFR exon 20 insertions may predict efficacy of first-line ICI-combined regimen. Lung Cancer 2024;195:107933. [Crossref] [PubMed]
7. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol 2021;39:3391-402. [Crossref] [PubMed]
8. Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med 2023;389:2039-51. [Crossref] [PubMed]
9. Wang M, Yang JC, Mitchell PL, et al. Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Cancer Discov 2022;12:1676-89. [Crossref] [PubMed]
10. Wang M, Fan Y, Sun M, et al. Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial. Lancet Respir Med 2024;12:217-24. [Crossref] [PubMed]
11. Yang JC, Wang M, Doucet L, et al. Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B). J Clin Oncol 2025;43:3198-208. [Crossref] [PubMed]
12. Xu Y, Yang JC, Zhao Y, et al. Genetic biomarker study of sunvozertinib for clinical prognosis and prediction in NSCLC with EGFR exon 20 insertion mutation. Cell Rep Med 2025;6:102121. [Crossref] [PubMed]
13. Zhao Y, Yao X, Li R, et al. Efficacy of chemotherapy combined with immunotherapy in advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations: A retrospective comparative study. Cancer Pathog Ther 2026;4:241-8. [Crossref] [PubMed]
14. Han B, Zhou C, Zheng W, et al. OA03.04 A Phase 1b Study Of Furmonertinib, an Oral, Brain Penetrant, Selective EGFR Inhibitor, in Patients with Advanced NSCLC with EGFR Exon 20 Insertions. Journal of Thoracic Oncology 2023;18:S49.
15. Yang S, Liu Y, Zhao J, et al. EGFR exon 20 insertions mutation in lung adenocarcinoma and its response by high-dose of Furmonertinib: a real-world study. BMC Cancer 2025;25:900. [Crossref] [PubMed]
16. Spira A, Cho BC, Felip E, et al. FURVENT: Phase 3 trial of firmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004). Lung Cancer 2025;199:108066. [Crossref] [PubMed]
17. Yang JJ, Mu Y, Wang ZH, et al. Andamertinib in Advanced NSCLC With EGFR Exon 20 Insertions After Platinum-Based Chemotherapy or Immunotherapy: Results From the Phase 2 KANNON Study. J Thorac Oncol 2026;21:103518. [Crossref] [PubMed]
18. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in Patients With Epidermal Growth Factor Receptor Exon 20 Insertion-Positive Non-Small Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy With or Without Amivantamab. J Clin Oncol 2025;43:2387-97. [Crossref] [PubMed]
19. Duan J, Wu L, Yang K, et al. Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial. J Thorac Oncol 2024;19:314-24. [Crossref] [PubMed]
20. Milgram BC, Borrelli DR, Brooijmans N, et al. Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer. J Med Chem 2025;68:2403-21. [Crossref] [PubMed]
21. Pagliarini RA, Henderson JA, Milgram BC, et al. STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models. Clin Cancer Res 2025;31:3002-18. [Crossref] [PubMed]
22. Gazzah A, Lin CC, Ruiter G, et al. Trial in progress: First-in-human study of PFL-721/STX-721 in participants with locally advanced or metastatic non-small cell lung cancer harboring EGFR exon 20 insertion mutations. J Clin Oncol 2025;43:TPS3173.
23. Zeng L, Song L, Liu L, et al. First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer. Med 2024;5:445-458.e3. [Crossref] [PubMed]
24. van Veggel BAMH, van der Wekken AJ, Paats MS, et al. A phase 2 trial combining afatinib with cetuximab in patients with EGFR exon 20 insertion-positive non-small cell lung cancer. Cancer 2024;130:683-91. [Crossref] [PubMed]
25. Zhao S, Zhuang W, Han B, et al. Phase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer. Nat Commun 2023;14:3468. [Crossref] [PubMed]
26. Hong SD, Wang YS, Zhao HY, et al. Izalontamab brengitecan (Iza-bren; BL-B01D1), a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, for patients with EGFR-mutated NSCLC: pooled analysis of phase I and phase II trials. Ann Oncol 2026;37:813-24. [Crossref] [PubMed]
27. Seo J, Curran E, Whitty JA, et al. Patient preferences for EGFR mutation-targeted therapies in non-small cell lung cancer, with a focus on Exon 20 insertions. Lung Cancer 2025;209:108796. [Crossref] [PubMed]