YK-029A in the landscape of treatments for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations

Non-small cell lung cancer (NSCLC) is a major cause of cancer-related morbidity and mortality worldwide. Although curable in early stages, patients with recurrent and/or metastatic NSCLC require long-term systemic cancer therapy with a palliative intent. Treatment of advanced disease has undergone rapid transformation over the last few decades and the momentum with which new drugs are being developed and approved continues to increase. A major treatment strategy revolves around tailored therapy based on tumor genomic drivers. This was all spear-headed by the discovery of mutations in epidermal growth factor receptor (EGFR) which are frequently noted in NSCLC, more common in some geographic regions such as Asia (1,2). Tumors with the most prevalent activating EGFR mutations, exon 19 deletions and exon 21 L858R point mutations, showed dramatic response to EGFR tyrosine kinase inhibitors (TKIs), leading to multiple approvals (3,4). In fact, third-generation TKI osimertinib is now the first-line treatment as a monotherapy or with chemotherapy for newly diagnosed EGFR-mutated NSCLC with the most common mutations (5-7).

Despite these optimistic findings, the presence of less common mutations such as EGFR exon 20 insertions presents a unique challenge due to ongoing resistance to osimertinib and other EGFR-TKIs resulting in suboptimal response to therapy (8-10). Since exon 20 insertion mutations account for up to 10% of all EGFR-mutated patients, additional therapeutic options are urgently needed (11-13). The current first-line recommended therapy, combination platinum chemotherapy plus amivantamab, was approved by the Food and Drug Administration (FDA) in March 2024 following findings of the phase III PAPILLON trial showing a superior progression-free survival (PFS) of 11.4 month compared to 6.7 months for platinum chemotherapy alone (14). Mobocertinib is a TKI that had accelerated approval for EGFR exon 20 insertion positive NSCLC based on promising results from the phase I/II trial (15). However, the approval was voluntarily withdrawn by the manufacturer as it did not meet the primary endpoint of PFS in the confirmatory phase III EXCLAIM-2 trial, highlighting the challenges around targeting EGFR exon 20 insertion mutations (16,17). Several other TKIs are currently undergoing investigation for use in this space, including sunvozertinib, furmonertinib, and zipalertinib. In the article “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”, Duan et al. presented their data for a novel EGFR TKI, YK-029A for use in patients with EGFR exon 20 insertion mutations.

YK-029A was developed as a third-generation EGFR-TKI for oral administration using a novel computer-aided design. YK-029A increases hydrophobic interactions with the Phe723 of EGFR at the P-loop and acts as a covalent inhibitor targeting exon 20 insertion (18). Early results have shown promising efficacy for YK-029A. In the phase I open label study by Duan et al., patients aged 18 to 75 with locally advanced or metastatic NSCLC with EGFR mutations who were not candidates for surgery or radiation were enrolled to receive YK-029A (19). Patients were excluded if they had received chemoimmunotherapy or large field radiation in the preceding 4 weeks or had symptomatic brain metastases. Patients received gradually escalating doses from 50 to 250 mg/day as part of dose escalation phase, and patients in the dose expansion phase received 200 mg/day in a 28-day cycle. One hundred and eight patients were enrolled in safety analysis, with 28 treatment naïve patients with exon 20 insertion mutation that underwent the dose-expansion phase, of which 26 were included in final efficacy analysis. Objective response rate (ORR) was an impressive 73.1% [95% confidence interval (CI): 52.21% to 88.43%] and median PFS was 9.3 months (95% CI: 74.87% to 99.05%) by independent review committee (19).

Based on these promising results, the agent is marching ahead with a phase III trial. It should be noted, however, that a few other orally administered third generation EGFR-TKIs including sunvozertinib, furmonertinib and, zipalertinib, are also surging forward in this space (Table 1) (21,23,24). With YK-029A and these drugs all entering phase III trials for the frontline indication, this has become a rather crowded space for agents targeting EGFR exon 20 insertion mutation, all with promising early findings and a favorable tolerability profile. Amivantamab, which is currently approved by US FDA for treatment of this disease, stands apart from these agents as it is an intravenous bispecific monoclonal antibody against EGFR and mesenchymal epithelial transition factor (MET) that binds extracellularly, bypassing resistance at the TKI binding site (20). Although YK-029A boasts one of the highest ORR of comparable agents, no patients achieved complete response (CR) in the study by Duan et al. Mobocertinib, sunvozertinib, furmonertinib, and zipalertinib also did not achieve any CR (15,21,23,24). This contrasts with the CR observed in 4% of patients who received amivantamab and 4% in amivantamab + chemotherapy (14,20). YK-029A’s median PFS was also numerically higher than other comparable agents but lower than that of amivantamab plus chemotherapy. YK-029A’s ORR was similar to that of amivantamab with chemotherapy; however, cross-trial comparisons should be viewed with caution and, unfortunately, there are currently no randomized head-to-head comparisons between these drugs.

From a tolerability perspective, TKIs targeting EGFR have common on-target and off-target side effects, mostly involving skin and mucosa with intensity being dependent on the degree of wild-type EGFR inhibition (4). YK-029A’s most common toxicities are like those of comparable EGFR-TKIs in use and undergoing investigation. Low-grade rash and diarrhea occurred in over a third of patients treated with YK-029A. Importantly, grade 3 and above toxicities, most common of which was diarrhea, occurred in 38% of patients. These incidences are numerically similar to what is seen with amivantamab, mobocertinib, and sunvozertinib (17,19,22). However, no grade 3+ toxicities were reported in trials of furmonertinib and zipalertinib (23,24). Interestingly, a rather unique association with YK-029A as compared to other agents in this space was anemia, which occurred in over half of patients. Also, these agents appear to have a milder side effect profile compared to amivantamab plus chemotherapy, which had a high rate (75%) of grade 3 and above toxicities (14).

While the early data on YK-209A presented by Duan et al. certainly sound promising, it should be noted that there were multiple limitations—small sample size, lack of control group, and the fact that all participants were from the Asia-Pacific region. All these limitations pose a challenge to whether the results can be generalizable internationally. Also, it is unknown how YK-029A will perform against current standard treatments including combination platinum chemotherapy. Amivantamab with platinum-based chemotherapy is currently the only FDA-approved first-line treatment option for EGFR exon 20 insertion mutation positive NSCLC patients, based on the PAPILLON study which reported an ORR of 73% and PFS of 11.4 months, although bearing significant toxicities (75% grade 3 and higher) (14). Despite all these positive moves, treatment of EGFR exon 20 insertion mutation positive NSCLC remains a challenge and an unmet need. Current available treatments are intravenous and are associated with significant toxicity. There is a continued quest for tolerable oral agents with durable efficacy. Whether YK-029A will be that agent can only be answered by globally conducted randomized controlled studies with appropriate control arms, but the early signals of high ORR and PFS certainly make this compound noteworthy (14,19,20).

In summary, based on the study published by Duan et al., YK-029A is a promising, well-tolerated and efficacious drug for EGFR exon 20 insertion mutation positive NSCLC. The current landscape of treatment for NSCLC with EGFR exon 20 insertion mutations, however, is burgeoning with many EGFR-TKIs, each of which seem to have a favorable efficacy and tolerability profile. This is an exciting time in the field, and it remains to be seen whether one agent will emerge with superior efficacy and tolerability over the others. In addition, since exon 20 mutations are heterogenous, further research will be needed to characterize and distinguish whether specific exon 20 insertion mutation variants respond better to specific drugs. Finally, penetration through the blood-brain barrier would be a critical point to consider in choosing a therapeutic agent since metastases to the central nervous system occur relatively frequently in this disease. So far this has not been robustly characterized.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-8/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-8/coif). N.S. has participated in advisory boards for J&J, Astra Zeneca and Takeda, who are makers of some agents mentioned in this manuscript. These commitments have been completed and have absolutely no influence on the manuscript. 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. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7:78985-93. [Crossref] [PubMed]
2. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:2866-74. [Crossref] [PubMed]
3. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017;376:629-40. [Crossref] [PubMed]
4. Fu K, Xie F, Wang F, et al. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol 2022;15:173. [Crossref] [PubMed]
5. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
6. Planchard D, Feng PH, Karaseva N, et al. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open 2021;6:100271. [Crossref] [PubMed]
7. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
8. Choudhury NJ, Schoenfeld AJ, Flynn J, et al. Response to Standard Therapies and Comprehensive Genomic Analysis for Patients with Lung Adenocarcinoma with EGFR Exon 20 Insertions. Clin Cancer Res 2021;27:2920-7. [Crossref] [PubMed]
9. Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes. Curr Med Res Opin 2022;38:1341-50. [Crossref] [PubMed]
10. Yang GJ, Li J, Xu HY, et al. Osimertinib for Chinese advanced non-small cell lung cancer patients harboring diverse EGFR exon 20 insertion mutations. Lung Cancer 2021;152:39-48. [Crossref] [PubMed]
11. Chouaid C, Filleron T, Debieuvre D, et al. A Real-World Study of Patients with Advanced Non-squamous Non-small Cell Lung Cancer with EGFR Exon 20 Insertion: Clinical Characteristics and Outcomes. Target Oncol 2021;16:801-11. [Crossref] [PubMed]
12. Arcila ME, Nafa K, Chaft JE, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 2013;12:220-9. [Crossref] [PubMed]
13. Van Sanden S, Murton M, Bobrowska A, et al. Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis. Target Oncol 2022;17:153-66. [Crossref] [PubMed]
14. 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]
15. Zhou C, Ramalingam SS, Kim TM, et al. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol 2021;7:e214761. [Crossref] [PubMed]
16. Jänne PA, Wang BC, Cho BC, et al. 507O EXCLAIM-2: Phase III trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC. Ann Oncol 2023;34:S1663-4. [Crossref]
17. Riely GJ, Neal JW, Camidge DR, et al. Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial. Cancer Discov 2021;11:1688-99. [Crossref] [PubMed]
18. Liu B, Gao F, Zhao H, et al. Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC. Eur J Med Chem 2023;258:115590. [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. 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]
21. 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]
22. 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]
23. Sa H, Shi Y, Ding C, et al. A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations. J Cancer Res Clin Oncol 2023;149:7729-42. [Crossref] [PubMed]
24. Piotrowska Z, Tan DS, Smit EF, et al. Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions. J Clin Oncol 2023;41:4218-25. [Crossref] [PubMed]