The future of EGFR exon 20 targeting in non-small cell lung cancer

Twο decades after launch of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC), EGFR exon 20 insertions (ex20ins) still represent a major unmet need in thoracic oncology. The corresponding oncoprotein superstructure is especially problematic, as it combines steric hinderance against all 3 conventional TKI generations (G) that cover classic EGFR mutations, i.e., exon 19 deletions (del19) and p.L858R, with a close resemblance to the wild-type protein that rendered early ex20ins-specific drugs very toxic (1). One striking example was the recent withdrawal from the United States (U.S.) and other markets of mobocertinib, which had shown promising efficacy for pretreated patients in phase 2 (2,3), but never gained approval by the European Medicines Agency (EMA) mainly due to gastrointestinal toxicity, and also failed the confirmatory first-line phase 3 study vs. standard chemotherapy (4). While this was a major setback for the field, progress continues, and Duan et al. show us with a recent article in the Journal of Thoracic Oncology where we are heading towards (5).

This work offers a first clinical glimpse on YK-029A, a novel 3G EGFR ex20ins-active TKI with structure-guided design, good oral bioavailability, and promising preclinical results (6). Within a multicenter dose-escalation and dose expansion phase 1 trial comprising several cohorts, NSCLC patients with various EGFR mutations received YK-029A orally administered using the traditional 3+3 principle at doses of 50, 100, 150, 200, and 250 mg/d (5). Included in the dose expansion part as cohort 6, were also 26 evaluable treatment-naive patients with EGFR ex20ins, who achieved an impressive objective response rate (ORR) of 73% according to the independent review committee (IRC), a disease control rate (DCR) of 92%, and a median progression-free survival (PFS) of 9.3 months (95% confidence interval: 5.9–not estimable). Interestingly, the efficacy appeared to be higher for tumors with near-loop (ORR 75% according to the IRC) compared to far-loop variants (ORR 67%), similar to what was expected based on preclinical data (7), and had been already described for amivantamab (ORR 41% vs. 25%, respectively) (8), sunvozertinib (ORR 48% vs. 36%), and zipalertinib (ORR 42% vs. 22%) (9-11), albeit at a higher level for YK-029A compared to other drugs. On the other hand, the pharmacokinetics and tolerability of YK-029A were also very good with a long half-life permitting administration once daily, saturated absorption at dose levels above 100 mg, achievement of a plasma steady state after 8 consecutive days of administration, and no dose-limiting toxicities up to the maximum analyzed dose of 250 mg (5). The most common side effects were anemia (51%), diarrhea (49%), and rash (34%), with grade ≥3 treatment-emergent adverse events (TEAEs) in 38% of participants. Grade 3 diarrhea occurred in 7% of patients, while the rate of treatment discontinuation due to adverse event (AE) was only 3% (3/108), both much lower than what had been previously observed with the now withdrawn first-in-class drug mobocertinib (21% grade 3 diarrhea and 17% discontinuation due to AE) (3).

Another important recent development in the field was the positive first-line phase 3 PAPILLON trial of the EGFR/MET-directed bispecific antibody amivantamab combined with platinum-based doublet chemotherapy, which achieved an ORR of 73%, comparable to that of YK-029A monotherapy, and a median PFS of 11.4 months, vs. 47% and 6.7 months for the chemotherapy control arm, respectively (12). While these results are also very good and will definitely lead to a new EMA approval for amivantamab upfront soon (NB. FDA already granted approval on March 1 2024), they suffer from two main issues: first, the chemotherapy associated toxicity with relatively high rates of grade 3 AEs (75%) and treatment discontinuation (24%) in patients who received the combined therapy; and second, the shorter first-line PFS of the experimental arm with 11.4 months compared to the combined PFS of the first and second line (PFS2) at 17.2 months for patients in the control arm, 76% of which received amivantamab as already approved after chemotherapy (12). Viewed from a different perspective, these results furthermore suggest that the ongoing first-line phase 3 trial of YK-029A as monotherapy (NCT05767892) will probably also be positive, since this drug achieved a higher ORR and longer PFS in the phase 1 study, than chemotherapy in PAPILLON (73% vs. 47%, and 9.3 vs. 6.7 months, respectively) (5,12). Other EGFR ex20ins-active TKI with published first-line efficacy data and ongoing first-line monotherapy trials are furmonertinib and sunvozertinib (13,14) (Table 1). These studies to advance targeted drugs in the first-line are particularly important for the field, because a high attrition of 30–40% between the first and the second treatment line has been reported for patients with ex20ins or other EGFR mutations in the real-world setting (15,16). Of note, YK-029A is currently also under investigation for NSCLC patients with rare EGFR mutations and EGFR T790M (NCT05767866), who generally have a worse prognosis and shorter survival than patients with classic EGFR mutations (17), but the potential in the field is even greater.

Recently, the MARIPOSA phase 3 trial showed how the first-line efficacy of 3G TKI for classic EGFR mutations can be augmented by combination with amivantamab, resulting in a PFS benefit of approximately 7–9 months compared to osimertinib monotherapy, with manageable side effects and a discontinuation rate of approximately 10% (18). Hence, a similar strategy becomes now an attractive perspective for YK-029A and other ex20ins-specific 3G EGFR TKI, as well (Table 1). In combination with amivantamab these drugs would postpone administration chemotherapy for ex20ins-mutated tumors until the second line and—based on the results of MARIPOSA and CHRYSALIS (18,19)—would probably also retain good efficacy for various high-risk subsets of EGFR-driven disease, like patients with brain metastases and TP53 co-mutations (17). However, dissemination of benefit from novel pharmaceuticals for rare mutations, such as EGFR ex20ins, will also require additional key measures besides conventional clinical trials and cutting-edge translational research, like earlier drug access through accelerated or conditional approvals based on real-world synthetic control arms, central cost regulation for the weaker social strata, as well as better patient adherence through closer clinical monitoring and digital tools (20). Furthermore, it remains questionable whether we could ever achieve cure of EGFR-positive NSCLC using molecularly targeted therapies alone (21). For this, a better understanding of the immunologic tumor microenvironment in exon20ins-positive disease will be essential (22) in order to develop novel strategies of immunomodulation beyond programmed cell death 1/programmed death-ligand 1 [PD-(L)1] inhibitors, which possess no activity against these tumors (23). Ultimately, our best hope for the long-term control of NSCLC with EGFR ex20ins rests on the combination of next-generation immunotherapeutics, like multispecific antibodies and T-cell receptor (TCR)-transgenic T cells (24,25), with next-generation targeted drugs, like YK-029A, whose entering the clinical arena is therefore an important milestone (5).

Acknowledgments

Funding: This work was funded by the German Center for Lung Research (DZL).

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-24-10/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-10/coif). P.C. declares research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda; speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda; support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda; and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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. Vyse S, Huang PH. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 2019;4:5. [Crossref] [PubMed]
2. Christopoulos P, Prawitz T, Hong JL, et al. Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations. Lung Cancer 2023;179:107191. [Crossref] [PubMed]
3. 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]
4. Takeda. Takeda Provides Update on EXKIVITY® (mobocertinib). 2023. Available online: https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Provides-Update-on-EXKIVITY-mobocertinib/. Accessed 15 Jan 2024.
5. 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]
6. 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]
7. 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]
8. 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]
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. Janne P, Wang M, Mitchell P, et al. OA15.02 Phase 1 Studies of DZD9008, an Oral Selective EGFR/HER2 Inhibitor in Advanced NSCLC with EGFR Exon20 Insertion Mutations. J Thor Oncol 2021;16:S874. [Crossref]
11. 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]
12. 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]
13. Xu Y, Yang JCH, Chiu CH, et al. Efficacy and safety of sunvozertinib in treatment naïve NSCLC patients with EGFR exon20 insertion mutations. J Clin Oncol 2023;41:9073. [Crossref]
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. J Thor Oncol 2023;18:S49. [Crossref]
15. Christopoulos P, Kluck K, Kirchner M, et al. The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions. Eur J Cancer 2022;170:106-18. [Crossref] [PubMed]
16. Magios N, Bozorgmehr F, Volckmar AL, et al. Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer. Ther Adv Med Oncol 2021;13:1758835921996509. [Crossref] [PubMed]
17. Christopoulos P, Kirchner M, Roeper J, et al. Risk stratification of EGFR(+) lung cancer diagnosed with panel-based next-generation sequencing. Lung Cancer 2020;148:105-12. [Crossref] [PubMed]
18. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
19. Lee SH, Cho BC, Han JY, et al. Amivantamab and lazertinib in treatment-naïve EGFR-mutated advanced non–small-cell lung cancer (NSCLC): Long-term follow-up and ctDNA results from CHRYSALIS. J Clin Oncol 2023;41:9134. [Crossref]
20. Christopoulos P, Schlenk R, Kazdal D, et al. Real-world data for precision cancer medicine-A European perspective. Genes Chromosomes Cancer 2023;62:557-63. [Crossref] [PubMed]
21. Christopoulos P. Can we cure metastatic EGFR-mutated lung cancer today? Transl Cancer Res 2023;12:209-12. [Crossref] [PubMed]
22. Kirchner M, Kluck K, Brandt R, et al. The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma. ESMO Open 2021;6:100253. [Crossref] [PubMed]
23. Christopoulos P, Ou SH, Lin J, et al. Systematic review and meta-analysis of immunotherapy effectiveness for pretreated patients with non-small cell lung cancer harboring EGFR exon 20 insertions (ESMO 2021 congress abstract 1224P). Ann Oncol 2021;32:S972. [Crossref]
24. Gaissmaier L, Elshiaty M, Christopoulos P. Breaking Bottlenecks for the TCR Therapy of Cancer. Cells 2020;9:2095. [Crossref] [PubMed]
25. Elshiaty M, Schindler H, Christopoulos P. Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer. Int J Mol Sci 2021;22:5632. [Crossref] [PubMed]