A new era for EGFR exon20 targeting in non-small cell lung cancer

Among epidermal growth factor receptor (EGFR) alterations in non-small cell lung cancer (NSCLC), exon 20 insertions (ex20ins) are still the most problematic. While median overall survival (OS) for patients with classical EGFR mutations receiving third-generation (3G) tyrosine kinase inhibitors (TKIs) currently exceeds 3 years, these drugs have minimal only activity for ex20ins (1,2). The respective oncoprotein superstructure combines steric hinderance against all conventional EGFR inhibitors, while remaining very similar to wild-type EGFR, which caused severe toxicity problems with early ex20ins-specific drugs (3). One striking example was mobocertinib, which caused severe gastrointestinal toxicity and was withdrawn from market after failing the randomized first-line study versus (vs.) standard chemotherapy (4), despite promising initial results for a phase 2 trial (5,6). However, progress continues, and just one year later targeted drugs have now already arrived in the frontline setting.

In this context, the phase III PAPILLON study evaluated the efficacy of the combination of chemotherapy plus amivantamab, a bispecific antibody targeting the EGFR and mesenchymal-to-epithelial transition (MET) proteins, vs. chemotherapy alone in treatment-naive patients with EGFR ex20ins. The results, recently published in the New England Journal of Medicine, demonstrated superior efficacy of the combination compared to chemotherapy alone, with an objective response rate (ORR) of 73% [95% confidence interval (CI): 65–80%] and a median progression-free survival (PFS) of 11.4 months (95% CI: 9.8–13.7) in the experimental arm vs. 47% (95% CI: 39–56%) and 6.7 months (95% CI: 5.6–7.3) in the chemotherapy control arm. Amivantamab was already approved in the second-line for EGFR ex20ins NSCLC, but its efficacy as monotherapy is much lower for pre-treated patients with ORR <40% and a median PFS of 6.9 months (95% CI: 5.6–8.6) (7), so that both U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) considered PAPILLON results to be practice-changing and granted approvals in March and June 2024, respectively. One main reason for the importance of this development is the relatively high attrition rate for NSCLC with ex20ins and other EGFR mutations between the first and second treatment lines: based on real-world data, about 30–40% of newly diagnosed patients may never get the chance to receive amivantamab if this were withheld until the time of chemotherapy failure (2,8). In contrast, with the PAPILLON approval we can now guarantee that every patient has the opportunity to benefit from both chemotherapy and amivantamab, which becomes even more important because immunotherapy as a third main modality has negligible activity against these tumors (9). Notably, toxicity also increases for patients receiving combined therapy, for example grade 3 adverse events (AEs) were observed in 75% of patients in the amivantamab and chemotherapy vs. 54% in the chemotherapy-only arm of PAPILLON (Table 1) (10). Therefore, for successful application of the PAPILLON regiment in clinical practice physicians will need to take into account the general condition and comorbidities of each patient and select suitable cases based on individualized risk-to-benefit assessment, inasmuch as an OS benefit from the combined first-line therapy has not been demonstrated yet. However, other recent developments may help overcome tolerability issues easier in the future.

Of particular importance in this respect are the results of the phase 3 PALOMA study announced at the American Society for Clinical Oncology (ASCO) annual congress in June 2024 (14). In a randomized comparison of 418 patients with refractory EGFR-mutated NSCLC receiving amivantamab with lazertinib in various treatment lines, the subcutaneous administration of amivantamab (n=206) not only improved administration time (<5 minutes vs. 5 hours for the first application) and patient convenience (85% vs. 52% based on in self-reporting), but was also associated with fewer infusion-related reactions (13% vs. 66%), less thromboembolic events (9% vs. 14%) and longer OS [hazard ratio (HR) =0.62, P=0.002] compared to the intravenous route (n=212), which is the current standard for this drug. When the respective approval comes in 2025, it will significantly improve the tolerability of amivantamab, while other studies, like COCOON (NCT06120140) are ongoing to mitigate dermatologic toxicity. Skin problems, like rash and paronychia, are the main limiting side effect of amivantamab and warrant prophylactic measures, similar to these recommended under EGFR TKI, along with close monitoring and early dose adjustments aggravating symptoms.

Another important development for the field is the advent of novel EGFR ex20ins-specific TKI with higher efficacy and better tolerability than mobocertinib (Table 1). For example, YK-029A, a novel 3G compound chemically designed based on the structural characteristics of the target protein (15) could show an impressive ORR of 73.1% (95% CI: 52.2–88.4%) according to the independent review committee (IRC) among 26 therapy-naïve patients in the phase 1 trial (11). With a disease control rate (DCR) of 92.3% (95% CI: 74.87–99.05%), median PFS of 9.3 months (95% CI: 5.9–not estimable), and discontinuation rate due to AEs <5% (3/108), all results were very good and set the base for an ongoing randomized phase 3 trial in the first-line setting (NCT05767892). A similar situation is currently shared by sunvozertinib and furmonertinib, as well (Table 1). Interestingly, tumors with near-loop appear to be more sensitive than tumors with far-loop ex20ins variants (e.g., ORR 75% vs. 67% for YK-029), which is in line with what was expected based on preclinical data (16), and the experience with amivantamab (ORR 41% vs. 25%, respectively) (11,17,18). From a broader perspective, another implication of the PAPILLON results is actually that all these ongoing first-line phase 3 trials of novel ex20ins specific TKI will probably also be positive, since these compounds have already demonstrated higher ORRs and better PFS in their studies so far than what could be achieved with chemotherapy in PAPILLON (10-13) (Table 1). In which direction could the field move after that?

Recent results from, the MARIPOSA phase 3 trial have demonstrated that the benefit from 3G EGFR TKI in the first-line can be further improved by the additional administration of amivantamab, with a further prolongation of PFS amounting to approximately 7–9 months if conventional restaging without defined intervals for brain magnetic resonance imaging (MRI) scans is considered, similar to the practice in all other EGFR studies (e.g., FLAURA, FLAURA-2), as well. Besides, side effects were manageable with a discontinuation rate of approximately 10% (19). Consequently, a similar strategy could in the future be also pursued for EGFR ex20ins-mutated NSCLC by combining next-generation TKI with antibodies (Table 1). If these novel targeted drugs were given together with amivantamab in the first line, the administration of chemotherapy could be postponed further. Moreover, such a combination would probably also ensure good efficacy for specific subsets of EGFR disease with adverse prognosis, like patients with brain metastases or TP53 mutations (20), if we extrapolated from the results of MARIPOSA and CHRYSALIS (19,21). Besides, other studies are investigating the combination of novel exon20-active TKI with chemotherapy or antiangiogenics (e.g., NCT06348927 and NCT06195189 for sunvozertinib; NCT06339242 and NCT05334277 for furmonertinib). That being said, it remains questionable today whether cure of EGFR-positive NSCLC can ever be achieved using molecularly targeted therapies and chemotherapy only (22). For this, novel immunomodulatory strategies to harness the immunologic microenvironment of exon20ins-positive tumors will be essential (23), as programmed death (ligand)-1 [PD-(L)1] inhibitors are not active against this disease (9). Ultimately, our highest chances of success in the fight against oncogene-driven lung cancer rely on the rational integration of novel targeted drugs (Table 1) with next-generation immunotherapeutics, such as transgenic TCR-T cells and multispecific antibodies, including amivantamab (24,25), whose advent in the first-line therefore signals the onset of new era for EGFR ex20ins NSCLC (10).

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://cco.amegroups.org/article/view/10.21037/cco-24-102/prf

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

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.org/article/view/10.21037/cco-24-102/coif). P.C. serves as an unpaid editorial board member of Chinese Clinical Oncology from September 2023 to August 2025. P.C. reports research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, and Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating in 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.

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