Epidermal growth factor receptor exon 20 insertion mutations: are we getting closer to solving the puzzle?

Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is one the success stories of precision medicine due to the development of targeted therapies which have dramatically changed the treatment and prognosis of this disease. However, it also illustrates the complexity of cancer molecular biology and the challenges of developing targeted therapies in rare molecular subtypes. The EGFR exon 19 deletion and exon 21 L858R are exquisitely sensitive to the EGFR tyrosine kinase inhibitors (TKIs). However, other EGFR mutations have variable sensitivity and EGFR exon 20 insertion mutations (EGFR exon20ins) are resistant to currently available EGFR TKIs (1). EGFR exon20ins are located in the C-helix that stabilize EGFR protein in the active state independent of ligand activation. EGFR exon20ins have a higher half-maximal inhibitory concentration (IC₅₀) than the sensitive EGFR mutations, and the first- and second-generation EGFR TKIs were unable to achieve therapeutic levels (2,3). The one exception is the A763_Y764insFQEA mutation which is sensitive to first- and second-generation EGFR TKIs.

Clinically, EGFR exon20ins are estimated to represent approximately 2–4% of EGFR mutant NSCLC, and this subset includes numerous different insertion mutations within exon 20 (4). The patient and clinical characteristics of EGFR exon20ins subset are similar to patients with other EGFR mutations (5). Historically, for patients with metastatic disease the standard first-line therapy has been a platinum-based chemotherapy, and EGFR TKIs were used as second-line therapy despite their modest activity.

Recently single agent amivantamab, an EGFR and mesenchymal-epithelial transition (MET) factor bispecific antibody, demonstrated single agent activity in a single arm trial in previously treated patients. The objective response rate (ORR), median duration of response (DoR) and median progression-free survival (PFS) observed were 40%, 11.1 months, and 8.3 months, respectively. The most common adverse events were rash, infusion related reactions, and paronychia, and dose reductions and discontinuations were reported in 13% and 4% of patients, respectively (6).

A phase III trial compared the combination of carboplatin and pemetrexed with and without amivantamab in treatment naïve patients. The amivantamab combination compared to chemotherapy alone demonstrated a higher ORR (73% and 47%, respectively), longer DoR (9.7 and 4.4 months, respectively), and longer PFS [median 11.4 and 6.7 months, respectively; hazard ratio (HR) of 0.40; P<0.001]. In the amivantamab arm the adverse events leading to dose interruptions, dose reductions, and discontinuations were observed in 69%, 48%, and 24% of patients, respectively. A subcutaneous formulation may become available which will reduce the rate of infusion related reactions and the burden of the infusion schedule, but the EGFR-related adverse events continued to be relevant (7). This trial established the combination of carboplatin, pemetrexed and amivantamab as a standard first-line therapy, albeit with an adverse event profile which raised questions about the tolerability, especially in elderly or frail patients.

The EGFR TKI mobocertinib was designed to target EGFR exon20ins and was investigated in a phase I/II and phase III trials (8,9). In the phase I/II trial among patients who had previously received platinum-based therapy the ORR, median DoR, and median PFS were 28%, 17.5 months, and 7.3 months. Based on these results a phase III trial of mobocertinib compared to platinum-based therapy in the first-line patients was initiated, and the trial was stopped at the first interim analysis. In the mobocertinib and chemotherapy treatment arms the ORR was 32% and 30%, respectively, and the median PFS was 9.59 and 9.63 months, respectively (HR of 1.038; P=0.803). When compared to phase III trial of chemotherapy and amivantamab the ORR of the investigational arm is lower, and the median PFS of the chemotherapy alone arm was longer. These trial results led to mobocertinib being voluntarily withdrawn.

Clinically, there is an unmet need for more active and better tolerated therapies for this patient population. Sunvozertinib (DZD9008) is an EGFR TKI with high selectivity for EGFR exon20ins and relative sparing of EGFR wild-type. Wang and colleagues recently reported the results of a single arm phase II trial in patients with EGFR exon20ins who had received prior platinum-based therapy (10). The ORR was 61%, which was sufficient to reject the null hypothesis. Responses were observed in a variety of EGFR exon20ins, and whether the mutation was classified as near or far loop. With a median follow-up time of 5.6 months the median DoR was immature, and with a median follow-up time of 6.9 months the median PFS was immature. The most common treatment-related adverse events (all grades) were diarrhea (68%), rash (54%), increased creatinine phosphokinase (52%), anemia (49%), creatine increased (38%), and paronychia (33%). The most common grade ≥3 treatment-related adverse events were increased creatine phosphokinase (17%), diarrhea (8%), anemia (6%), and stomatitis (3%). Treatment related adverse events led to dose interruption, reduction and discontinuation in 38%, 29%, and 10% of patients respectively. The most common treatment related adverse event leading to treatment discontinuation was interstitial lung disease (6%).

The results of this phase II study demonstrate that sunvozertinib should be developed further, especially given the limitations of currently available therapies. With all the limitations of cross trial comparisons, the ORR is higher than previous trials and the higher than the threshold of 30% which has been associated with regulatory approval (11). The short follow-up time and lack of the data maturity raises doubts about the durability of the benefit and requires further follow-up given past experiences with novel EGFR TKIs (12). Central nervous system (CNS) disease progression can be problematic in this disease and blood brain barrier penetration of targeted therapies can be variable. Of the patients enrolled in this trial, 31 patients had baseline brain metastases, and the investigators required imaging of CNS lesions every 6 weeks in patients with baseline CNS metastases, and if clinically indicated if patients without baseline metastases. Hopefully, with further follow-up an assessment of CNS activity will be available. The adverse events and tolerability profile are reasonable, and the adverse events appear manageable. We will have to observe to see if these results are observed in future studies with a larger and broader patient population, and with specific attention to the rate of interstitial lung disease, grade ≥3 adverse events, and adverse events leading to treatment discontinuation.

Historically, novel targeted therapies have been compared to first-line chemotherapy in the first-line setting with the primary endpoint of PFS. The recent negative phase III trial of single agent mobocertinib, and the positive phase III trial of osimertinib with chemotherapy have raised questions if monotherapy is the best strategy (13). In the EGFR exon20ins patient population the variation observed in the PFS on the chemotherapy alone treatment arms in the recent phase III trials introduces an additional degree of uncertainty. The higher ORR observed with sunvozertinib relative to mobocertinib and amivantamab is reassuring, but ideally, we would have additional PFS data before deciding on the trial first-line trial design. An international phase III trial of sunvozertinib compared with chemotherapy in patients with EGFR exon20ins in the first-line setting has been initiated (NCT05668988) with the primary endpoint of PFS by blinded independent central review.

Other EGFR TKIs have demonstrated preliminary activity in EGFR exon20ins patient population. Furmonertinib demonstrated activity in a phase 1b study at 160 and 240 mg daily, and a phase III trial is evaluating furmonertinib the two dose levels compared to platinum-pemetrexed chemotherapy is planned (14,15). Patients will be randomized 1:1:1, and the primary endpoint is PFS by blinded independent central review (NCT05607550). Interestingly, zipalertinib revealed activity in the EGFR exon20ins patient population in a phase I/II trial, and the phase III trial will compared platinum-pemetrexed with and without zipalertinib (NCT05973773) (16).

The results of these phase III trials will define the role of these EGFR TKIs which target EGFR exon20 ins and may provide insight into whether single agent of combination therapy is better treatment paradigm for this patient population. Despite our previous struggles in developing targeted therapies for this patient population, we are moving closer to developing targeted therapies that are both tolerable and efficacious.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/tlcr-24-786/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-786/coif). T.E.S. reports participation in advisory boards with Takeda, G1 Therapeutics, Spectrum Pharmaceuticals, Gilead Sciences, AstraZeneca, Coherus Biosciences, Blueprint Medicines, Boehringer Ingelheim, Pfizer, and Abbvie; support for attending meetings and/or travel from Pfizer; participation on a data safety monitoring board from GlaxoSmithKline; and support for clinical trials from AstraZeneca, Seagen, Mirati Therapeutics, Genentech/Roche, Nuvalent, and Inc. (Institution). 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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