Summary:

Amivantamab is the only FDA-approved therapy for non–small cell lung cancer (NSCLC) with EGFR exon 20 insertions. Unfortunately, patients eventually develop progression of disease on this therapy, and most do not respond to this treatment. In this issue of Cancer Discovery, Gonzalvez and colleagues and Riely and colleagues highlight preclinical and early clinical data supporting mobocertinib as a potentially efficacious agent for NSCLC with EGFR exon 20 insertions.

See related article by Riely et al., p. 1688.

See related article by Gonzalvez et al., p. 1672.

EGFR exon 20 insertions are found in approximately 10% of EGFR-mutant non–small cell lung cancers (NSCLC), which accounts for an estimated 2% of the total NSCLC population (1). These patients are more commonly never-smokers and 20% to 40% have brain metastases (1, 2). Amivantamab is the only FDA-approved therapy for patients with NSCLC with EGFR exon 20 insertions. However, patients eventually develop progression of disease on amivantamab, and most patients do not respond to this treatment.

Pharmacologic inhibitors that are approved for other EGFR mutations have been evaluated in patients with EGFR exon 20 insertions; unfortunately, little clinical benefit has been observed at the standard doses. These approved EGFR inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) inhibit wild-type EGFR much more strongly than many EGFR exon 20 insertions, which may limit effective dosing of patients with EGFR exon 20 insertions (3). Osimertinib at a higher dose of 160 mg daily demonstrated activity in patients with EGFR exon 20 insertions, but this was evaluated in a select patient population with small numbers (4). This increased osimertinib dose is under evaluation for EGFR exon 20 insertion–positive NSCLC, but is not approved for this indication. There are many drugs in development that are targeting EGFR exon 20 insertions. This article discusses these newer agents, with a focus on mobocertinib and its place in the emerging armamentarium against EGFR exon 20 insertions.

Mobocertinib was developed as an orally administered, irreversible inhibitor of EGFR exon 20 insertions (1, 3). Out of a panel of nearly 500 kinases, it was highly selective for EGFR. Preclinical studies in cell lines demonstrated that mobocertinib has lower IC50 against EGFR exon 20 insertions than against wild-type EGFR, which suggests stronger inhibition of EGFR exon 20 insertions than wild-type EGFR at similar doses. Western blotting and IHC demonstrated on-target effects against EGFR exon 20 insertions in both cell lines and mouse models as evidenced by dose-dependent decreases in phosphorylated EGFR and phosphorylated ERK that were greater than comparators (erlotinib, gefitinib, afatinib, or osimertinib). Additionally, mouse models of EGFR exon 20 insertion NSCLC treated with mobocertinib were observed to have significant tumor reduction, which was greater than seen with other EGFR inhibitors (e.g., erlotinib or osimertinib). However, mobocertinib was not effective in an EGFR exon 20 insertion NSCLC brain metastasis model (3).

Based on the encouraging preclinical data, Riely and colleagues evaluated mobocertinib in a phase I/II trial. The recommended phase II dose (RP2D) was determined to be 160 mg daily (1). Based on preliminary data from this trial, mobocertinib received breakthrough therapy designation by the FDA for NSCLC with EGFR exon 20 insertions. There were 28 patients with EGFR exon 20 insertion–mutant NSCLC treated at the RP2D who were evaluable for efficacy. The majority of patients received ≥ 3 prior systemic therapies for advanced disease. The confirmed objective response rate (ORR) by investigator review was 43%. These responses were durable, with a median duration of response of 14 months. The median progression-free survival (PFS) at the RP2D was 7.3 months. The ORR did not significantly differ by type of EGFR exon 20 insertion; however, the numbers were small, which precludes definitive conclusions in this regard (1). Unfortunately, no data were available on comutations (e.g., mutations in TP53) and how they may affect efficacy of mobocertinib in these patients. Additionally, there were no preclinical data provided comparing the antitumor activity of mobicertinib to amivantamab. Some patients had a response and later developed progressive disease, whereas other patients simply did not respond to mobocertinib. However, correlative data are lacking from this trial on potential mechanisms of innate or acquired resistance to mobocertinib.

Mobocertinib did not appear effective for patients with brain metastases in the phase I/II trial, which is in agreement with preclinical data (1, 3). Although the intracranial ORR was not reported, the ORR was much lower in patients with baseline brain metastases at 25% when compared with patients without baseline brain metastases who had an ORR of 56%. Patients with brain metastasis also had a much lower PFS, median 3.7 months versus 10.2 months (1). Despite not knowing how many patients developed progressive central nervous system (CNS) disease on this trial, these data do indicate a clear CNS liability for mobocertinib. This suggests that patients treated with mobocertinib should not have local therapy omitted for the management of CNS disease when such local therapy is feasible.

There were a significant number of side effects characteristic of EGFR inhibition observed on the phase I/II trial of mobocertinib, principally diarrhea and skin toxicity (1). This was despite the preclinical data demonstrating much lower IC50 for EGFR exon 20 insertions when compared with wild-type EGFR (3). Thus, there may be less selectivity for EGFR exon 20 insertions in humans than was observed in the preclinical data.

Recently, a larger data set of 114 mobocertinib-treated patients with NSCLC with EGFR exon 20 insertions and previous platinum-based chemotherapy was presented. This study demonstrated a lower ORR of only 26% by independent committee review; however, the PFS was the same as the phase I/II study discussed above. Similarly, a CNS liability was hinted at, with a lower ORR observed in patients with baseline brain metastases (2).

Standard first-line therapy for patients with stage IV NSCLC with EGFR exon 20 insertions is platinum-based doublets with or without immunotherapy. The benefit of immunotherapy alone for patients with EGFR exon 20 insertions is unclear. Similarly, whether the addition of immunotherapy to platinum-based doublets benefits patients with NSCLC with EGFR exon 20 insertions is also unknown. Thus, the current benchmark in the first-line setting is an ORR of about 50% to platinum-based doublets and a median PFS of four to six months (1). Second-line systemic therapy for these patients historically consisted of docetaxel with or without ramucirumab, with an ORR of 10% to 25% and median PFS of 3 to 4 months in molecularly unselected patients (5).

Amivantamab recently received FDA approval for NSCLC with EGFR exon 20 insertions. This drug is an intravenously administered bispecific antibody targeting EGFR and c-MET. A phase II trial of amivantamab demonstrated efficacy in 81 previously treated patients with an ORR by independent review committee of 40%, a median PFS of 8.3 months, and a median overall survival of 22.8 months (6). Amivantamab appears to have fewer grade ≥ 3 treatment-related adverse events in cross-trial comparisons versus mobocertinib, 16% versus 40% to 46% (1, 2, 6). Amivantamab was approved without a line of therapy restriction. While we do not yet have efficacy data on this agent in the first-line setting, some providers may treat patients with amivantamab in the first-line setting given its better side-effect profile when compared with platinum-based doublets with or without immunotherapy. It is possible amivantamab may be more efficacious than platinum-based doublet regimens in the first line given its similar effectiveness in previously treated patients. Currently, this agent is being evaluated in a phase III trial in combination with platinum-based doublets versus platinum-based doublets alone (NCT04538664).

Other novel agents are being evaluated for this patient subgroup. DZD9008 and CLN-081 have yet to report results. Although larger trials evaluating poziotinib for this patient population have been reported, these trials have not demonstrated a practice-changing efficacy signal (7).

How will we utilize mobicertinib if it later becomes available outside of clinical trials? Some previously treated patients and/or their providers may prefer the lack of intravenous administration and opt for mobocertinib. However, many patients and/or providers will be utilizing mobocertinib following progression of disease on amivantamab. Given the different mechanisms of action, it is not anticipated there will be much cross-resistance between these newer therapies. Thus, efficacy of mobocertinib following amivantamab may very well be similar to what has been highlighted above. Whether either of these drugs will have a future place in first-line therapy remains to be seen, with ongoing trials evaluating this question.

The efficacy data observed with mobocertinib or amivantamab monotherapy are not what we would expect to see of a highly effective targeted therapy (e.g., alectinib or lorlatinib in ALK fusions or osimertinib in classic EGFR mutations). Thus, better patient selection and/or novel combinations with these EGFR exon 20 therapies may be needed. Additionally, effective therapies targeting EGFR exon 20 insertions that have good CNS penetrance are urgently needed. Preclinical data on other targets have suggested that combining tyrosine kinase inhibitors and antibody-based therapies against the same receptor may have enhanced and/or synergistic efficacy when compared with either monotherapy (8). Thus, whether combination mobocertinib and amivantamab will have a role in future patient management remains to be determined. Caution should be advised, however, if this combination is evaluated due to potential overlapping EGFR-related toxicities. The development of mobocertinib is an advancement for patients with NSCLC with EGFR exon 20 insertions. However, there is still much work left to be done to improve therapies for this patient subgroup.

J.M. Pacheco reports personal fees from Takeda outside the submitted work, consulting fees from AstraZeneca, Blueprint Medicine, Gerson Lehrman Group, Hengrui Pharmaceuticals, Jazz Pharmaceuticals, Novartis, and Pfizer, honorarium from Genentech, and research funds from Pfizer.

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