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

Abstract

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

©2021 American Association for Cancer Research.

Figures

Figure 1.

Schema for the dose-escalation phase of the phase 1/2 trial of mobocertinib. The dose-escalation phase followed a conventional 3+3 design. The dose level for each new cohort was up to 100% higher than the dose level in the previous cohort until a grade 2 drug-related toxicity of diarrhea or skin rash occurred, based on expected class effects for EGFR TKIs, or until other DLTs were identified. Further dose escalation involved increments of ≤50% of the previous dose, depending on safety findings Abbreviations: bid, twice daily; DLTs, dose-limiting toxicities; EGFR, epidermal growth factor receptor; EGFR, epidermal growth factor receptor gene; MTD, maximum tolerated dose; daily, once daily; RP2D, recommended phase 2 dose a Seven patients were enrolled in the dose escalation to evaluate DLT; additional patients were included to further confirm safety observations.

Figure 2.

Mean plasma concentrations of mobocertinib A. following the first oral administration of mobocertinib on Cycle 1, Day 1 and B. following repeated oral dosing on Cycle 2, Day 1 in patients with NSCLC in the dose-escalation study (semi-log scale). Abbreviations: NSCLC, non–small cell lung cancer. Preliminary pharmacokinetic data as January 27, 2020.

Figure 3.

Response to mobocertinib in patients with EGFRex20ins mutations treated at 160 mg daily (n=28). A. Best percentage change from baseline in target lesions by molecular subtype. Mutations by patient are shown under the figure. B. Plot showing objective responses by time on treatment and baseline CNS metastases status. Three patients were excluded from these plots: 1 patient had nonmeasurable baseline target lesions, and 2 patients had no follow-up scans. Abbreviations: CNS, central nervous system, EGFRex20ins, epidermal growth factor receptor gene exon 20 insertion; IO, immune-oncology therapy; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor. a Active brain metastases were either never treated or progressed after radiation.