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

Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations

“…Mobocertinib at 160 mg daily was chosen as the maximum tolerated dose and the recommended phase 2 dose (RP2D). 5 Pharmacokinetic data showed mobocertinib had a median time to maximum plasma concentrations (T max ) of 4 hours and a geometric mean effective half-life of 11-17 hours across the 20 to 160 mg daily dosing based on accumulation. Following administration of mobocertinib from 5 to 180 mg orally daily, the area under the concentration-time curve from time 0 to 24 hours (AUC 0-24 ) increased in a dose-dependent manner.…”

“…Dose interruption, dose reduction, and dose discontinuation was seen in 74 (54%), 23 (17%), and 22 (16%) patients, respectively. 5 The efficacy of mobocertinib was assessed among 70 previously treated NSCLC patients harboring EGFR ex20ins mutations from both the phase 1 and the phase 2 portions, including 12 patients in 5-40mg daily cohorts, nine in 80 mg total daily (80 mg daily and 40 mg twice daily), 21 in 120 mg daily, and 28 in 160 mg daily. 5 More specifically, these 28 patients treated with mobocertinib at 160 mg daily had not received (N = 22) or responded (N = 6) to a previous EGFR TKI.…”

“…5 The efficacy of mobocertinib was assessed among 70 previously treated NSCLC patients harboring EGFR ex20ins mutations from both the phase 1 and the phase 2 portions, including 12 patients in 5-40mg daily cohorts, nine in 80 mg total daily (80 mg daily and 40 mg twice daily), 21 in 120 mg daily, and 28 in 160 mg daily. 5 More specifically, these 28 patients treated with mobocertinib at 160 mg daily had not received (N = 22) or responded (N = 6) to a previous EGFR TKI. The confirmed objective response rate (ORR) and disease control rate (DCR) by investigator assessment (IA) were 0% and 25% for 5-40mg daily cohorts, 22% and 89% for 80 mg total daily, 19% and 71% for 120 mg daily, respectively.…”

An open-label expanded access program of afatinib in EGFR tyrosine kinase inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations

“…Osimertinib has also demonstrated activity against uncommon activating EGFR mutations in a single-arm phase II study [25]. Treatment options for exon 20 mutations remain an unmet need, but several agents are in clinical development such as poziotinib and mobocertinib which has shown promise in phase II trials [26,27].…”

Real-world Outcomes of First-line Afatinib in Patients with Non-small Cell Lung Cancer and Uncommon EGFR Mutations in South Korea

“…For example, a phase III study of mobocertinib (TAK-788), a novel, irreversible, small-molecule EGFR inhibitor speci cally designed to target exon 20 insertion mutants, has been conducted in patients with advanced NSCLC harboring these mutations 33 . Preclinical data and phase I/II studies have reported that mobocertinib demonstrates antitumor activity with manageable toxicity in patients with advanced EGFR exon 20 insertion mutations 33,34 . Furthermore, the phase 1 CHRYSALIS trial (NCT02609776) showed that amivantamab, a bispeci c antibody directed against EGF and MET receptors, induces an objective response in 40% of patients with previously treated NSCLC harboring EGFR exon 20 insertion mutations, with 47% maintaining their response for at least 6 months and 47% remaining on therapy after a median follow-up of over 9 months 35 .…”