Background: Mobocertinib, an oral tyrosine kinase inhibitor selectively targeting epidermal growth factor receptor (EGFR) exon 20 insertion (EGFR ex20ins) mutations, demonstrated meaningful clinical benefit in platinum-pretreated patients (PPPs) with EGFR ex20ins+ non–small-cell lung cancer (NSCLC). In a phase 1/2 study of mobocertinib 160 mg once daily, independent review committee (IRC)-confirmed objective response rate (ORR) was 28%, with a manageable safety profile. The most common adverse events (AEs) were gastrointestinal (GI) and skin-related toxicities.
Objectives: To characterize GI and skin toxicities and their management and to describe the impact of dose reductions due to AEs on efficacy of mobocertinib.
Methods: We report onset, duration, and frequency of GI (nausea, vomiting, diarrhea) and skin-related toxicities in PPPs from the phase 1/2 study (NCT02716116); explore the relationship between diarrhea and covariates; and describe AE management. We also report ORR, duration of response (DoR), and progression-free survival (PFS) per IRC in patients with and without AEs leading to dose reductions.
Results: Among 114 PPPs, 97% had ≥1 GI toxicities (all-grade and grade 3/4: diarrhea, 93% and 22%; nausea, 40% and 4%; vomiting, 41% and 3%). Few patients had GI toxicities leading to dose reduction (diarrhea: 11%; nausea: 5%; vomiting: 3%) or discontinuation (4%; 4%; and 2%, respectively). Onset was within ≤7 days in 67% of patients with all-grade diarrhea; median onset was 5 days (range: 1-253). Among patients whose diarrhea resolved (56%), median time to resolution was 2 days for all-grade events and 6.5 days for maximum grade 3 diarrhea events. Antidiarrheal medication was used in 74% of patient, most commonly, loperamide-containing medications. Statistically significant predictors of grade ≥2 diarrhea were mobocertinib plasma exposure (40-mg dose increase; hazard ratio [HR], 1.11 [95% CI, 1.04-1.19]) and age (≥75 vs <75 years; HR, 2.13 [95% CI, 1.38-3.30]). Skin-related toxicities were observed in 92% of patients (grade 3/4: 4%; dose reduced: 7%; discontinuation: <1%). Median time to onset of skin toxicities was 9 days (range: 1-309). Median time to resolution of grade 3 events was 35 days. The most common skin toxicities were rash (85%; types included: rash [46%], pruritus [25%], dermatitis acneiform [19%], and rash maculopapular [14%]), paronychia (39%), and dry skin (36%). Management commonly included skin care, topical corticosteroids (43%), and topical antibiotics (28%). Dose reductions due to AEs were reported in 29 PPPs (25%), most due to GI toxicity. Among PPPs with (n = 29) and without (n = 85) dose reductions due to AEs, ORR was 21% (95% CI, 8.0-39.7) and 31% (21.1-41.5), respectively; DoR: 5.7 months (3.7, not reached [NR]) and 17.5 months (7.4, NR); and PFS: 5.9 months (3.7-11.0) and 7.3 months (5.5-10.8) (all per IRC).
Conclusions: Diarrhea and rash, the most common AEs among mobocertinib-treated patients, typically occurred early, were mostly low grade, and were often managed with pharmaceutical interventions. Efficacy outcomes were affected by dose reductions due to AEs, primarily GI toxicity. Early recognition and proactive management of these AEs to potentially minimize dose reductions may improve outcomes with mobocertinib for PPPs with EGFR ex20ins+ NSCLC.
