First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations

Abstract

ImportanceNon–small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations.ObjectiveTo determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations.Design, Setting, and ParticipantsThis multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible.InterventionOsimertinib, 80 mg once daily, was administered orally to patients.Main Outcomes and MeasuresThe primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis.ResultsOf the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths.Conclusions and RelevanceOsimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population.Trial RegistrationJapan Registry of Clinical Trials Identifier: jRCTs071200002

Osimertinib in uncommon EGFR exon 21 L861R and EGFR exon 18 deletion-insertion mutant non-small cell lung cancer—case report

“…Similarly, the rare S768I mutation in EGFR exon 20 has also been shown to have the longest PFS of 14.7 months. Recently, both a retrospective and prospective phase 2 non-randomised study (UNICORN) demonstrated clinical activity of osimertinib in uncommon EGFR mutations with an ORR of up to 66% ( 9 , 10 ). Despite this, none of the trials included patients with EGFR exon 18 deletion-insertion (p.E709_T710) which resulted in our decision to utilise osimertinib instead of afatinib based on its superior intracranial efficacy and favourable side effect profile.…”

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO)

“…ESMO Open (2023) 40 Phase II 17/17 17 17/2/0 47% (23% to 72%) 8.7 (1.9-13.9) 94% (71% to 100%) 10.5 (3.7-15.2) 47% (23% to 72%) 0% Okuma et al. JAMA Oncol (2024) (UNICORN—Japan) 41 Phase II 40/40 40 32/8/7 55% (38.5% to 70.7%) 22.7 (9.5-NR) 90% (76.3% to 97.2%) 9.4 months (3.7-15.2) 53.1% (36% to 69%) 75% (41% to 93%) Major uEGFR: G719X, L861X, and S768I; minor uEGFR: any EGFR alteration other than major uEGFR, T790M, and classical EGFR mutations. CI, confidence interval; DCR, disease control rate; DOR, duration of response; EGFR, epidermal growth factor receptor; mPFS, median progression-free survival; NA, not available; NR, not reached; NSCLC, non-small-cell lung cancer; ORR, overall response rate; TKI, tyrosine kinase inhibitor; uEGFR, uncommon alterations of EGFR .…”

Afatinib Plus Bevacizumab Treatment for a Patient With EGFR S645C–Mutant Non–Small Cell Lung Cancer: A Case Report

“…For NSCLC with uncommon point mutations in EGFR, osimertinib yielded a 55% response rate and a median progression-free survival (PFS) of 9.4 months in the single-arm phase II UNICORN study. 13 The EGFR variants in the 40 evaluable patients included E709X, G719X, S768I, and L861Q, which are among the most frequently described uncommon mutations. In a phase III study of 109 previously untreated patients with advanced NSCLC and uncommon EGFR point mutations (excluding de novo T790M), afatinib demonstrated superior PFS (median 10.5 v 5.7 months; hazard ratio, 0.422; P 5 .0007) and a numerically higher response rate (61.4% v 47.1%, P 5 .2069) compared with platinum doublet chemotherapy (ACHILLES/TORG1834).…”