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. 2024 Jan 1;10(1):43-51.
doi: 10.1001/jamaoncol.2023.5013.

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial

Yusuke Okuma  1 , Kaoru Kubota  2 , Mototsugu Shimokawa  3 , Kana Hashimoto  4 , Yosuke Kawashima  5 , Tomohiro Sakamoto  6 , Hiroshi Wakui  7 , Shuji Murakami  8 , Kyoichi Okishio  9 , Kenji Hayashihara  10 , Yuichiro Ohe  1 ; Tokyo Cooperative Oncology Group (TCOG)
Affiliations

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial

Yusuke Okuma et al. JAMA Oncol. .

Abstract

Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations.

Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations.

Design, setting, and participants: This 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.

Intervention: Osimertinib, 80 mg once daily, was administered orally to patients.

Main outcomes and measures: The 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.

Results: Of 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 relevance: Osimertinib 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 registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Okuma reported receiving personal fees from AstraZeneca, Chugai Pharma, Eli Lilly, Eisai, Ono Pharmaceutical, Takeda, and Taiho Pharmaceutical and grants from AbbVie GK and Merck Sharp & Dohme outside the submitted work. Dr Kubota reported receiving personal fees from Taiho Pharmaceutical, Pfizer, Chugai, Ono, AstraZeneca, Shionogi, Merck, Eli Lilly, Novartis, MSD, Kyowa-Kirin, Bristol Myers Squibb, Sawai, Nippon Boehringer Ingelheim, Nihon Kayaku, and Takeda outside the submitted work. Dr Hashimoto reported receiving honoraria for lectures from AstraZeneca. Dr Kawashima reported receiving personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical Co, Eli Lilly and Co, AstraZeneca, Life Technologies Japan Ltd, and Kyowa Kirin Co Ltd outside the submitted work. Dr Sakamoto reported receiving personal fees from Chugai Pharmaceutical Co Ltd, Eli Lilly Japan KK, and Novartis Pharma KK and personal fees from Ono Pharmaceutical Co Ltd, MSD KK, Janssen Pharmaceutical KK, AstraZeneca KK, Kyowa Kirin Co Ltd, Merck KGaA, Novartis Pharma KK, Takeda Pharmaceutical Co Ltd, Taiho Pharmaceutical Co Ltd, Amgen Inc, Illumina KK, Pfizer Japan Inc, Hisamitsu Pharmaceutical Co Inc, and Daiichi Sankyo Co Ltd outside the submitted work. Dr Wakui reported receiving personal fees from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharma, Pfizer, Taiho Pharma, Takeda Pharma, and UCB outside the submitted work. Dr Murakami reported receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda Pharmaceutical, and Eli Lilly outside the submitted work. Dr Okishio reported receiving personal fees from Bristol Myers Squibb KK, AstraZeneca KK, Chugai Phamaceutical Co Ltd, Nippon Kayaku Co Ltd, Takeda Pharmaceutical Co Ltd, Taiho Pharmaceutical Co Ltd, and Sawai Pharmaceutical Co Ltd outside the submitted work. Dr Ohe reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from Eisai, Celtrion, Ono, BMS, Takeda, MSD, and Daiichi Sankyo; grants from AnHeart Therapeutics; and personal fees and grants from Chugai, Lilly, and Janssen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Flowchart
Figure 2.
Figure 2.. Changes in Tumor Size With Mutation Information and Patients Who Had an Osimertinib-Associated Response
A, Waterfall plot: best percentage change with osimertinib in target lesions from baseline by independent review. The horizontal dashed line indicates the borderline between partial response (PR) and stable disease (SD). B, Swimmer’s plot of all patients, arranged by survival: time to response and duration of response. AEs indicates adverse effects; PACC, P-loop and αC-helix compressing; NE, not evaluable; and PD, progressive disease.
Figure 3.
Figure 3.. Time to Event Data in Patients With Metastatic Non–Small Cell Lung Cancer Harboring Uncommon EGFR Mutations (Excluding Exon 20 Insertions) Treated With First-Line Osimertinib
A, Progression-free survival (PFS). B, Time to treatment failure (TTF). C, Overall survival (OS). D, Duration of response (DoR); reported for the 22 of 40 patients who were responders. NR indicates not reached.
See this image and copyright information in PMC

Comment in

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