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

Author(s): Yusuke Okuma, MD, PhD¹; Kaoru Kubota, MD, PhD²; Mototsugu Shimokawa, PhD³; Kana Hashimoto, MD⁴; Yosuke Kawashima, MD⁵; Tomohiro Sakamoto, MD, PhD⁶; Hiroshi Wakui, MD, PhD⁷; Shuji Murakami, MD, PhD⁸; Kyoichi Okishio, MD, PhD⁹; Kenji Hayashihara, MD, PhD¹⁰; Yuichiro Ohe, MD, PhD¹

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

Dr. Anjan Patel's Thoughts

This study demonstrates activity of osimertinib in uncommon EGFR mutations. Of note, these were non-exon-20 mutations and included some with compound mutations. Response rates were reasonable and this justifies using targeted therapy in these uncommon subgroups.

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

Author Affiliations

¹Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; ²Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; ³Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; ⁴Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; ⁵Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; ⁶Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan; ⁷Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan; ⁸Division of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; ⁹National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan; ¹⁰National Hospital Organization Ibarakihigashi National Hospital, Tokai-mura, Naka-gun, Ibaraki, Japan

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.