A multicentre, open-label, single-group, phase II non-randomised UNICORN study met its primary endpoint, with osimertinib showing clinical activity with manageable side effects in previously untreated patients with metastatic non-small cell lung cancer (NSCLC) harbouring uncommon EGFR mutations other than the exon 20 insertion. The overall response rate (ORR) was 55.0%, a median progression-free survival (PFS) was 9.4 months, and a median duration of response (DoR) was 22.7 months.
First-line osimertinib may be a promising treatment option in this population according to Dr. Yusuke Okuma of the Department of Thoracic Oncology, National Cancer Center Hospital in Tokyo, Japan, and colleagues from the Tokyo Cooperative Oncology Group (TCOG) who reported the findings on 22 November 2023 in the JAMA Oncology.
The authors explained in the background that EGFR mutations occur among 30-35% of East Asian and 10-15% of White patients. Two subtypes of common EGFR mutations are exon 19 deletion occurring in 40-50% of cases and exon 21 L858R substitution in 30-40% of cases. The remaining 14% of mutations are termed uncommon EGFR mutations and consist of exon 20 insertions (5%) and other mutations in exons 18 to 21 with exon 18 G719X, exon 20 S768I, and exon 21 L861Q being representative. Approximately 14% of uncommon EGFR mutations coexist with other EGFR mutations, either with other common EGFR mutations or with other uncommon EGFR mutations, and together are termed compound mutations.
Common EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs) with RR of 60-70% and PFS of 9-19 months. Uncommon EGFR mutations represent a range of diverse mutations, and the rarity of individual mutations is a barrier to drug development. Although first-generation EGFR TKIs are insufficiently effective for this patient population, afatinib, a second-generation EGFR TKI, was approved by the US Food and Drug Administration. Osimertinib, a third-generation EGFR TKI, provided better clinical benefits and milder side effects than first-generation EGFR TKIs in the FLAURA study for common EGFR mutations.
However, osimertinib efficacy appears limited for uncommon EGFR mutations, with a reported RR of 50% and PFS of 8.2 months in previous studies. Notably, 39% of patients in these studies were previously untreated with chemotherapy. Therefore, the efficacy of osimertinib for uncommon EGFR mutations may have been underestimated for patients previously treated with chemotherapy and overestimated by investigator or retrospective assessment.
To address these limitations, the Japanese investigators conducted UNICORN (Uncommon EGFR Mutations Conducted With Osimertinib in Patients With NSCLC), multicentre, open-label, single-group, phase II study of osimertinib among patients with previously untreated NSCLC harbouring uncommon EGFR mutations other than exon 20 insertions. Patients have been enrolled from 10 April 2020 to 31 May 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. Patients received osimertinib, 80 mg once daily.
The primary endpoint was the ORR. The secondary endpoints were disease control rate (DCR), PFS, time to treatment failure (TTF), overall survival (OS), DoR, and safety of osimertinib. Patients were included in the study on an intention-to-treat basis.
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 (50.0%), S768I (25.0%), and L861Q (20.0%). The ORR was 55.0% (90% confidence interval [CI] 40.9%-68.5%).
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%). 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). Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI 12.3 months to NR) and NR. 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).
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.
The authors commented about the study limitations, including the small sample size, inclusion of only one ethnicity, the small number of patients with each subtype of uncommon EGFR mutations, and lack of investigation of the mechanisms of resistance to osimertinib. Owing to the nature of uncommon EGFR mutations, the results are inconsistent, including heterogeneous subtypes of mutations. However, this is a common problem when conducting clinical trials among rare tumours.
An ongoing phase III study of uncommon EGFR mutation–positive NSCLC will compare afatinib and platinum-based chemotherapy based on the size effect. As an additional phase III study comparing osimertinib and afatinib is unlikely, the findings from the UNICORN study are the first to confirm first-line osimertinib as a treatment option for previously untreated patients with NSCLC and uncommon EGFR mutations.
Future studies should include more patients, particularly those for whom osimertinib’s capacity for central nervous system control may be demonstrated. Circulating tumour DNA could be used to track responses and investigate the mechanisms of resistance in tumour and/or serum samples when progression occurs among patients with uncommon EGFR mutations.
In an invited commentary, Drs. Victoria E. Wang of the Department of Medicine and Helen Diller Comprehensive Cancer Center, University of California in San Francisco, CA, US, and Justin F. Gainor of the Department of Medicine, Massachusetts General Hospital in Boston, MA, US wrote that we are approaching the twentieth anniversary of the discovery of EGFR mutations in NSCLC, a finding that catalyzed a new paradigm of precision medicine. Uncommon EGFR mutations were generally excluded from early clinical trials of osimertinib, but several studies have since emerged.
In an international, retrospective case series of 60 patients with uncommon EGFR mutations, osimertinib was associated with an ORR of 61% and median PFS of 9.5 months. In a prospective phase II KCSG-LU15-09 study that enrolled 37 patients with atypical EGFR mutations treated with osimertinib in Korea, the ORR and median PFS were 50% and 8.2 months. Together with the UNICORN, these studies demonstrate consistent results and support consideration of osimertinib for patients with uncommon EGFR mutations.
A critical question moving forward is whether all uncommon EGFR mutations should be treated using the same approach. The short answer according to the commentators is no. Atypical EGFR mutations represent a diverse and heterogenous group, and treatment of these patients using small molecules must be individualised, accounting for the molecular nature of each mutation and its functional impact on the protein and drug interaction to guide treatment.
The UNICORN study highlights that for rare mutations where randomised clinical studies are not readily available, well-conducted, prospective single-arm studies may provide important insights. In addition, real-world series/registries and basket trials, may be important to examine the activity of targeted therapies on increasingly rare molecular subgroups. Next-generation sequencing should be broadly applied to improve identification of these mutations (and other oncogenic drivers), since some EGFR alterations (e.g. E709X, exon 20, and kinase domain duplications) may be missed using polymerase chain reaction alone.
Despite continued advances in the management of advanced, EGFR-mutated NSCLC, patients continue to relapse while undergoing targeted therapies. Recent strategies to augment the activity of TKIs with novel combinations have offered hope for improving existing standards. Such strategies have included combinations with chemotherapy, bispecific antibodies, and antibody drug conjugates. While most of these approaches are initially being explored in patients with classic EGFR mutations, such antibody-based therapeutics have the potential to inhibit a broad array of EGFR mutations, both classic and atypical, due to their ability to promote receptor internalisation and target downregulation in a mutation agnostic manner.
The UNICORN study was an investigator-initiated study receiving financial support from AstraZeneca. The study was sponsored by the TCOG and supported by the Clinical Research Support Center Kyushu in receiving assistance with data management and other support.
References
- Okuma Y, Kubota K, Shimokawa M, et al. and the Tokyo Cooperative Oncology Group (TCOG). First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations The UNICORN Phase 2 Nonrandomized Clinical Trial. JAMA Oncology; Published online 22 November 2023. doi: 10.1001/jamaoncol.2023.5013.
- Wang VE, Gainor JF. Osimertinib in Patients With Non–Small Cell Lung Cancer and Uncommon EGFR Mutations—Chasing Unicorns? JAMA Oncology; Published online 22 November 2023. doi: 10.1001/jamaoncol.2023.5004