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

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer

There was a 28% reduction in mortality. Patients who achieved a complete response (CR) or clearance of circulating tumor DNA (ctDNA) also experienced better outcomes.