Central Nervous System Outcomes of Lazertinib Versus Gefitinib in EGFR-Mutated Advanced NSCLC: A LASER301 Subset Analysis

Author(s): Ross A. Soo, MBBS, PhD¹; Byoung Chul Cho, MD, PhD²; Joo-Hang Kim, MD³; Myung-Ju Ahn, MD, PhD⁴; Ki Hyeong Lee, MD⁵; Anastasia Zimina, MD⁶; Sergey Orlov, MD⁷; Igor Bondarenko, MD, PhD⁸; Yun-Gyoo Lee, MD⁹; Yueh Ni Lim, MD¹⁰; Sung Sook Lee, MD¹¹; Kyung-Hee Lee, MD, PhD¹²; Yong Kek Pang, MD¹³; Chin Heng Fong, MD¹⁴; Jin Hyoung Kang, MD¹⁵; Chun Sen Lim, MD¹⁶; Pongwut Danchaivijitr, MD¹⁷; Saadettin Kilickap, MD¹⁸; James Chih-Hsin Yang, MD, PhD¹⁹; Cagatay Arslan, MD²⁰; Hana Lee, MS²¹; Seong Nam Park, MPH²¹; Irfan Cicin, MD²²

Source: https://doi.org/10.1016/j.jtho.2023.08.017

Dr. Maen Hussein's Thoughts

Lazertinib, third generation EGFR inhibitor, has good activity in patients with brain mets promising…

INTRODUCTION

Lazertinib, a third-generation mutant-selective EGFR tyrosine kinase inhibitor, improved progression-free survival compared with gefitinib in the phase 3 LASER301 study (ClinicalTrials.gov Identifier: NCT04248829). Here, we report the efficacy of lazertinib and gefitinib in patients with baseline central nervous system (CNS) metastases.

METHODS

Treatment-naive patients with EGFR–mutated advanced NSCLC were randomized one-to-one to lazertinib (240 mg/d) or gefitinib (250 mg/d). Patients with asymptomatic or stable CNS metastases were included if any planned radiation, surgery, or steroids were completed more than 2 weeks before randomization. For patients with CNS metastases confirmed at screening or subsequently suspected, CNS imaging was performed every 6 weeks for 18 months, then every 12 weeks. End points assessed by blinded independent central review and Response Evaluation Criteria in Solid Tumors version 1.1 included intracranial progression-free survival, intracranial objective response rate, and intracranial duration of response.

RESULTS

Of the 393 patients enrolled in LASER301, 86 (lazertinib, n = 45; gefitinib, n = 41) had measurable and or non-measurable baseline CNS metastases. The median intracranial progression-free survival in the lazertinib group was 28.2 months (95% confidence interval [CI]: 14.8–28.2) versus 8.4 months (95% CI: 6.7–not reached [NR]) in the gefitinib group (hazard ratio = 0.42, 95% CI: 0.20–0.89, p = 0.02). Among patients with measurable CNS lesions, the intracranial objective response rate was numerically higher with lazertinib (94%; n = 17) versus gefitinib (73%; n = 11, p = 0.124). The median intracranial duration of response with lazertinib was NR (8.3–NR) versus 6.3 months (2.8–NR) with gefitinib. Tolerability was similar to the overall LASER301 population.

CONCLUSIONS

In patients with CNS metastases, lazertinib significantly improved intracranial progression-free survival compared with gefitinib, with more durable responses.

Author Affiliations

¹Department of Haematology-Oncology, National University Cancer Institute, Singapore; ²Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; ³CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; ⁴Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ⁵Division of Medical Oncology, Department of Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea; ⁶State Budgetary Healthcare Institution of Omsk Region, Omsk, Russia; ⁷Pavlov State Medical University, Ulitsa L’va Tolstogo, St. Petersburg, Russia; ⁸Oncology and Medical Radiology Department, Dnipropetrovsk Medical Academy, Dnipro, Ukraine; ⁹Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ¹⁰Hospital Umum Sarawak, Jalan Hospital, Kuching, Malaysia; ¹¹Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; ¹²Division of Hematology/Oncology, Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea; ¹³University Malaya Medical Centre, University of Malaya, Petaling Jaya, Malaysia; ¹⁴Hospital Pulau Pinang, Pulau Pinang, Malaysia; ¹⁵Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; ¹⁶Oncology Department, Hospital Sultan Ismail, Jalan Mutiara Emas Utama, Johor, Malaysia; ¹⁷Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ¹⁸Department of Medical Oncology, İstinye University Faculty of Medicine, Liv Hospital Ankara, Ankara, Turkey; ¹⁹National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei City, Taiwan; ²⁰Department of Medical Oncology, Izmir University of Economics Medical Point Hospital, İzmir, Turkey; ²¹Yuhan Corporation, Seoul, Republic of Korea; ²²Department of Medical Oncology, Trakya University Medical Center, Edirne, Turkey

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.