ASCO has updated two living guidelines on the systemic treatment of stage IV non–small cell lung cancer (NSCLC) with and without driver alterations with the inclusion of new evidence-based treatment recommendations.1,2 Among the updates, the guidelines add the recently approved RAS GTPase family inhibitor adagrasib and a newly approved monoclonal antibody combination regimen to the recommended treatment landscape for select patients with NSCLC.
Updated Recommendations: Stage IV NSCLC With Driver Alterations
For the new version of the guidelines, the panel reviewed several new studies to inform the updated recommendations. However, only one study was identified during the literature search of stage IV NSCLC with driver alterations: the open-label, phase I/II KRYSTAL-1 study (ClinicalTrials.gov identifier NCT03785249) of adagrasib in patients with NSCLC and KRAS G12C–mutated solid tumors.
The study found that twice-daily treatment with 600 mg of adagrasib in patients with KRAS G12C–mutated solid tumors was associated with a confirmed overall response rate of 42.9%, a median progression-free survival of 6.5 months, and a median overall survival of 11.7 months.3
Based on the efficacy and safety data from the KRYSTAL-1 study, the U.S. Food and Drug Administration (FDA) approved adagrasib in December 2022 for the treatment of adults with KRAS G12C–mutated locally advanced or metastatic NSCLC.4
“The development in NSCLC continues daily, and it’s truly an exciting time,” said guideline Expert Panel Co-Chair Ishmael A. Jaiyesimi, DO, MS, of Corewell Health William Beaumont University Hospital. “One needs to continue to be vigilant daily for the new advances.”
Ishmael A. Jaiyesimi, DO, MS
Given the positive data from KRYSTAL-1 and the subsequent approval by the FDA, the guideline now recommends that clinicians may offer single-agent adagrasib to patients with advanced NSCLC and a KRAS G12C mutation who have received prior systemic therapy with chemotherapy and anti–PD-L1 therapy. The evidence quality of the evidence-based recommendation is low, and the strength of recommendation is ranked as weak.
In addition to adagrasib, the guideline also recommends sotorasib monotherapy as another option for patients with advanced NSCLC and a KRAS G12C mutation who have received prior systemic therapy, based on data from the phase II CodeBreaK 100 trial.5 This is an unchanged recommendation from a previous version of the guideline.
Updated Recommendations: Stage IV NSCLC Without Driver Alterations
Considering recently published clinical trial data, the ASCO living guideline on stage IV NSCLC without driver alterations now recommends that clinicians may offer cemiplimab-rwlc plus chemotherapy in patients with squamous cell carcinoma and nonsquamous cell carcinoma who have a PD-L1 tumor proportion score (TPS) of 0% to 49% and a performance status (PS) of 0 to 1.
This recommendation is based on results from the phase III EMPOWER-Lung 3 study, which evaluated cemiplimab plus platinum-doublet chemotherapy as a first-line treatment strategy in patients with advanced NSCLC, irrespective of PD-L1 expression or histology and without EGFR, ALK, or ROS1 alterations.6 In this study, treatment with cemiplimab plus chemotherapy was associated with a median overall survival of 21.9 months compared with 13.0 months with placebo plus chemotherapy.6
In November 2022, the FDA approved the treatment combination comprising cemiplimab plus platinum-based chemotherapy for the treatment of adults with advanced NSCLC with no EGFR, ALK, or ROS1 aberrations, based on data from the EMPOWER-Lung 3 study.7
Durvalumab and tremelimumab plus platinum-based chemotherapy may also be offered to patients with squamous cell carcinoma and nonsquamous cell carcinoma who have a PD-L1 TPS of 0% to 49% and a PS of 0 to 1, according to new recommendations in the updated guideline. The recommendations for double immunotherapy with combination chemotherapy were based on data from the open-label, phase III POSEIDON study. In this study, patients with metastatic NSCLC who received tremelimumab, durvalumab, and chemotherapy as first-line treatment had a median overall survival of 14.0 vs 11.7 months in patients who received chemotherapy alone.8
Data from the POSEIDON study provided the basis for an FDA approval in November 2022 for tremelimumab in combination with durvalumab and platinum-based chemotherapy for the treatment of adults with metastatic NSCLC and no sensitizing EGFR mutation or ALK genomic tumor aberrations.9
Evidence quality for these evidence-based recommendations in NSCLC without driver alterations were rated moderate with a weak strength of recommendation.
“Living guidelines continue to be important in NSCLC, like in other areas of cancer medicine, due to new advances and developments in immune checkpoint inhibitors with and without chemotherapy and targeted therapy,” Dr. Jaiyesimi said.
Guideline Panel Co-Chair Dwight H. Owen, MD, MS, of The Ohio State University, Columbus, explained that the current guidelines represent “an up-to-date, accurate, and evidence-based” resource that is particularly important for stage IV NSCLC, given that “the field is moving at such a rapid pace.”
Dwight H. Owen, MD, MS
“As we continue to review these data, we will reevaluate those recommendations,” Dr. Owen added. “I think we are continually reassessing the methodology for identifying and prioritizing data…,so we are continually trying to find ways to make that transparent as to when we are basing evidence-based decisions on high-quality evidence vs when we are less certain.”
Dr. Owen suggested that as the pace of development in NSCLC management options quickens, there will be a greater push toward making future recommendations “relevant but not overburdensome,” and providing recommendations that are accessible and ultimately helpful for oncologists and for practitioners “to help them make the best decisions with their patients.”
1. Singh N, Jaiyesimi IA, Ismaila N, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, version 2023.1. J Clin Oncol. April 6, 2023 (early release online).
2. Singh N, Jaiyesimi IA, Ismaila N, et al: Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO living guideline, version 2023.1. J Clin Oncol. April 6, 2023 (early release online).
3. Jänne PA, Riely GJ, Gadgeel SM, et al: Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med 387:120-131, 2022.
4. U.S. Food and Drug Administration: FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc. Accessed March 20, 2023.
5. Li B, Skoulidis F, Falchook G, et al: Registrational phase 2 trial of sotorasib in KRAS p.G12C mutant NSCLC: First disclosure of the CodebreaK 100 primary analysis. J Thorac Oncol 16(suppl): Abstract PS01, 2021.
6. Gogishvili M, Melkadze T, Makharadze T, et al: Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: A randomized, controlled, double-blind phase 3 trial. Nat Med 28:2374-2380, 2022.
7. U.S. Food and Drug Administration: FDA approves cemiplimab-rwlc in combination with platinum-based chemotherapy for non-small cell lung cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-combination-platinum-based-chemotherapy-non-small-cell-lung-cancer. Accessed March 20, 2023.
8. Johnson ML, Cho BC, Luft A, et al: Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: The phase III POSEIDON study. J Clin Oncol 41:1213-1227, 2023.
9. U.S. Food and Drug Administration: FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non. Accessed March 20, 2023.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, April 7, 2023. All rights reserved.