ASCO Issues Updated Guidelines for Stage IV NSCLC With and Without Driver Alterations

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ASCO has issued new evidence-based updates to two living guidelines on the treatment of stage IV NSCLC with and without driver alterations.1,2

Updated Recommendations: Stage IV NSCLC With Driver Alterations

The most “extensive work” in the updates occurred in the guideline on stage IV NSCLC with driver alterations, said Expert Panel Co-Chair Jyoti D. Patel, MD, of Northwestern Medicine. “There have been a number of studies that have read out that absolutely changed our standard of care for patients,” she added.

Jyoti D. Patel, MD

Jyoti D. Patel, MD

These studies include the FLAURA2 study, which found significant improvements in progression-free survival with continuous upfront chemotherapy added to first-line osimertinib in patients with classic sensitizing EGFR mutations.3 The positive data from this study are reflected in the guideline recommendations.

Recommendations for osimertinib are made for patients with exon 19 deletion and exon 21 L858R substitution, whereas osimertinib or afatinib is recommended for patients with other activating EGFR alterations such as G719X, L861Q, and S768I.1

Dr. Patel noted that the current knowledge gaps relate to how these strategies impact overall survival and subsequent therapy. Additionally, for patients with EGFR mutations who have concerns about disease progression, Dr. Patel said the addition of chemotherapy may lengthen the time until the cancer progresses.

However, Dr. Patel explained that there are cost considerations for receiving infusions every 3 weeks. In addition, there are side effects of additional chemotherapy, such as fatigue and the lowering of blood counts.

Dr. Patel added that there have also been several trials reported in the past year that highlight the benefit of adding other therapies, such as bispecific antibodies, to intensify initial therapy.

In patients with an exon 20 insertion alteration, for instance, the guideline suggests the use of chemotherapy and the bispecific antibody amivantamab-vmjw, based on data from the phase III PAPILLON trial.1 The trial, which compared first-line treatment with amivantamab plus carboplatin and pemetrexed chemotherapy vs chemotherapy alone, reported improvement in progression-free survival and response rates for patients with EGFR exon 20 insertion alterations.4

Several other treatment recommendations are made for ALK, ROS1, BRAF V600E, MET exon 14 skipping mutation, RET and NTRK rearrangements, HER2, and KRAS G12C mutations.

Updated Recommendations: Stage IV NSCLC Without Driver Alterations

Recommendations in the guideline on therapy for stage IV NSCLC without driver alterations have been divided according to PD-L1 status/expression. For squamous and nonsquamous cell carcinomas, the guideline recommends the use of single-agent pembrolizumab, cemiplimab-rwlc, or atezolizumab in patients with PD-L1 expression tumor proportion score (TPS) ≥ 50%. This recommendation is supported by data from the phase III KEYNOTE-024 (pembrolizumab), EMPOWER-Lung 1 (cemiplimab), and IMpower110 (atezolizumab) trials.5-7

For patients with PD-L1 expression and TPS between 1% and 49%, the guideline also recommends the use of pembrolizumab plus carboplatin and pemetrexed or cemiplimab plus carboplatin and pemetrexed in nonsquamous cell carcinoma. These recommendations are based on data from the phase III KEYNOTE-407 and EMPOWER-Lung 3 trials.8,9

The guideline makes several treatment recommendations for patients with nonsquamous cell carcinoma and unknown or negative PD-L1 expression and a TPS of 0%, including nivolumab and ipilimumab, in addition to antibody and chemotherapy combinations. The recommendation for nivolumab and ipilimumab was based on data from the phase III CheckMate 227 trial.10

Platinum doublet chemotherapy is recommended for patients previously treated with immune checkpoint therapy without chemotherapy. For patients who have previously been treated with chemotherapy and immune checkpoint therapy, the guideline recommends docetaxel with or without ramuciru­mab, pemetrexed, or gemcitabine.

Shared Recommendations

Dr. Patel noted that one of the most important aspects of care in advanced-stage NSCLC with or without driver alterations is the application of appropriate molecular testing. “All treatment comes from understanding the genetic profile of the patient,” she commented, “and that’s stressed in both of these guidelines.”

Dwight H. Owen, MD

Dwight H. Owen, MD

As such, the guideline on therapy for stage IV NSCLC with driver alterations recommends that all biomarkers should be available at the time of treatment decision-making.1 “Although this is not a new recommendation, the Expert Panel continues to strongly reinforce this given the complex landscape of targetable alterations and the importance of offering the most effective treatment first,” said Expert Panel Co-Chair Dwight H. Owen, MD, of The Ohio State University Comprehensive Cancer Center–James.

In addition, the guideline on therapy for stage IV ­NSCLC without driver alterations highlights the importance of expanded molecular testing in patients with advanced NSCLC, including actionable alterations that have recently emerged, such as KRAS G12C55 or ERBB2 mutations, to guide treatment decisions beyond first-line therapy.

Both guidelines also touch upon out-of-pocket cost considerations for patients, and how these costs represent a barrier to treatment initiation and adherence. The guidelines suggest that clinicians should perform a routine financial toxicity assessment and discuss with patients any financial issues in accessing care.

Additionally, the two living guidelines discuss potential health disparities in treatment access as well as clinical care and outcomes. For instance, the guidelines note that many members of racial and ethnic minority groups experience a disproportionate number of comorbidities, face several obstacles to care access, and are less likely to be insured, and individuals in rural regions are less likely to live conveniently near appropriate treatment facilities compared with urban residents.

Given the number of identified health disparities, the guidelines emphasize clinician awareness of treatment challenges in different populations and suggest that both health-care providers and health care systems should strive for high-quality care for vulnerable populations. 


1. Jaiyesimi IA, Leighl NB, Ismaila N, et al: Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, version 2023.3. J Clin Oncol 42:e1-e22, 2024.

2. Jaiyesimi IA, Leighl NB, Ismaila N, et al: Therapy for stage IV non-small cell lung cancer without driver alterations: ASCO living guideline, version 2023.3. J Clin Oncol 41:e51-e62, 2023.

3. Planchard D, Jänne PA, Cheng Y, et al: Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 389:1935-1948, 2023.

4. Zhou C, Tang KJ, Cho BC, et al: Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med 389:2039-2051, 2023.

5. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol 39:2339-2349, 2021.

6. Özgüroğlu M, Kilickap S, Sezer A, et al: First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1). Lancet Oncol 24:989-1001, 2023.

7. Jassem J, de Marinis F, Giaccone G, et al: Updated overall survival analysis from IMpower110. J Thorac Oncol 16:1872-1882, 2021.

8. Novello S, Kowalski DM, Luft A, et al: Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer. J Clin Oncol 41:1999-2006, 2023.

9. Gogishvili M, Melkadze T, Makharadze T, et al: Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer. Nat Med 28:2374-2380, 2022.

10. Brahmer JR, Lee JS, Ciuleanu TE, et al: Five-year survival outcomes with nivolu­mab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol 41:1200-1212, 2023.

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, February 29, 2024. All rights reserved.