The Phase 3 Non-Small Cell Lung Cancer (NSCLC) Treatment ASCO Guidelines has recently been updated, with the revisions based on the results of the Phase 3 LAURA trial. The findings were presented at the 2024 ASCO Annual Meeting and published simultaneously in the New England Journal of Medicine [1, 2]. The new guidelines include a recommendation to use the EGFR-TKI osimertinib in patients with unresectable Stage III NSCLC who have EGFR exon 19 deletions or exon 21 L858R mutations after definitive chemoradiotherapy (CRT).

Key Points:

• ASCO has issued a rapid guideline update for the treatment of Stage III NSCLC, based on the results of the Phase III LAURA trial.
• The updated guidelines recommend using the tyrosine kinase inhibitor (TKI) osimertinib in patients with unresectable Stage III NSCLC who have EGFR exon 19 deletions or exon 21 L858R mutations, following definitive CRT.

“Osimertinib showed a significant improvement in progression-free survival (PFS),” said Dr. Navneet Singh, co-chair of the ASCO expert panel. “This provides a new treatment option for patients with unresectable Phase 3 NSCLC and EGFR mutations who have completed CRT.”

Positive Results from the LAURA Trial

The LAURA trial is the first study to assess the efficacy of a targeted therapy in patients with unresectable Stage III NSCLC. A total of 216 patients were enrolled and randomly assigned in a 2:1 ratio to receive either osimertinib (143 patients) or placebo (73 patients). The median PFS for the osimertinib group was 39.1 months, compared to just 5.6 months for the placebo group (HR=0.16, 95% CI: 0.10-0.24; P<0.001) [2].

The PFS benefit with osimertinib was consistent across various pre-specified and exploratory subgroups, including disease stage (IIIA or IIIB/IIIC), the use of concurrent or sequential CRT, EGFR mutation type, and smoking history. At the time of publication, overall survival (OS) data were only 20% mature. Per the study protocol, patients in the placebo group were allowed to cross over to receive osimertinib after disease progression, and 81% of them did.

“While overall survival is the ultimate benchmark for the efficacy of any new treatment strategy, the impressive PFS benefit seen with osimertinib raises expectations. Clinicians and patients alike hope that the observed PFS gains will translate into a similarly significant OS benefit,” Dr. Singh noted. “Though OS data are still pending, the PFS improvement is remarkable, and it prompts discussions about the value of using osimertinib as consolidation therapy for all patients with EGFR-mutant, unresectable Stage III NSCLC who complete CRT.”

A New Standard of Care

The guideline update rates the evidence supporting the inclusion of osimertinib as moderate in quality and gives the recommendation a “strong” rating [1]. Other aspects of the guideline for managing Stage III NSCLC remain unchanged.

Recommendation 5.8: Patients with unresectable Stage III NSCLC and EGFR exon 19 deletions or exon 21 L858R mutations can receive consolidation therapy with osimertinib after definitive chemoradiotherapy (concurrent or sequential platinum-based chemotherapy and thoracic radiation) (Evidence level: moderate; Recommendation grade: strong).

Of the 2 million patients diagnosed with NSCLC each year, 20% to 30% have Stage III disease, and up to 90% of these patients have unresectable disease [3]. Before the LAURA trial, consolidation therapy with durvalumab was considered the standard of care for these patients, despite uncertain benefits. Now, that standard has shifted. “It is important to note that patients with EGFR mutations should not receive durvalumab as consolidation therapy,” Dr. Singh emphasized.

Considering Adverse Events

In the LAURA trial, patients receiving osimertinib experienced more grade 3 or higher adverse events (AEs) than those on placebo (35% vs 12%). Radiation pneumonitis (48% vs 38%) and AEs leading to treatment discontinuation (13% vs 5%) were also more common with osimertinib. In the osimertinib group, 56% of patients had their dose interrupted due to AEs, and 8% had their dose reduced, compared to 25% and 1%, respectively, in the placebo group [2].

Dr. Singh advised that clinicians must be aware of the higher incidence of some AEs with osimertinib. “It is essential to discuss the risks and benefits of osimertinib consolidation therapy with each patient so that this new treatment strategy can be applied judiciously.”

Emphasizing Biomarker Testing

The expert panel underscored the importance of molecular testing for actionable driver mutations, with the LAURA trial results (combined with findings from other studies like ADAURA and PACIFIC) reaffirming the value of biomarker testing in guiding therapy for NSCLC [2, 4, 5]. Patients with EGFR mutations stand to benefit from consolidation with EGFR-TKI, rather than an immune checkpoint inhibitor. Dr. Singh noted that LAURA “highlights the necessity of predictive biomarker testing—particularly for EGFR mutations—at all stages of NSCLC.”

References:

1. Daly ME, Navneet S, Ismaila N. Management of stage III non–small cell lung cancer: ASCO rapid guideline update. J Clin Oncol. Published online: July 23, 2024.
2. Lu Shan, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. Published online June 2, 2024.
3. Zhang Ying, Vaccarella S, Morgan E, et al. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol. 2023;24(11):1206-1218.
4. Herbst Roy S, Wu Yi-Long, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol. 2023;41(10):1830-1840.
5. Spigel David R, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311.