Editor’s Note: The 2024 World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer (IASLC), is currently underway in San Diego, USA. Oncology Frontier has invited leading Chinese lung cancer experts to analyze the key research data from this conference. This article highlights Dr. Nan Bi from the Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, as she shares her thoughts on the LAURA study results (Abstract No. OA12.03).

The LAURA study is a randomized, global, multicenter, double-blind, placebo-controlled Phase III clinical trial that enrolled 216 patients with unresectable Stage III EGFR-mutated non-small cell lung cancer (NSCLC) who had not progressed following definitive chemoradiotherapy. Patients from over 15 countries and more than 145 centers across the U.S., Europe, South America, and Asia were randomly assigned in a 2:1 ratio to receive osimertinib (80 mg QD) or placebo as consolidation therapy until disease progression, death, or discontinuation for other reasons. The results of this study were first presented at the 2024 ASCO meeting and simultaneously published in The New England Journal of Medicine (NEJM).

The LAURA study showed that the median progression-free survival (PFS) in the osimertinib consolidation group for patients with unresectable Stage III NSCLC who had not progressed after chemoradiotherapy was 39.1 months, compared to only 5.6 months in the placebo group (P < 0.001, HR = 0.16). The 2-year PFS rate was 65% in the osimertinib group, significantly higher than the 13% in the placebo group. While overall survival (OS) data are still immature, the 3-year OS was 84% in the osimertinib group and 74% in the placebo group (P = 0.530, HR = 0.81).

The significance of the LAURA study lies in filling the final gap in precision treatment for EGFR-mutant NSCLC. For operable EGFR-mutant NSCLC patients, the ADAURA study demonstrated that 3 years of adjuvant osimertinib therapy provided a survival benefit compared to placebo, with a 5-year OS improvement of approximately 10% (88% in the osimertinib group vs. 78% in the placebo group, P < 0.001, HR = 0.49). For patients with advanced EGFR-mutant NSCLC, the FLAURA study showed that third-generation TKIs provided both OS and PFS benefits compared to first-generation TKIs, with further reduction in the risk of brain metastasis, making them the preferred treatment option. The FLAURA2 study revealed that combining osimertinib with chemotherapy extended median PFS by about 9 months compared to osimertinib monotherapy. Although the OS data are not yet mature, there is a positive trend, and this could become a new first-line treatment approach.

However, for patients with unresectable Stage III EGFR-mutant NSCLC, there has long been a lack of high-level evidence-based guidance, making clinical decision-making challenging. In the PACIFIC study, only about 6% of patients had EGFR mutations, and subgroup analysis did not show a survival benefit from durvalumab consolidation in these patients. The LAURA study provides important evidence-based guidance for this patient population, potentially rewriting clinical guidelines and establishing targeted consolidation therapy with osimertinib as the standard of care for EGFR-mutant NSCLC.

At this year’s WCLC, a detailed safety analysis from the LAURA study was presented. Overall, the incidence of Grade ≥3 toxicities and serious adverse events was 35% and 38%, respectively, in the osimertinib group, higher than the 12% and 15% observed in the placebo group. Radiation pneumonitis was the most common adverse event, occurring in 48% of patients in the osimertinib group compared to 38% in the placebo group. Most cases of pneumonitis were mild to moderate, with Grade 3 radiation pneumonitis occurring in 2% of patients, and no Grade 4/5 pneumonitis observed. Among patients who developed pneumonitis, 87% continued osimertinib without recurrence. Additionally, 8% of patients in the osimertinib group developed interstitial lung disease (ILD), including 2 cases of Grade 5 ILD. Overall, despite slightly higher rates of adverse events and pneumonitis in the osimertinib group compared to placebo, the safety profile was consistent with expectations and considered manageable. Given the significant PFS benefit, osimertinib consolidation therapy after definitive chemoradiotherapy should become the new standard for unresectable Stage III NSCLC patients with EGFR mutations.

Exploring Radiotherapy and Targeted Therapy in EGFR-Mutant LA-NSCLC

Even before the LAURA study results were announced, researchers had already been exploring the combination of radiotherapy and targeted therapy for patients with EGFR-mutant LA-NSCLC. The RECEL study showed that erlotinib plus radiotherapy significantly improved median PFS compared to concurrent chemoradiotherapy (24.5 months vs. 9.0 months, P < 0.001). The WJOG6911L study reported that median PFS for gefitinib combined with radiotherapy was 18.6 months, with a median OS of 61.1 months. The REFRACT study, led by the National Cancer Center and Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, was the largest real-world study to date (N = 440) on treatment patterns and long-term survival in patients with Stage III EGFR-mutant NSCLC. It showed that the median PFS in the TKI plus radiotherapy group was 26.2 months, significantly better than the 12.4 months in the chemoradiotherapy group and the 16.2 months in the TKI monotherapy group. The median OS in the radiotherapy plus TKI group was 67.4 months, also superior to the 51.0 months observed with chemoradiotherapy alone. These findings highlight that LA-NSCLC differs from advanced NSCLC, and the addition of local radiotherapy can significantly improve patient outcomes.

Most of these studies used first-generation TKIs, with brain metastasis being the most common mode of treatment failure. Compared to first-generation TKIs, third-generation TKIs like osimertinib have better penetration of the blood-brain barrier and improved intracranial control. In the LAURA study, the incidence of brain metastasis was only 8%, and combining radiotherapy with third-generation TKIs may further enhance survival outcomes for patients.

Future Outlook

The LAURA study has ushered in the era of targeted consolidation therapy for LA-NSCLC, but several new challenges remain in clinical practice.

For instance, although the LAURA study has shown a preliminary trend of OS benefit, whether the final OS will be positive requires longer follow-up. Additionally, the optimal timing and duration of targeted therapy need further exploration. Compared to the 3 years of adjuvant therapy in the ADAURA study, the LAURA study continued osimertinib until progression or intolerance. Whether this will result in new long-term toxicities is yet to be determined.

In clinical practice, some EGFR-positive LA-NSCLC patients have large tumor burdens or rapidly progressing disease, making concurrent chemoradiotherapy difficult to tolerate. In such cases, could upfront induction targeted therapy followed by the LAURA regimen help reduce the risk of pneumonitis and improve treatment completion rates?

Moreover, could a “chemotherapy-free” treatment approach for EGFR-mutant patients reduce toxicity without compromising efficacy? This is especially important for patients who cannot tolerate chemotherapy. The ADVANCE study is a multicenter, open-label, randomized controlled trial enrolling patients with unresectable Stage III EGFR-mutant non-squamous NSCLC. It compares induction therapy with almonertinib followed by concurrent radiotherapy plus almonertinib and consolidation therapy with almonertinib, against concurrent chemoradiotherapy. Preliminary results, presented at this year’s ESMO meeting, have already demonstrated significant PFS benefits and better safety data. The final results are eagerly awaited to provide more treatment options and new strategies for clinical practice.