Osimertinib significantly improved progression-free survival compared with placebo in patients with unresectable stage III EGFR-mutated non–small-cell lung cancer (NSCLC) following definitive chemoradiotherapy. These findings of the phase III LAURA trial suggest that osimertinib may become a new standard of care for unresectable stage III EGFR-mutated NSCLC, adding to the established indications for osimertinib, according to experts who spoke at the 2024 ASCO Annual Meeting Plenary Session, where these data were presented by lead author Suresh S. Ramalingam, MD, FACP, FASCO, of Winship Cancer Institute of Emory University, Atlanta.1 The results of LAURA were published simultaneously in The New England Journal of Medicine.2
“These results emphasize that EGFR mutation testing is now critical for stage III patients to ensure optimal outcomes.”— Suresh S. Ramalingam, MD, FACP, FASCO
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In LAURA, median progression-free survival was 39.1 months with osimertinib vs 6 months for the placebo group—a more than six times longer disease-free interval—representing an 84% improvement in disease progression (P < .001). In addition, osimertinib prevented new cancer growth, achieved higher objective response rates, and reduced the rate of new brain metastasis compared to placebo. The benefits of osimertinib were seen across all prespecified subgroups.
“There are currently no approved targeted treatments specifically for unresectable stage III EGFR-mutated NSCLC. The LAURA study showed a statistically significant and clinically meaningful improvement in progression-free survival vs placebo in patients with unresectable EGFR-mutated NSCLC following definitive chemoradiotherapy. With the superior efficacy results along with the robust magnitude of benefit in the LAURA study, osimertinib provides a solution to a large unmet need for this patient population. These data suggest that osimertinib will become a new standard of care for patients with unresectable stage III EGFR-mutated NSCLC following definitive chemoradiotherapy,” stated Dr. Ramalingam.
Mutation Testing Becomes Crucial
“These results emphasize that EGFR mutation testing is now critical for stage III patients to ensure optimal outcomes,” he added. He noted that this year is the 20th anniversary of the pivotal discovery of EGFR mutations in lung cancer. Dr. Ramalingam’s presentation was greeted with a standing ovation at the ASCO Annual Meeting Plenary Session.
Dr. Ramalingam explained that the current standard of care for these patients is concomitant chemoradiation therapy followed by immune checkpoint inhibitors. “We have learned that there is no improvement in outcomes with immunotherapy [in this group of patients], but before LAURA, we had some evidence that EGFR inhibition is beneficial,” he explained.
The third-generation EGFR inhibitor osimertinib is currently approved for the first-line treatment of stage IV EGFR-mutated NSCLC, as well as for adjuvant therapy in stage IB, II, and IIIA resectable EGFR-mutated NSCLC. LAURA was designed to evaluate osimertinib in yet another setting—stage III unresectable EGFR-mutated NSCLC.
Study Details
The international, randomized, placebo-controlled phase III -LAURA trial enrolled 216 patients with unresectable stage III EGFR-mutated NSCLC and randomly assigned them 2:1 to receive osimertinib (n = 143) or placebo (n = 76) after they had undergone definitive platinum-based chemoradiotherapy with no evidence of disease progression. Treatment was continued until disease progression or toxicity. Placebo patients were allowed to cross over to osimertinib.
“Osimertinib had a significant impact on new cancer growth, particularly in the brain.”— Suresh S. Ramalingam, MD, FACP, FASCO
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The primary endpoint was progression-free survival, and all participants had computed tomography of the chest and brain at baseline and specified intervals. The median age of participants was about 63 years old. Female participants comprised 63% of the osimertinib arm and 58% of the placebo arm. Asian participants comprised 81% of the osimertinib arm and 85% of the placebo arm. Never-smokers comprised 63% of the osimertinib arm and 67% of the placebo arm.
“Osimertinib had a significant impact on new cancer lesions, particularly in the brain,” Dr. Ramalingam told listeners. At 12 months, 74% of the osimertinib group had not experienced disease progression compared to 22% of the placebo group. At 24 months, 65% of the osimertinib group had no progression vs 13% of the placebo group. At 24 months, new brain lesions occurred in only 8% of the osimertinib group vs 29% of the placebo group. Objective response rates were also higher with osimertinib treatment, with a reduction in tumor size of at least 30% after treatment seen in 57% of osimertinib-treated patients compared with 33% of placebo recipients.
In a subgroup analysis, the progression-free survival benefit of osimertinib over placebo was observed regardless of the type of chemoradiotherapy received and regardless of the presence of stage IIIA, IIIB, or IIIC disease. Across all subgroups, the improvement in progression-free survival was 65% with osimertinib. Eighty-one percent of the placebo participants who experienced disease progression crossed over to osimertinib treatment.
Survival data were only 20% mature at the time of the ASCO Annual Meeting presentation, but overall survival showed a trend in favor of osimertinib, with 19% improvement. “This was observed despite 81% of the controls crossing over to osimertinib at disease progression,” Dr. Ramalingam pointed out. Overall survival will be reported when the data are 80% mature, he added.
Safety Profile
All-cause adverse events were reported in 98% of osimertinib patients vs 88% of placebo patients. “There were no unexpected safety signals,” Dr. Ramalingam said.
Grade 3 or higher adverse events were reported in 35% of the osimertinib group vs 12% of placebo patients. Serious adverse events were reported in 38% vs 15%, respectively. As would be expected, the adverse event profile of the osimertinib and placebo groups differed somewhat. The most common adverse events in both arms of the study included radiation pneumonitis, diarrhea, rash, and COVID-19. These events were slightly more frequent in the osimertinib arm and were mostly grades 1 and 2. Adverse events leading to treatment discontinuation were reported in 13% of the osimertinib group and 9% of the placebo group.
Additional Commentary
ASCO Expert David R. Spigel, MD, Chief Scientific Officer of the Sarah Cannon Research Institute, Nashville, said there are three main reasons why osimertinib should be the new standard of care for this population with unresectable stage III EGFR-mutated NSCLC.
David R. Spigel, MD
“First, the 84% reduction in risk of cancer progression and death is meaningful to patients and providers. Second, I applaud the investigators for offering the chance for placebo patients to cross over to osimertinib. And third, in the real world, when patients [have disease progression], they don’t always get the next line of therapy. In fact, 40% never make it to the next therapy,” Dr. Spigel said.
“This will be practice-changing as soon as the label for osimertinib is expanded,” Dr. Spigel predicted.
DISCLOSURE: The study was funded by AstraZeneca. Dr. Ramalingam has received institutional research funding from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Pfizer, and Takeda; payment for travel, accommodations, or other expenses from AbbVie; and has a relationship with the American Cancer Society. Dr. Spigel has a leadership role with ASCO; a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Ipsen, Jazz Pharmaceuticals, Lyell Immunopharma, MedImmune, Monte Rosa Therapeutics, Novartis, Novocure, and Sanofi/Aventis; has received institutional research funding from AbbVie, Aeglea Biotherapeutics, Agios, Amgen, AnHeart Therapeutics, Apollomics, Arcus Biosciences, Arrys Therapeutics, Ascendis Pharma, Asher Biotherapeutics, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Celgene, Celldex, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, Ellipses Pharma, EMD Serono, Endeavor Biomedicines, Erasca, Evelo Biosciences, Faeth Therapeutics, Foundation Bio, Fujifilm, G1 Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Immunogen, Incyte, Ipsen, Janssen Oncology, Janux Therapeutics, Jazz Pharmaceuticals, Kronos Bio, Lilly, Loxo, Lyell Immunopharma, Macrogenics, MedImmune, Merck, Millennium, Moderna Therapeutics, Monte Rosa Therapeutics, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Peloton Therapeutics, Pfizer, Phanes Therapeutics, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Seagen, Shenzhen Chipscreen Biosciences, Stemline Therapeutics, Strata Oncology, Synthekine, Taiho Oncology, Takeda, Tango Therapeutics, Tarveda Therapeutics, Tesaro, Tizona Therapeutics, Transgene, University of Texas Southwestern Medical Center–Simmons Cancer Center, Verastem, and Zai Lab; and has received payments for travel, accommodations, and other expenses from AstraZeneca, Genentech, and Novartis.
REFERENCEs
1. Ramalingam SS, Kato T, Dong X, et al: Osimertinib after definitive chemoradiotherapy in patients with unresectable stage III epidermal growth factor receptor-mutated NSCLC: Primary results of the phase 3 LAURA study. 2024 ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2024.
EXPERT POINT OF VIEW
“These results are phenomenal and clinically meaningful—they will affect practice immediately,” stated invited discussant Lecia Sequist, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, Boston. “An extension of progression-free survival can be very meaningful for patients. Until now, patients with stage III unresectable EGFR-mutated non–small cell lung cancer (NSCLC) have not had the means to access this therapy.”
Lecia Sequist, MD, MPH
She explained: “Unlike other trials, LAURA continued treatment until disease progression. This acknowledges that stage III NSCLC is unlikely to be cured. In other phase III trials of stage III patients, 40% or fewer survived for 5 years. Perhaps it is more realistic and transparent to tell patients they may not be cured.”
Dr. Sequist continued: “In this study, about 80% of placebo patients crossed over to osimertinib. But relying on crossover leaves some patients stranded, because progressive lung cancer renders them unfit for further therapy. The current standard of care should be an EGFR tyrosine kinase inhibitor upfront. LAURA strongly supports the use of osimertinib immediately upfront.”
An advantage of long-term osimertinib is suppression of brain metastasis, but the downsides include cost, side effects, quality of life, and overtreatment. It may be that subsets of EGFR-mutated NSCLC will not need indefinite treatment, she suggested.
“The results of this trial are immediately practice-changing and imply that genotyping of patients with lung cancer is imperative,” Dr. Sequist concluded.
DISCLOSURE: Dr. Sequist has received institutional research funding from AstraZeneca, Delfi Diagnostics, and Novartis.
