Osimertinib prolongs progression-free lung cancer survival after chemotherapy

Abstract

Investigators for the phase 3 LAURA trial reported that for patients with unresectable stage III non–small cell lung cancer (NSCLC) harboring an EGFR mutation after chemoradiotherapy, osimertinib significantly prolonged progression-free survival (PFS) versus a placebo. The study appears in The New England Journal of Medicine (doi:10.1056/NEJMoa2402614).

“This is the first randomized trial conducted specifically for patients with unresectable stage III lung cancer with EGFR mutation,” says Suresh S. Ramalingam, MD, professor of hematology and medical oncology and executive director of the Winship Cancer Institute at the Emory University School of Medicine and LAURA trial investigator. “The study shows a clear benefit with osimertinib compared to placebo in terms of progression-free survival and lower risk of brain progression.”

Study results show that treatment with osimertinib reduced the risk of progression or death by 84% in comparison with the placebo. The study was presented during a press briefing at the 2024 annual meeting of the American Society of Clinical Oncology held in Chicago, Illinois.

The LAURA trial included patients at least 18 years old (20 years old in Japan) with locally advanced and unresectable stage III NSCLC harboring an EGFR exon 19 deletion or L858R mutation from August 2018 through July 2022. None of the patients had disease progression after definitive chemoradiotherapy. A total of 216 patients underwent randomization; 143 were assigned to receive osimertinib, and 73 received the placebo.

The median age of the patients was 62 years in the osimertinib arm and 64 years in the placebo group. Most were male (63% in the osimertinib arm and 58% in the placebo arm). The majority never smoked (71% and 67%, respectively).

Both groups included enrollment from Asian countries (81% in the osimertinib arm vs. 85% in the placebo arm), had stage IIIB disease (47% vs. 52%) and adenocarcinoma (97% vs. 95%), and harbored EGFR exon 19 deletions (52% vs. 59%). Also, most received concurrent chemoradiotherapy: 92% in the osimertinib group and 85% in the placebo group.

Patients needed to have a World Health Organization (WHO) performance-status score of 0 or 1. (Note that this was based on a scale of 0–5, with a higher number indicating more disability.) Six weeks was the maximum interval between the last dose of chemoradiotherapy and randomization. At the baseline, patients were largely balanced between the two groups, although there were more patients with a WHO performance-status score of 0 in the osimertinib group versus the placebo group (56% vs. 42%).

The patients were randomly assigned 2:1 to receive 80 mg of oral osimertinib or the placebo once per day. Blinded independent central review (BICR) of PFS per the Response Evaluation Criteria in Solid Tumors (Version 1.1) was the trial’s primary end point. Secondary end points included overall survival (OS), central nervous system PFS, and safety.

Treatment continued until BICR-determined disease progression, unacceptable toxicity, or other discontinuation criteria agreed upon beforehand occurred. Tumor assessments were conducted via chest CT/MRI and brain MRI initially, every 8 weeks up until week 48, and then every 12 weeks until BICR-confirmed progression.

Responses to prior chemoradiotherapy included complete responses (3% for the osimertinib patients vs. 4% for the placebo patients), partial responses (47% vs. 37%), and stable disease (43% vs. 51%). For both groups, only 8% were not evaluable. The median duration of response was 36.9 months for the osimertinib group and 6.5 months for the placebo group.

Additional data showed that 22 patients in the osimertinib arm developed new lesions, whereas 68 patients in the placebo arm did. Sites of new lesions included the brain (8 osimertinib patients vs. 29 placebo patients), lungs (6 vs. 29), and liver (3 vs. 7).

Dr Ramalingam says that the findings for osimertinib following chemoradiotherapy were consistent with the known safety profile of the EGFR inhibitor and that the side effects were manageable. He adds that most adverse effects were minor (grade 1/2), did not lead to treatment discontinuation, and were consistent with results from previous studies.

The most common any-grade adverse effects reported in at least 10% of patients included radiation pneumonitis (48% of patients in the osimertinib group vs. 38% of patients in the placebo group), diarrhea (36% vs. 14%), rash (24% vs. 14%), COVID-19 (20% vs. 8%), paronychia (17% vs. 1%), and coughing (16% vs. 10%). Also, the osimertinib and placebo groups showed decreased appetites (15% vs. 5%), dry skin (13% vs. 5%), pruritus (13% vs. 7%), stomatitis (12% vs. 3%), decreased white blood cell counts (12% vs. 3%), pneumonia (11% vs. 8%), anemia (10% vs. 4%), and musculoskeletal chest pain (3% vs. 12%).

Grade 3 or higher adverse effects in the osimertinib arm included pneumonia (3%), radiation pneumonitis (2%), diarrhea (2%), COVID-19 (1%), decreased appetite (1%), dry skin (1%), decreased white blood cell counts (1%), and anemia (1%).

“This study is extremely important and immediately practice changing,” says Nate Pennell, MD, PhD, professor in the Department of Medicine and deputy associate director for clinical research at Case Comprehensive Cancer Center at the Cleveland Clinic in Cleveland, Ohio. “We have been preferentially treating patients with metastatic NSCLC with EGFR mutations for almost 20 years with the understanding that targeted therapy is more effective and less toxic than chemotherapy; and for the last several years, we have also been using osimertinib in the adjuvant setting after surgery for patients with stage I–III EGFR mutation+ NSCLC due to improvements in survival.” Dr Pennell notes that the only group that did not benefit from osimertinib was the 30%–40% of patients with unresectable stage III NSCLC. With the LAURA trial, there is also a very large and clinically significant 84% improvement in PFS. “Although we need to wait for overall survival analysis in a few years to be completely certain of this strategy, this is virtually identical to the improvement seen in the adjuvant trial (ADAURA) that led to an improvement in OS, so it is well worth using now.”

Dr Pennell says that a key takeaway message from the study—and topic—for clinicians and researchers is that every patient with nonsquamous NSCLC, with the possible exception of stage IA patients, should now have molecular testing done at the time of diagnosis to ensure that all patients with EGFR mutations are identified and can access targeted therapy with osimertinib in the adjuvant or consolidation setting. He adds that patients with stage IB–IIIA EGFRm+ NSCLC should receive 3 years of osimertinib after surgery and chemotherapy if appropriate, whereas patients with unresectable stage III EGFRm+ NSCLC now should receive indefinite osimertinib after definitive chemoradiation.

“One important element that is of concern,” says Dr Pennell, “is the use of indefinite osimertinib after chemoradiation, as opposed to a fixed time of 3 years, as was done in the ADAURA study. In the placebo arm of LAURA, 87% of patients progressed within 2 years, indicating that most patients with unresectable stage III NSCLC are not cured with chemoradiation alone, and their prognosis is more similar to that of patients with stage IV disease. Since the treatment of people with stage IV disease until progression is a standard practice, osimertinib administration without a predefined duration for people with unresectable stage III disease makes more sense.”

Dr Pennell says that future studies trying to identify patients who need indefinite treatment versus those who may need shorter duration or even no consolidation treatment should be a priority.

The LAURA trial (NCT03521154 at ClinicalTrials.gov) was funded by AstraZeneca.