Osimertinib Approaches EU Approval in Locally Advanced EGFR+ NSCLC After Chemoradiation

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of osimertinib (Tagrisso) for the treatment of adult patients with locally advanced, unresectable non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations and whose disease has not progressed during or following platinum-based chemoradiation therapy.¹

The positive opinion was based on data from the phase 3 LAURA trial (NCT03521154) in which treatment with osimertinib (n = 143) led to an 84% reduction in the risk of disease progression or death vs placebo (n = 73; HR, 0.16; 95% CI, 0.10-0.24; P <.001).² Median progression-free survival (PFS) as assessed by blinded independent central review (BICR) was 39.1 months (95% CI, 31.5-not calculable [NC]) with osimertinib vs 5.6 months (95% CI, 3.7-7.4) with placebo. Overall survival (OS) data were immature at the time of the last analysis, and follow-up is ongoing to assess OS as a secondary end point.

“The LAURA results build on the established efficacy of osimertinib and support the approval of the first targeted therapy for patients with unresectable, EGFR-mutated lung cancer,” Manuel Cobo, MD, specialist physician of the Medical Oncology Service at the Carlos Haya University Hospital in Malaga, Spain, stated in a news release.¹ “[This] positive recommendation marks an important step towards offering patients in Europe a targeted treatment option that can extend the time before their disease progresses by more than three years.”

Earlier in September 2024 the FDA approved osimertinib for the treatment of patients with EGFR-mutant NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation based on data from LAURA.³

Findings from the trial, which were presented at the 2024 ASCO Annual Meeting and published in the New England Journal of Medicine, were so compelling that ASCO issued a rapid guideline update on the management of stage III NSCLC endorsing the use of osimertinib after definitive chemoradiotherapy in patients with unresectable stage III NSCLC with an EGFR exon 19 deletion or exon 21 L858R mutation.^4,5

LAURA was a double-blind, placebo-controlled trial that enrolled patients at least 18 years of age, or at least 20 years of age in Japan, with locally advanced, unresectable, stage III NSCLC harboring an EGFR exon 19 deletion or L858R mutation without disease progression following definitive chemoradiotherapy.² Patients needed to have a WHO performance status of 0 or 1 and no more than a 6-week interval between the last dose of chemoradiotherapy and random assignment.

Patients were randomly assigned 2:1 to receive 80 mg of oral osimertinib or placebo once per day. Treatment continued until BICR-assessed disease progression per RECIST 1.1 criteria, unacceptable toxicity, or other discontinuation criteria were met.

Notably, patients in both arms were allowed to receive open-label osimertinib following BICR-confirmed disease progression. Tumor assessments were performed via chest CT/MRI and brain MRI at baseline, then once every 8 weeks until week 48, then once every 12 weeks thereafter until BICR-confirmed progression.

The primary end point was BICR-assessed PFS per RECIST 1.1 criteria. Secondary end points included OS, central nervous system PFS, and safety.

Additional efficacy results indicated that the 12- and 24-month PFS rates in the osimertinib arm were 74% and 65%, respectively. Those respective rates were 22% and 13% in the placebo arm. Despite 81% of patients having crossed over to receive osimertinib from the placebo arm an OS trend favoring osimertinib was noted (HR, 0.81; 95% CI, 0.42-1.56; P = .530).

Responses were also more common with osimertinib. The objective response rate was 57% (95% CI, 49%-66%) with osimertinib vs 33% (95% CI, 22%-45%) with placebo. The disease control rates were 89% (95% CI, 83%-94%) and 79% (95% CI, 68%-88%) with osimertinib and placebo, respectively. The median duration of response was also prolonged with osimertinib, at 36.9 months (95% CI, 30.1-NC) vs 6.5 months (95% CI, 3.6-8.3) with placebo.

Regarding safety the most common any-grade adverse effects (AEs) that occurred in at least 10% of patients included radiation pneumonitis (osimertinib, 48%; placebo, 38%), diarrhea (36%; 14%), rash (24%; 14%), COVID-19 (20%; 8%), paronychia (17%; 1%), cough (16%; 10%), decreased appetite (15%; 5%), dry skin (13%; 5%), pruritus (13%; 7%), stomatitis (12%; 3%), decreased white blood cell count (12%; 3%), pneumonia (11%; 8%), anemia (10%; 4%), and musculoskeletal chest pain (3%; 12%).

Grade 3 or higher AEs 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 count (1%), and anemia (1%).

“[This] news reinforces [osimertinib]as the backbone therapy in EGFR-mutated NSCLC, meeting the critical unmet need for an effective targeted treatment option in the unresectable setting,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said.¹ “[Osimertinib] has now demonstrated its benefit across all stages of EGFR-mutated lung cancer, representing a pivotal step in transforming care for patients who are urgently in need of innovative therapies that can help extend their lives.”

References

1. Tagrisso recommended for approval in the EU by CHMP for patients with unresectable EGFR-mutated lung cancer. News release. AstraZeneca. November 18, 2024. Accessed November 20, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-recommended-for-eu-approval-laura.html
2. Tagrisso approved in the US for patients with unresectable, stage III EGFR-mutated lung cancer. News release. AstraZeneca. September 26, 2024. Accessed November 20, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/tagrisso-us-approval-in-unresectable-lung-cancer.html
3. Lu S, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614
4. Daly ME, Singh N, Ismaila N, et al. Management of stage III non–small cell lung cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2024;42(25). doi:10.1200/JCO-24-01324
5. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4