Osimertinib extends PFS by 3.2 years in LAURA

12 Jul 2024 byElvira Manzano
Osimertinib extends PFS by 3.2 years in LAURA

Osimertinib extends progression-free survival (PFS) sevenfold longer than placebo in patients with unresectable stage III EGFR-mutated non–small cell lung cancer (NSCLC) following definitive chemoradiotherapy, as shown in the primary analysis of the phase III LAURA study presented at ASCO 2024. This breakthrough makes osimertinib the first EGFR inhibitor to show benefit in a stage III setting.

The median PFS was 39.1 months with osimertinib vs 5.6 months with placebo (hazard ratio [HR], 0.16, 95 percent confidence interval [CI], 0.10–0.24; p=0.001), for a difference of 33.5 months. The benefit was consistent across subgroups. [ASCO 2024, abstract LBA4]

“For the first time, we’ve established osimertinib as the new standard of care [SoC] for patients with unresectable stage III EGFR-mutated disease following chemoradiation,” said lead investigator Dr Suresh Ramalingam, Professor of Hematology and Medical Oncology and Executive Director of Winship Cancer Institute at Emory University in Atlanta, US, who received a standing ovation from ASCO attendees following his presentation.

‘Practice changing’

Study discussant Dr David Sigel, a medical oncologist at the Sarah Cannon Research Institute, Nashville, Tennessee, US, described the results as “outstanding.”

“To have an 84-percent reduction in the risk of cancer progression or death is meaningful for patients,” he commented following Ramalingam’s presentation. “This will be practice changing as soon as the label gets expanded. This is because in advanced lung cancer, about 40 percent of patients will never make it to the next line of therapy.”  

Osimertinib is already approved for locally advanced or metastatic EGFR-mutated NSCLC and as an adjuvant therapy for resected stage IB–IIIA disease, but not for unresectable stage III EGFR-mutated NSCLC.

The need for new therapy

Ramalingam shared that nearly one-third of patients with NSCLC present with stage III disease. Of these, 60–90 percent will have unresectable disease either because the tumour is invading the neighbouring organs or there is extensive involvement of the lymph node.

The current SoC for unresectable stage III disease is chemoradiation followed by checkpoint blockade with durvalumab for 1 year. However, according to Ramalingam, whether PD-L1 inhibition benefits patients with EGFR mutations remains uncertain.

“A post hoc analysis of the pivotal PACIFIC study failed to show any difference in PFS or overall survival [OS] outcomes between durvalumab and placebo in patients with EGFR mutation,” recalled Ramalingam. [J Thorac Oncol 2023;18:657-663]

“We’ve known that patients with EGFR-mutant NSCLC show poor response to PD-1 or PD-L1 inhibitors. When PD-L1 expression is high, the benefit is not there. That’s why we need an effective therapy,” he added. “We are, therefore, excited that osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, is here.”

Looking into LAURA

LAURA enrolled 216 patients with stage III EGFR-mutated NSCLC whose disease had not progressed after chemoradiotherapy. They were randomized 2:1 to receive osimertinib 80 mg (n=143) or placebo (n=73) once daily until disease progression or unacceptable toxicity. Disease progression was verified with CT scans and MRI at baseline and intervals. PFS was the primary endpoint. OS and safety were among the secondary endpoints. [N Engl J Med 2024;doi;10.1056/NEJMoa2402614]

Overall, patients had a median age of 63 years, >60 percent were female, and more than two-thirds had never smoked. Those who progressed while on placebo could switch to osimertinib. “Eighty-one percent did,” said Ramalingam.

The majority of the patients had stage IIIB disease and were treated with concurrent chemoradiation. Nearly all had adenocarcinoma. A majority (52–59 percent) had exon 19 deletions.

Outcomes overwhelmingly favour osimertinib

One-year PFS, assessed by blinded independent central review, was 74 percent with osimertinib vs 22 percent with placebo. At 24 months, the rates were 65 percent and 13 percent, respectively. The PFS benefit held across subgroups and was statistically significant among Asians, who comprised over 80 percent of both study arms.

“OS was immature at this time, but we’ve seen a favourable trend,” said Ramalingam. “This was despite a high proportion of patients  crossing over from the control arm.” Full OS results are expected within 2 years.

During follow-up, 22 percent of patients on osimertinib developed new lesions vs 68 percent of those on placebo. No new safety signals were detected.

The most common adverse events (AEs) of any grade in the osimertinib and placebo groups, respectively, were radiation pneumonitis (48 percent vs 38 percent), diarrhoea (36 percent vs 14 percent), rash (24 percent vs 14 percent), and COVID-19 (20 percent vs 8 percent). Grade ≥3 AEs were more frequent with osimertinib than placebo (35 percent vs 12 percent), as were serious AEs (38 percent vs 15 percent).

“Many of the AEs were spillover events from chemoradiation,” explained Ramalingam. “Additionally, patients were on osimertinib nearly four times longer than placebo, which contributed to higher rates of AE in the study arm.”

“Based on these results, osimertinib will be the new SoC for unresectable locally advanced NSCLC harbouring EGFR mutations,” he emphasized. “EGFR-mutation testing is critical for stage III patients to ensure optimal treatment. Unfortunately, the current testing rate is still not 100 percent.”