Indefinite course of osimertinib dramatically improves PFS in stage 3 EGFR-mutated NSCLC

Treatment with an indefinite course of osimertinib dramatically improves progression-free survival for patients with stage 3 non-small cell cancer, according to the results of the LAURA trial. The median PFS was 39.1 months in the osimertinib group, compared to 5.6 months with the placebo group.

The results from the phase III trial, published in the New England Journal of Medicine, were presented by senior author Suresh S. Ramalingam at the plenary session of the 2024 American Society of Clinical Oncology Annual Meeting in Chicago June 2. 

Osimertinib (Tagrisso) is sponsored by AstraZeneca Pharmaceuticals LP.

The presentation was interrupted by a standing ovation as the audience was shown the Kaplan-Meier curves for PFS.

“We believe that osimertinib will become the new standard of care for patients with unresectable stage 3 EGFR-mutated non-small cell lung cancer,” said Ramalingam, executive director of the Winship Cancer Institute of Emory University, Roberto C. Goizueta Distinguished Chair for Cancer Research, professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine,  and associate vice president for cancer at Woodruff Health Sciences Center. 

The overall survival data has not reached maturity. 

Osimertinib resulted in a significant PFS benefit as compared with placebo: the median  PFS was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). 

The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. 

Interim overall survival data (maturity, 20%) showed 36-month OS among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53).

The LAURA trial results come as the field celebrates the twentieth anniversary of the discovery of the EGFR mutation in NSCLC (The Cancer Letter, May 31, 2024). The Cancer Letter and the Cancer History Project are marking the anniversary with an ongoing series.

In this setting, PFS provides a clinically meaningful benefit, said medical oncologist Lecia Sequist, program director of the Cancer Early Detection and Diagnostics Clinic at the Massachusetts General Hospital and the Landry Family Professor of Medicine at Harvard Medical School. Sequist was the discussant at the session.

PFS promises to provide clinical benefit in and of itself, due to the high rates of central nervous system metastases in the disease. Anecdotal evidence suggests that delay of CNS metastases improves quality of life, regardless of length of survival.

Sequist described a case in which a patient’s unresectable stage 3 EGFR-mutated NSCLC metastasized to the brain. That progression hampered the patient’s ability to read and do simple math, “which is a huge change from her previous high-functioning professional life,” Sequist said. 

Treatment paradigm shift

The LAURA trial divided 216 patients into an exerimental arm and placebo arm at a 2:1 ratio. Patients continued treatment until CNS metastasis or unacceptable toxicity. And participants in the placebo group whose disease metastasized could switch to osimertinib as crossover therapy.

LAURA’s control arm used placebo, as opposed to durvalumab, an immunotherapy that has become the standard of care for stage 3 NSCLC .

This choice was made because  patients with the EGFR mutation show less than a 5% response rate to PD-1 blockade, Ramalingam said. 

Also, using durvalumab in the control arm would have delayed potential crossover to osimertinib, owing to toxicity issues, Ramalingam said. 

“We would have to wait for two to three months before these patients will be able to get a TKI, and I don’t believe that’s appropriate clinical care for those patients,” he said. 

Further, LAURA’s treatment protocol differed from what is typical for stage 3 NSCLC. Rather than a defined, short-term course of treatment, the new trial specified an indefinite course of osimertinib. 

This marks a move away from the standard practice of treating the disease with curative intent. 

“It essentially acknowledges that stage 3 unresectable lung cancer is unlikely to be a curable diagnosis,” Sequist said. “Historically, we have framed therapy for stage 3 lung cancer as being given with curative intent—but is that point of view appropriate?” 

In five major phase III randomized trials in unresectable stage 3 NSCLC done over the last 20 years, no more than 40% of participants survived to the five-year mark, Sequist said. 

“Perhaps a treatment paradigm which acknowledges [that], most likely, we cannot achieve cure is a more transparent, patient-centric approach,” she said.

The audience responded with a surge of questions about the proposed indefinite treatment, as well as osimertinib’s potential to change practice in other ways. 

“Given how active the agent is, do you think that there’s an opportunity to even reduce the amount of therapy upfront, the chemotherapy or the radiation therapy?” asked plenary co-chair Angela DeMichele, co-leader of the Breast Cancer Research Program, co-director of the 2-PREVENT Breast Cancer Translational Center of Excellence, and Mariann T. and Robert J. MacDonald Professor in Breast Cancer Care Excellence at the University of Pennsylvania. 

Some researchers are looking into moving osimertinib treatment ahead of chemoradiotherapy, and even questioning chemoradiotherapy’s role in patients with stage 3 NSCLC, Ramalingam said. 

Therapy for stage 4 has also come into question, Sequist said. 

“It seems that unresectable stage 3 and stage 4 are really becoming much more of a conglomerate group, where we have to do a better job of understanding which patients really might benefit from intensifying local therapy to where the bulk of disease is, and which patients would be best served by systemic therapy alone,” Sequist said.  

At 20% maturity, the LAURA trial’s OS data shows multiple crossings of the curves. Still, Ramalingam said he is hopeful that the clinical benefit of the osimertinib regimen will become apparent once the data mature, which he anticipates will occur within the next two years. 

“It is our hope that these very robust PFS results will translate into overall survival,” he said.