‘Practice Changing’ Trial for Inoperable Locally Advanced NSCLC


CHICAGO — Patients without disease progression following chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC) should receive osimertinib (Tagrisso) if they harbor EGFR mutations, experts said here.

In the randomized LAURA trial, median progression-free survival (PFS) increased seven-fold when patients received the EGFR inhibitor after definitive chemoradiation, improving from 5.6 months with placebo to an “outstanding” 39.1 months with osimertinib (HR 0.16, 95% CI 0.10-0.24, P<0.001).

Despite 81% of patients on the placebo arm crossing over upon disease progression, there was still a trend toward an overall survival (OS) benefit, reported Suresh Ramalingam, MD, of the Winship Cancer Institute at Emory University School of Medicine in Atlanta, at the American Society of Clinical Oncology (ASCO) annual meeting.

Interim survival analyses showed 3-year OS rates of 84% in the osimertinib arm versus 74% in the placebo arm (HR 0.81, 95% CI 0.42-1.56, P=0.53), according to findings of the double-blind trial, which was published simultaneously in the New England Journal of Medicine.

“Osimertinib will become the new standard of care for patients with locally advanced non-small cell lung cancer following definitive chemoradiation,” Ramalingam said during a press briefing.

“This will be practice changing,” said ASCO-designated expert David Spigel, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, during the press conference. “It really is outstanding.”

Spigel called the 84% reduction in the risk of disease progression or death with osimertinib meaningful both for patients and for the providers overseeing their care. Another reason the drug will become standard of care in this setting, Spigel added, is that “in lung cancer, about 40% of patients will never make it to the next line of therapy.”

An important question will be how long patients require treatment, said Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, who was not involved in the study.

“In this trial, the patients were treated until progression,” he told MedPage Today. “I’m hoping that with minimal residual disease analysis, some patients might need less therapy, which would be perhaps fewer side effects and less inconvenience.”

In his introductory remarks, Ramalingam explained that nearly one-third of patients diagnosed with NSCLC present with stage III disease. Of those, 60% to 90% will have unresectable disease either because the tumor is invading neighboring organs or because there is too much lymph node involvement.

Standard of care for these patients is chemoradiation followed by checkpoint blockade with durvalumab (Imfinzi) based on the results of the PACIFIC trial. But whether the PD-L1 inhibitor benefits patients with EGFR mutations has been up for debate, and a recently published post hoc analysis of this subgroup in PACIFIC showed no significant PFS or OS benefit with the addition of durvalumab:

  • PFS: median 11.2 vs 10.9 months with placebo (HR 0.91, 95% CI 0.39-2.13)
  • OS: median 46.8 vs 43 months (HR 1.02, 95% CI 0.39-2.63)

No targeted agents are currently approved in stage III NSCLC following definitive chemoradiotherapy. In metastatic NSCLC, single-agent osimertinib is the standard and preferred first-line option in the U.S. for patients with EGFR-mutant disease, though the agent is also now approved in combination with first-line chemotherapy based on a PFS benefit in FLAURA-2. The third-generation EGFR inhibitor is also approved as adjuvant therapy in patients with operable NSCLC who harbor EGFR mutations, where it has demonstrated an OS benefit.

Molecular Testing ‘Critical,’ but Barriers Persist

In his presentation, Ramalingam argued that to achieve the optimal outcomes shown in the LAURA trial, EGFR mutation testing should be conducted for all patients with stage III disease. Unfortunately, he said, the testing rate is still not 100%. “It’s way short of that,” he said.

Ramalingam cited practical barriers, such as not attaining sufficient tissue initially; barriers related to insurance coverage; and also awareness at large.

“I don’t think everybody is fully aware of the implications, the value of molecular testing, and how critical it is to make treatment decisions for patients,” he said.

ASCO’s Chief Medical Officer Julie Gralow, MD, a breast cancer expert who moderated the press briefing, expressed frustration over fighting prior authorizations to get molecular testing for patients.

“You will get it approved, it just takes so much time and effort and resources,” she said. “These are FDA-approved therapies that have a diagnostic that goes along with them, it should be covered, there are games being played at the payer level.”

It’s not just lung cancer, she added. “For many cancers now we need to be doing next-gen sequencing, broader molecular testing, and we’ve got to take out all the barriers that we can.”

Study Details

Ramalingam presented the primary analysis of the LAURA trial, a double-blind phase III study that randomized 216 patients with unresectable stage III NSCLC who had undergone definitive chemoradiation, had no evidence of disease progression during or after it, and harbored EGFR mutations (exon 19 deletions or L858R). Patients were randomized 2:1 to receive oral osimertinib (80 mg per day) or placebo until disease progression or unacceptable toxicity.

Baseline characteristics were well balanced, though more patients had a World Health Organization performance-status score of 0 in the osimertinib group (56% vs 42% in the placebo group). Overall, participants had a median age of 62-64, more than 60% were women, and more than two-thirds were never smokers. Most (over 80%) were enrolled from Asia, which was a stratification factor in the trial.

Stage IIIB disease was the most common disease stage (47-52%), followed by IIIA (33-36%) and IIIC (15-17%). The vast majority of patients were treated with concurrent rather than sequential chemoradiation, nearly all had adenocarcinoma, and a majority (52-59%) had exon 19 deletions.

The primary analysis for PFS was assessed by blinded independent central review. At 1 and 2 years, the PFS rates were 74% and 65% in the osimertinib arm versus 22% and 13% in the placebo arm. The PFS benefit was consistent across key subgroups, said Ramalingam.

During follow-up, 22% of patients on osimertinib developed new lesions as compared with 68% of those on placebo, most commonly in the brain (8% vs 29%), a common site of metastasis in EGFR-mutant disease, or new lung lesions (6% vs 29%).

Objective response rates were nearly twice as higher in the osimertinib arm (57% vs 33% with placebo), with a median duration of response of 36.9 months versus 6.5 months, respectively.

No new safety signals were detected, said Ramalingam. The most common adverse events (AEs) of any grade in the osimertinib and placebo arms, respectively, were radiation pneumonitis (48% vs 38%), diarrhea (36% vs 14%), rash (24% vs 14%), and COVID-19 (20% vs 8%). Grade ≥3 AEs were more frequent with osimertinib (35% vs 12%), as were serious AEs (38% vs 15%).

Many AEs were spillover events from chemoradiation, Ramalingam said, and he noted that patients were on osimertinib for nearly four times as long as placebo, which contributed to higher AE rates in the study arm.

There were three (2%) fatal AEs in the osimertinib arm (pneumonia, pneumonitis, and a traffic accident) and two (3%) in the placebo arm (aortic aneurysm rupture and myocardial infarction).

  • author['full_name']

    Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.

Disclosures

The study was funded by AstraZeneca.

Ramalingam disclosed relationships with AstraZeneca, Amgen, Arcus Biosciences, Array Biopharma, Bristol Myers Squibb, Janssen, Merck, Pfizer, and Takeda Oncology.

Spigel disclosed relationships with multiple pharmaceutical companies, including AstraZeneca.

Gralow had no disclosures.

Herbst reported relationships with the American Association for Cancer Research, the American Cancer Society, AbbVie, AstraZeneca, BMS, Bolt Biotherapeutics, Checkpoint Therapeutics, Candel Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, eFFECTOR Therapeutics, EMD Serono, Genentech/Roche, Gilead/Forty Seven, HiberCell, I-Mab, Immune-Onc Therapeutics, IASLC, Immunocore, Janssen, Johnson & Johnson, Junshi Pharmaceuticals, Lilly, Loxo, Merck, Mirati Therapeutics, NextCure, Novartis, Normunity, Ocean Biomedical, OncoCyte, Oncternal Therapeutics, Pfizer, Refactor Health, Regeneron, Revelar, Ribon Therapeutics, Sanofi, Seagen, the Society for Immunotherapy of Cancer, SWOG, and Xencor.

Primary Source

New England Journal of Medicine

Source Reference: Lu S, et al “Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC” N Engl J Med 2024; DOI: 10.1056/NEJMoa2402614.



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