Osimertinib delays progression ‘way more’ than hoped in EGFR-mutant lung cancer
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Key takeaways:
- Osimertinib significantly improved PFS compared with placebo in patients with advanced EGFR-mutant NSCLC.
- Early OS trends favored osimertinib over placebo.
CHICAGO — Osimertinib following chemoradiotherapy drastically improved PFS compared with placebo in patients with advanced EGFR-mutant non-small cell lung cancer in a randomized phase 3 trial.
Blinded independent review and study investigators separately determined a greater than 80% risk reduction for those treated with the osimertinib-based regimen, according to results presented at ASCO Annual Meeting.
“When we saw the hazard ratio, we were very excited because it exceeded our expectations,” Suresh S. Ramalingam, MD, FACP, FASCO, executive director of Winship Cancer Institute of Emory University, told Healio.
“A hazard ratio of 0.16 with a median PFS of 39 vs. 5.5 months was way more than what we hoped to see,” he added. “We’re very excited for what this means for the patients who have this disease.”
Background and methodology
Roughly 33% of individuals who have NSCLC are diagnosed with stage III disease, and 60% to 90% have unresectable tumors, according to background information Ramalingam presented.
More than 30% of patients with unresectable stage III NSCLC have EGFR mutations, according to background information researchers provided.
Standard of care for this population includes consolidation durvalumab (Imfinzi, AstraZeneca) if individuals do not progress following chemoradiotherapy, but benefits of this regimen have not been clearly defined.
“There are no approved targeted therapies for unresectable stage III EGFR-mutant NSCLC,” Ramalingam said.
Osimertinib (Tagrisso, AstraZeneca) — a third-generation EGFR-directed tyrosine kinase inhibitor (TKI) — has been previously approved for adults with advanced or metastatic EGFR-mutant NSCLC or as adjuvant therapy for resectable EGFR-mutant NSCLC.
“No. 1, it has high mutation selectivity,” Ramalingam told Healio when asked about the success of osimertinib. “It targets a mutated cell, mutated receptor almost 200-fold more likely than [a] normal cell. That has huge implications in the side effect profile. It’s well tolerated and highly effective and, therefore, it has been incredibly successful.”
The LAURA study investigated osimertinib benefits in patients aged at least 18 years (at least 20 years in Japan) with unresectable stage III EGFR-mutant NSCLC with performance status of 0 or 1 who had previously received platinum-based concurrent chemoradiotherapy.
Researchers randomly assigned 216 patients in a 2:1 ratio to receive osimertinib (80 mg once a day) or placebo until progression or discontinuation. Participants received imaging, including brain MRIs, every 8 weeks until week 48, and then every 12 weeks.
Researchers evaluated PFS as the study’s primary endpoint and OS as a secondary endpoint.
Results
A blinded independent review determined osimertinib significantly improved PFS compared with placebo (HR = 0.16; 95% CI, 0.1-0.24).
Patients in the treatment arm had a median PFS of 39.1 months compared with 5.6 in the placebo arm.
Investigators also found osimertinib had superior PFS (HR = 0.19; 95% CI, 0.12-0.29).
Osimertinib delivered significant improvement in 1-year PFS vs. placebo (74% vs. 22%) and 2-year PFS (65% vs. 13%).
Trends favored osimertinib in the OS analysis as well (HR = 0.81; 95% CI, 0.42-1.56), although that analysis only had 20% maturity.
Researchers are not adjusting for crossover in their OS analysis, which drew praise from David R. Spigel, MD, chief scientific officer at Sarah Cannon Research Institute, who spoke as an invited expert to analyze the results.
“We need to applaud the study designers, the investigators for offering osimertinib [to] patients who progressed on the placebo arm,” Spigel said. “We don’t always do that because we’re trying to find an overall survival benefit, but in this case, it was the right thing to do. When patients progress, they don’t always get a chance to get that crossover therapy or that next line of therapy. In fact, in lung cancer, about 40% of patients will never make it to the next line of therapy, so to have an 84% reduction in your chance of cancer growing or dying by receiving osimertinib after chemoradiotherapy is the right thing to do, and this will be practice changing.”
The osimertinib cohort had more all-cause adverse events (98% vs. 88%), grade 3 or worse (35% vs. 12%) adverse events, serious adverse events (38% vs. 15%), radiation pneumonitis toxicities (48% vs. 38%; most grade 1 or 2), and adverse events leading to treatment discontinuation (13% vs. 5%).
“The majority of adverse events in the osimertinib arm were grade one or two and did not lead to treatment discontinuation,” Ramalingam said during his presentation.
Next steps
Julie R. Gralow, MD, FACP, FASCO, ASCO chief medical officer and executive vice president and press conference moderator, said osimertinib would “change standard practice,” but did question why it did not get tested against the standard of care.
Ramalingam told Healio it would have prevented patients in the control arm from crossing over in a timely fashion.
“Over the past 10 years, since immune checkpoint inhibitors have made their way in lung cancer, we’ve learned they don’t benefit patients with EGFR-mutated lung cancer given as a single agent or even in combination with chemotherapy. Randomized trials have shown that,” he said. “No. 2, if we had given durvalumab in the control group and the patient progresses, we have to wait for at least 2 to 3 months before we can expose them to a TKI because of the interaction between osimertinib — and any other TKI for that matter — and immune checkpoint inhibition, and that would not be beneficial to patients.”
Ramalingam noted future research should focus on osimertinib as a possible front-line therapy and overcoming resistance.
“We now have a good understanding of various mechanisms that drive resistance, and the next step would be to develop therapies for each of those diverse group of resistance mechanisms,” he told Healio.
Ramalingam, Gralow and others also stressed the importance of molecular testing. Barriers such as insurance issues, prior authorization and awareness, among others, prevent many from getting it.
“I don’t think everybody is fully aware of the implications of the value of molecular testing and how critical it is to make treatment decisions for patients,” Ramalingam said during a press conference. “I think together we all have a responsibility to educate everyone, the medical community and the patient. There are some states that are passing laws that require insurance companies to cover molecular profiling — we had that passed in our state of Georgia last year — and I hope more and more states will do. When you look at the situation beyond the United States, these problems are even greater because of a variety of reasons, resources being a key force.”
Ramalingam has high hopes though. He has seen immense progress in the treatment of lung cancer over the past 2 decades, like with osimertinib, and expects more to follow.
“When I entered the field as an oncologist more than 20 years ago, there were very little in terms of therapies for patients with lung cancer,” he said. “Now, my clinic is filled with patients who’ve been on drugs or off treatment for months, years, and have gone through so many milestones in their lives that are meaningful to them, and to be able to have a conversation not just about cancer, but about patients’ personal lives, how they’re doing, is really rewarding for me as an oncologist.
“When you look at the LAURA study and the patient population, in the control group, half the patients progressed in 5.5 months after completing chemoradiation, 90% of the patients progressed within 2 years. This is a disease that’s highly aggressive. To introduce a targeted therapy from which they can have benefits that last that long is, I think, truly practice changing.”
For more information:
Suresh S. Ramalingam, MD, FACP, FASCO, can be reached at ssramal@emory.edu.
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Ramalingam SS, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; May 31-June 4, 2024: Chicago.
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