Osimertinib New Standard of Care for Stage 3, EGFRm NSCLC

Hippensteele,Alana;

Primary results from the phase 3 LAURA study (NCT03521154) demonstrated that osimertinib (Tagrisso; AstraZeneca) showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients with unresectable stage 3 EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC), with exon 19 deletions or exon 21 (L858R) mutations, who have been treated with chemoradiotherapy (CRT), according to principal study investigator Suresh Ramalingam, MD, FACP, FASCO, during a plenary session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Additionally, the LAURA study showed no unexpected safety signals.^1,2

Ramalingam, executive director of Winship Cancer Institute of Emory University, explained that these results, which were simultaneously published in The New England Journal of Medicine, establish osimertinib as the new standard of care (SoC) for EGFRm NSCLC in this setting.^1,3

“The impressive [PFS] results from the LAURA phase 3 trial represent a major breakthrough for patients with stage 3 EGFRm lung cancer for whom no targeted treatments are available,” Ramalingam said. “Osimertinib delayed the risk of disease progression or death by an unprecedented 84% and should become the new [SoC] for patients in this setting based on these data.”¹

According to Ramalingam, patients with NSCLC are often diagnosed at locally advanced and advanced stage disease. Further, nearly a third of patients with unresectable stage 3 NSCLC have EGFR mutations.¹

“For these patients, the current [SoC] is giving chemotherapy with radiation together, followed by 1 year of immune checkpoint inhibition in the form of durvalumab [Imfinzi; AstraZeneca],” Ramalingam said during the ASCO presentation. “Now, while this has been used routinely over the past 2 years, whether this benefits patients with EGFR mutation has not been clear. In fact, a subset analysis of the pivotal PACIFIC study [NCT04612244] that showed durvalumab is a new [SoC] failed to show a difference in outcomes for patients with EGFR mutation between durvalumab and placebo. On the other hand, a number of smaller studies have shown that using EGFR inhibition in this setting may be beneficial.”¹

A third-generation central nervous system-active EGFR-tyrosine kinase inhibitor, osimertinib has been routinely used for EGFRm advanced/metastatic NSCLC and, more recently, has been used as adjuvant therapy for resectable EGFRm NSCLC. The global, double-blind, placebo-controlled phase 3 LAURA study investigated the efficacy and safety of osimertinib in unresectable stage 3 EGFRm NSCLC. Investigators randomly assigned patients (N=216) with unresectable EGFRm stage 3 NSCLC without progression during or after CRT to receive osimertinib (n=143) or placebo (n=73) until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point of the trial was PFS (as assessed by blinded independent central review).^1,3

“Patients were randomized 2 to 1 for treatment with osimertinib at 80 mg per day or placebo,” Ramalingam said. “Treatment was continued until the patients benefited from therapy or experienced some form of toxicity that made it unviable to continue the treatment. For patients in the placebo group who had confirmed progression, the study provided osimertinib as crossover therapy.”¹

Ramalingam noted that patients underwent CT scans of the chest at baseline and an MRI of the brain at baseline with follow up at regular intervals throughout the course of the study.¹

“I'm excited to say that osimertinib provided a clinically significant and statistically significant improvement in [PFS]. The median PFS was 39.1 months with osimertinib compared to 5.6 months for patients given placebo with a hazard ratio of 0.16 [95% confidence interval (CI), 0.10-0.24; P<0.001], which was statistically significant,” Ramalingam said. “The 2-year PFS rate was substantially better for patients treated with osimertinib.”^1,3

The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65-80) with osimertinib and 22% (95% CI, 13-32) with placebo. Interim overall survival (OS) data (maturity, 20%) showed 36-month OS among 84% of patients with osimertinib (95% CI, 75-89) and 74% with placebo (95% CI, 57-85), with a hazard ratio for death of 0.81 (95% CI, 0.42-1.56; P=0.53).^1,3

“When we look at percentage of patients that developed new lesions while they were on study treatment, 68% of patients in the placebo group developed a new cancer lesion compared to 22% in the osimertinib group,” Ramalingam said. “When we looked specifically at brain, which is a site for common disease progression for EGFRm NSCLC, the incidence was much lower for patients on osimertinib at 6% vs [placebo at] 28%.”¹

Similarly, Ramalingam noted that progression within the lung was also lower for patients receiving osimertinib vs placebo.¹

“All of this adds to the fact that osimertinib reduced the incidence of new lesions both within the chest and outside the chest, and particularly in the brain,” Ramalingam said.¹

Key Takeaways

Significant Improvement in Progression-Free Survival (PFS): The LAURA phase 3 study demonstrated that osimertinib (Tagrisso; AstraZeneca) significantly improved PFS for patients with unresectable stage 3 EGFR-mutated (EGFRm) non–small cell lung cancer (NSCLC) who were treated with chemoradiotherapy. The median PFS was 39.1 months for patients on osimertinib compared to 5.6 months for those on placebo, representing an unprecedented 84% reduction in the risk of disease progression or death.
New Standard of Care: Based on the results, osimertinib is the new standard of care for patients with EGFRm stage 3 NSCLC. This conclusion is supported by the substantial PFS benefit and the favorable safety profile observed in the study, despite a slightly higher incidence of radiation pneumonitis and common EGFR inhibitor-related adverse effects, such as skin rash and diarrhea.
Safety and Crossover Therapy: The study showed no new or unexpected safety signals for osimertinib. Additionally, patients in the placebo group who experienced disease progression were offered osimertinib as crossover therapy, reflecting a considerate trial design. This approach not only underscores the ethical aspect of providing effective treatment to all participants, but also highlights the practical importance of osimertinib in managing this patient population.

Adverse events [AEs] of grade 3 or higher occurred in 35% of patients in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. Based on these results, Ramalingam explained that no new safety concerns were present in the trial.^1,3

“There are spillover toxicities from prior chemotherapy and radiation, and radiation pneumonitis is the most common [AE] for this patient population. When you see the osimertinib group, there was a slightly higher incidence of radiation pneumonitis, and the skin rash and diarrhea that we see with EGFR inhibitors were seen, [but] these were all primarily low grade in severity, with very few grade 3 or 4 events,” Ramalingam said. “I would also point out that the duration of time for which patients were on treatment with osimertinib was almost 4 times higher, so they had more likelihood of reporting [AEs].”¹

Additionally, any AEs leading to discontinuation were reported in 13% vs 5% of patients for osimertinib vs placebo, respectively.¹

“At this point the [OS] results are not mature, as there is a high proportion of patients crossing over from the control arm. While we see a favorable trend towards osimertinib, we are not able to report on superiority of survival at this point,” Ramalingam said. “I will say that based on these results, osimertinib will become the new [SoC] for patients with locally advanced [NSCLC] following definitive [CRT], and EGFR mutation testing should be conducted for patients with stage 3 disease in order for patients to achieve optimal outcomes.”¹

David Spigel, MD, a board-certified medical oncologist and the chief scientific officer at Sarah Cannon Research Institute, commented on the trial results, providing 3 points regarding why the data show osimertinib is now the new SoC.¹

“Number 1, to have an 84% reduction in the risk of cancer progression or death is meaningful to not just patients, but the providers that are overseeing their care. The second point is the crossover. We need to applaud the study designers and investigators for offering osimertinib for patients who progressed on the placebo arm. We don't always do that, because we're trying to find an [OS] benefit. But in this case, it was the right thing to do,” Spigel said. “The third point is when patients progress, they don't always get a chance to get that crossover therapy or that next-line of therapy.”¹

In fact, in lung cancer, approximately 40% of patients will never make it to the next line of therapy, according to Spigel.¹

“To have an 84% reduction in your chance of cancer growing or dying by receiving osimertinib after [CRT] is the right thing to do, and this will be practice changing,” Spigel said. “Starting as soon as this becomes available and the label gets expanded, this will be how patients are treated wherever they can get access to this drug.”¹