Osimertinib Could Alter SOC for Stage III EGFR+ NSCLC

Suresh S. Ramalingam, MD, FACP, FASCO

Treatment with osimertinib (Tagrisso) following definitive chemoradiotherapy led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs placebo in patients with locally advanced, unresectable, stage III non–small cell lung cancer (NSCLC) harboring an EGFR mutation, according to data from the phase 3 LAURA trial (NCT03521154).^1,2

Findings presented during a press briefing at the 2024 ASCO Annual Meeting demonstrated that treatment with osimertinib reduced the risk of progression or death by 84% compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001). Patients treated with osimertinib (n = 143) experienced a median PFS of 39.1 months (95% CI, 31.5–not calculable [NC]) vs 5.6 months (95% CI, 3.7-7.4) for patients who received placebo (n = 73).¹

The 12- and 24-month PFS rates in the osimertinib arm were 74% and 65%, respectively. Those respective rates were 22% and 13% in the placebo arm.

“Based on these results, osimertinib will become the new standard of care for patients with [EGFR-mutated], locally advanced NSCLC following definitive chemoradiation. EGFR mutation testing should be conducted for patients with stage III disease in order for patients to achieve optimal outcomes,” lead study author Suresh S. Ramalingam, MD, FACP, FASCO, executive director of Winship Cancer Institute of Emory University and associate vice president for cancer of Woodruff Health Sciences Center in Atlanta, Georgia, said in the press briefing.

For patients with unresectable stage III NSCLC, consolidation durvalumab (Imfinzi) is the standard of care after chemoradiotherapy for patients who do not experience disease progression. However, the benefit of durvalumab consolidation is unclear for patients who harbor EGFR mutations, based on a post-hoc analysis from phase 3 PACIFIC trial (NCT02125461), which did not show a significant PFS difference between durvalumab (n = 24) and placebo (n = 11) in patients with EGFR-mutated disease (HR, 0.91; 95% CI, 0.39-2.13).³

Notably, no targeted therapies are currently approved for patients with EGFR-mutated, unresectable, stage III NSCLC.¹

LAURA was a double-blind, placebo-controlled trial that enrolled patients at least 18 years of age (or at least 20 years of age in Japan) with locally advanced, unresectable, stage III NSCLC harboring an EGFR exon 19 deletion or L858R mutation who did not experience disease progression following definitive chemoradiotherapy.^1,4 Patients needed to have a WHO performance status of 0 or 1, and the maximum interval between the last dose of chemoradiotherapy and randomization was 6 weeks.¹

Patients were randomly assigned 2:1 to receive 80 mg of oral osimertinib or placebo once per day. Treatment continued until blinded independent central review (BICR)–assessed disease progression per RECIST 1.1 criteria, unacceptable toxicity, or other discontinuation criteria were met.

Notably, patients in both arms were permitted to receive open-label osimertinib following BICR-confirmed disease progression. Tumor assessments were conducted via chest CT/MRI and brain MRI at baseline, then once every 8 weeks until week 48, then once every 12 weeks thereafter until BICR-confirmed progression.

Stratification factors included method of chemoradiotherapy (concurrent vs sequential), disease stage (IIIA vs IIIB/C), and location (China vs not China).

BICR-assessed PFS per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included overall survival (OS), central nervous system PFS, and safety.

Baseline characteristics showed the median age of patients was 62 years (range, 36-84) in the osimertinib arm and 64 years (range, 37-83) in the placebo arm. The majority of patients were male (osimertinib, 63%; placebo, 58%), never smoked (71%; 67%), were Asian (81%; 85%), had stage IIIB disease (47%; 52%), had adenocarcinoma (97%; 95%), harbored EGFR exon 19 deletions (52%; 59%), and received concurrent chemoradiotherapy (92%; 85%).

Responses to prior chemoradiotherapy included complete response (CR; osimertinib, 3%; placebo, 4%), partial response (PR; 47%; 37%), stable disease (SD; 43%; 51%), and not evaluable (8%; 8%).

OS data were immature at data cutoff; however, Ramalingam noted that a trend favoring osimertinib was observed, “[despite] a high proportion of patients crossing over from the control arm [81%].” The median OS was 54.0 months (95% CI, 46.5-NC) for osimertinib vs not reached (95% CI, 42.1-NC) for placebo (HR, 0.81; 95% CI, 0.42-1.56; P = .530).

Patients in the osimertinib arm experienced an objective response rate of 57% (95% CI, 49%-66%) compared with 33% (95% CI, 22%-45%) for those given placebo. The disease control rate was 89% (95% CI, 83%-94%) and 79% (95% CI, 68%-88%), respectively. The median duration of response was 36.9 months (95% CI, 30.1-NC) for osimertinib and 6.5 months (95% CI, 3.6-8.3) for placebo.

Additional data showed 22 patients in the osimertinib arm experienced new lesions compared with 68 patients in the placebo arm. Sites of new lesions included the brain (osimertinib, n = 8; placebo, n = 29), lung (n = 6; n = 29), liver (n = 3; n = 7), lymph nodes (n = 1; n = 7), bone (n = 1; n = 1), adrenal (n = 1; n = 0), peritoneum/omentum (n = 1; n = 0), pelvis (n = 1; n = 0), spleen (n = 0; n = 1), and other (n = 1; n = 0).

Regarding safety, Ramalingam said findings for osimertinib following chemoradiotherapy were consistent with the known safety profile of the EGFR inhibitor and manageable, noting that most adverse effects (AEs) were not serious, were grade 1/2, and did not lead to treatment discontinuation.

The most common any-grade AEs reported in at least 10% of patients included radiation pneumonitis (osimertinib, 48%; placebo, 38%), diarrhea (36%; 14%), rash (24%; 14%), COVID-19 (20%; 8%), paronychia (17%; 1%), cough (16%; 10%), decreased appetite (15%; 5%), dry skin (13%; 5%), pruritus (13%; 7%), stomatitis (12%; 3%), decreased white blood cell count (12%; 3%), pneumonia (11%; 8%), anemia (10%; 4%), and musculoskeletal chest pain (3%; 12%).

Grade 3 or higher AEs in the osimertinib arm included pneumonia (3%), radiation pneumonitis (2%), diarrhea (2%), COVID-19 (1%), decreased appetite (1%), dry skin (1%), decreased white blood cell count (1%), and anemia (1%).

“The LAURA trial is the first to define the role of EGFR-directed therapy in unresectable stage III disease. While the study did not compare osimertinib to the current standard-of-care immunotherapy, these data have major implications for both patients and oncologists and will change the standard of care for patients with EGFR mutations,” David R. Spigel, MD, chief scientific officer of Sarah Cannon Research Institute in Nashville, Tennessee, stated in a news release.²

Editor's note: The article on the LAURA study was published on June 2, 2024, from a press briefing, and was updated later on June 2, 2024, with additional information/data from the oral session.

References

1. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4
2. Osimertinib poised to change standard of care treatment for patients with locally advanced EGFR-mutated NSCLC. News release. ASCO. June 2, 2024. Accessed June 2, 2024. https://society.asco.org/about-asco/press-center/news-releases/osimertinib-poised-change-standard-care-treatment-patients
3. Naidoo J, Antonia S, Wu YL, et al. Brief report: durvalumab after chemoradiotherapy in unresectable stage III EGFR-mutant NSCLC: a post hoc subgroup analysis from PACIFIC. J Thorac Oncol. 2023;18(5):657-663. doi:10.1016/j.jtho.2023.02.009
4. A global study to assess the effects of osimertinib following chemoradiation in patients with stage III unresectable non-small cell lung cancer (LAURA). ClinicalTrials.gov. Updated April 26, 2024. Accessed June 2, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03521154