Phase 3 LAURA Study to Explore Efficacy of Maintenance Osimertinib in Stage III EGFR-Mutant NSCLC

The phase 3 LAURA clinical trial (NCT03521154) is currently enrolling patients with stage III, unresectable EGFR-mutant non–small cell lung cancer (NSCLC) to explore the efficacy and safety of the third-generation tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) as maintenance therapy following chemoradiation.

The current standard of care for this patient population is platinum-based chemoradiation therapy (CRT) followed by durvalumab (Imfinzi) consolidation therapy based on results of the phase 3 PACIFIC trial (NCT02125461); but only 6% of those harbored EGFR mutations, resulting in inconclusive results about the therapy’s efficacy due to the limited number of patients.

Despite limited data for patients with stage III EGFR-mutant NSCLC, evidence has suggested that these patients have superior local, but inferior distant, control following platinum-based CRT compared with those who have EGFR wild-type disease. This lack of activity with distant metastases, including those in the central nervous system (CNS), highlights the need for targeted therapy in patients with these disease features.

The irreversible, oral EGFR TKI osimertinib inhibits EGFR mutations potently and selectively, and has shown efficacy in NSCLC CNS metastases. The phase 3 FLAURA (NCT02296125) and phase 3 ADAURA (NCT02511106) clinical trials demonstrated efficacy of osimertinib monotherapy in the first-line metastatic and adjuvant settings, respectively, indicating potential benefit in patients with unresectable stage III EGFR-mutant NSCLC.

LAURA aims to evaluate the efficacy and safety of osimertinib as maintenance therapy in this population of patients with locally advanced, unresectable, EGFR-mutant stage III disease who did not progress during or after definitive platinum-based CRT. The primary end point of the study progression-free survival (PFS) per RECIST 1.1 according to blinded independent central review (BICR); secondary end points include CNS PFS, PFS by mutational status, overall survival (OS), safety, and tolerability. Patient-reported outcomes and correlation of baseline tumor and plasma biomarkers with clinical outcomes serve as exploratory end points.

Recruitment was initiated in July 2018, and patients will enroll across 17 countries and 132 clinical sites. To date, 15 countries have received regulatory approval to initiate the trial, 12 of which have their first active site and are ready to enroll patients. Ten countries have screened their first patient and 9 have begun to randomize patients.

The double-blind, randomized, placebo-controlled study includes a 2-part screening phase. For part 1, the EGFR mutational status is determined, and in part 2, patient eligibility is confirmed following CRT imaging for complete responses, partial responses, or stable disease. Patients who are eligible for the trial are 18 years or older in most countries (20 in Japan) and have unresectable stage IIIA/IIIB/IIIC EGFR-mutant NSCLC with either an EGFR exon 19 deletion or EGFR L858R.

A total of 200 patients will be randomized 2:1 to receive either 80 mg osimertinib once daily or placebo. Treatment will be administered until objective radiological disease progression by BICR per RECIST 1.1.

Post-progression, patients who received osimertinib in the experimental arm will be eligible to continue on open-label osimertinib, and patients in the placebo arm will have the option to receive the EGFR TKI following progression. Patients who receive additional therapy post-progression will be followed for PFS, time to first subsequent therapy, time to second subsequent therapy, and OS.

To be included in the trial, patients must have received concurrent or sequential CRT, which should include at least 2 cycles or 5 weekly doses of platinum-based chemotherapy. CRT had to be completed at least 6 weeks prior to study randomization with no evidence of disease progression during/after CRT, and patients also had to have creatinine levels ≤ 1.5 times the upper limit of normal or creatinine clearance ≥ 30 mL/min, as well as a World Health Organization performance status of 0 or 1.

Patients will be excluded from enrolling on to the study if they have a history of interstitial lung disease prior to CRT, symptomatic pneumonitis following CRT, or unresolved toxicity of CTCAE greater than grade 2 from prior CRT. Patients will also be ineligible for LAURA if they have received prior treatment with an EGFR TKI, chemotherapy, radiotherapy, immunotherapy, or an investigational agent for NSCLC beyond the definitive setting for stage III disease as part of CRT.

In February 2020, a few key protocol changes were made. Based on these changes, patients with squamous histology who have a pre-existing local positive EGFR test result are now eligible for screening in part 1. The minimum value for creatinine clearance was reduced from 50 mL/min to 30 mL/min. Patients may receive open-label osimertinib following a BICR-confirmed progression prior to PFS analysis; following analysis, patients may receive open-label treatment with osimertinib after investigator-assessed disease progression. A protocol change also called for an increased duration of monitoring of AEs of special interest during progression and survival follow-up.

Data for the primary PFS analysis are expected in August 2022.

_Reference

_{Lu S, Casarini I, Kato T, et al. LAURA: Osimertinib maintenance following definitive chemoradiation therapy (CRT) in patients with unresectable Stage III epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC). Presented at: ESMO Asia 2020 Congress; November 20-22, 2020; Virtual. Abstract #374TiP}