January 28, 2021 - The NeoADAURA trial will evaluate the safety and efficacy of neoadjuvant osimertinib, as a single agent or in combination with platinum-based chemotherapy compared with chemotherapy alone, in patients with resectable, stage II-IIIB non–small cell lung cancer whose tumors harbor EGFR mutations.
The NeoADAURA trial (NCT04351555) will evaluate the safety and efficacy of neoadjuvant osimertinib (Tagrisso), as a single agent or in combination with platinum-based chemotherapy compared with chemotherapy alone, in patients with resectable, stage II-IIIB non–small cell lung cancer (NSCLC) whose tumors harbor EGFR mutations, according to data presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC).1
The primary end point of the study is focused on evaluating major pathological response (MPR), which is defined as less than or equal to 10% of residual cancer cells in the lung tumor specimen following surgery per central assessment. The study sample was based on approximately a 90% power to identify a statistically significant 20 percentage point difference in MPR, with a 2-sided overall significance level of 5% when assuming a 20% MPR in the control arm.
One interim futility analysis will be performed based on MPR, the smallest treatment effect of absolute difference of 6% versus the control arm, will be performed; this will happen after approximately half of the study participants have undergone surgery.
Key secondary end points for the study include event-free survival, pathological complete response, downstaging, disease-free survival (DFS), overall survival (OS), MPR in patients with or without detectable EGFR mutations in plasma circulating tumor DNA at screening, disease-related symptoms and health-related quality of life, as well as safety and tolerability.
About 30% of patients with NSCLC present with resectable disease, and the primary treatment for this population is curative surgery; however, prognosis after surgery continues to be poor. Neoadjuvant or adjuvant chemotherapy is recommended for certain patients with resectable stage 3 disease, irrespective of EGFR status, as this has been proven to have clinical benefit.
For example, results from a prior phase 3 study showed that preoperative chemotherapy significantly improved outcomes for patients with stage IIB/IIIA NSCLC compared with surgery alone. The progression-free survival (PFS) rate at 3 years was 36.1% with preoperative chemotherapy versus 55.4% with surgery alone (P = .002). However, improved treatment options for patient with stage 2-3 disease are still needed, as the 5-year probability for OS is 65% for those with stage IIA disease, 56% for those with stage IIB disease, 41% for stage IIIA disease, and 24% for stage IIIB disease.
The third-generation, irreversible EGFR TKI osimertinib was developed to inhibit EGFR sensitizing mutations and T790M resistance mutations, as well as to have central nervous system (CNS) activity. In the pivotal phase 3 ADAURA trial (NCT02511106), the agent resulted in a statistically significant improvement in DFS at 24 months (HR, 0.20; 99.12% CI, 0.14-0.30; P <.001) in patients with resected, EGFR-mutated, stage IB-IIIA NSCLC.2 This benefit led to the December 2020 FDA approval of osimertinib for use as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations. Moreover, updated data presented during the 2020 ESMO Virtual Congress showed that the EGFR TKI reduced the risk for CNS death or progression by 82% in this patient population.3
Recent studies have suggested that treatment with an EGFR TKI treatment could be feasible in the neoadjuvant setting in that it could potentially result in reduced tumor burden and eliminate micrometastases.
“Combining an EGFR TKI and chemotherapy in the neoadjuvant setting may optimize tumor downstaging and micrometastatic eradication,” the NeoADAURA authors wrote in the poster. “In advanced disease, combining an EGFR TKI with chemotherapy has resulted in improved PFS versus EGFR TKI [monotherapy].”
Additionally, results from a recent phase 2 study (NCT03433469) indicated that neoadjuvant osimertinib was well tolerated in patients with stage I-IIIA NSCLC. Participants went to surgical resection without experiencing any unscheduled delays.
Because of the favorable efficacy and tolerability data that have been reported with osimertinib in the advanced and adjuvant settings, investigators have set out to examine the agent in the neoadjuvant setting for patients with resectable disease.
The randomized, controlled, multicenter NeoADAURA trial will enroll a total of 351 patients with resectable, stage II-IIIB NSCLC whose tumors harbor EGFR mutations. Participants will be stratified by disease stage (II vs III), ethnicity (non-Asian vs Chinese vs other Asian), and type of EGFR mutation (exon 19 deletion or L858R deletion).
To be eligible for enrollment, patients have to be aged 18 years and have primary nonsquamous stage II-IIIB N2 NSCLC with EGFR mutations confirmed on their baseline tumor biopsy sample, or primary NSCLC that has been deemed to be completely resectable by a multidisciplinary team, including a thoracic surgeon. Patients must also have an ECOG performance status of 0-1, acceptable organ and bone marrow function, and a life expectancy of greater than 6 months prior to randomization.
If patients previously received systemic therapy for their disease, had mixed small cell and NSCLC histology, underwent preoperative radiotherapy, or had bulky N2 disease, they could not participate. Moreover, patients who were candidates for segmentectomies or wedge resections only were also excluded. If they had T4 tumors infiltrating the aorta, esophagus, and/or heart; a history of, or current, interstitial lung disease (ILD), drug-induced ILD, or radiation pneumonitis; severe or uncontrolled systemic diseases or active infections; a history of allogeneic organ transplantation, primary immunodeficiency, or another primary malignancy, among other criteria; they could not participate.
Patients will be randomized 1:1:1 to receive either daily placebo plus investigator’s choice of pemetrexed at 500 mg/m2 plus carboplatin AUC5 mg/ml/min or cisplatin at 75 mg/m2 given in 3 cycles every 3 weeks; osimertinib at a daily dose of 80 mg plus investigator’s choice of pemetrexed plus carboplatin or cisplatin at the same dosing schedule or osimertinib at a daily dose of 80 mg for 9 weeks. The first 2 arms will be double-blinded, while the third arm will be open-label, sponsor-blind.
After patients received treatment, they will go on to undergo surgery, be evaluated for MPR and pCR, and then go on to receive adjuvant treatment with investigator’s choice of therapy. Participants will be followed for OS for 5 years after surgery. Investigators will evaluate patients 12 weeks and 24 weeks following surgery, and then every 24 weeks thereafter, until disease recurrence or consent is withdrawn. Notably, osimertinib will be offered to all patients who complete surgery, with or without post-surgical chemotherapy, for up to 3 years, or until disease recurrence.
In the trial, investigators will also evaluate health resource use by utilizing the EQ-5D-5L health state utility index and metabolic response per PERCIST criteria. They will also evaluate genetic, gene expression, and proteomic markers, as well as examine the relationship between molecular evidence of disease and clinical response end points. Other exploratory end points of the trial include evaluating the relationship between molecular aberrations and response and learning more about human leukocyte antigen alleles linked with susceptibility to drug-related adverse effects.
Enrollment for the NeoADAURA trial began in December 2020. The trial will be available in 23 countries including the United States, Mexico, Brazil, Austria, Germany, Italy, the United Kingdom, Russia, China, India, South Korea, and Vietnam. Data from the prior MPR analysis are anticipated to be available in 2024.