NAUTIKA1: A Multicenter Phase II Study with a PD-L1+ Cohort of Patients Receiving Atezolizumab (Atezo) with Low-Dose Stereotactic Body Radiation Therapy (SBRT) as Neoadjuvant Therapy for Resectable Stage IB-III NSCLC

Abstract

<h3>Purpose/Objective(s)</h3> Despite complete surgical resections, cure rates in early-stage NSCLC remain modest. Neoadjuvant and adjuvant chemotherapy (chemo) trials have shown a 5-year overall survival (OS) benefit of 5% in patients (pts) with resectable disease. Developing new treatment strategies to increase cure rates following resection remains critical. Phase III trials including IMpower030, Checkmate 816, AEGEAN, Keynote-671, and Checkmate 77T, tested checkpoint inhibitors (CPIs) in combination with chemo. Checkmate 816 met the primary endpoint with a pathological complete response (pCR) rate of 24% and event-free survival (EFS) in pts with resectable stage IB-IIIA NSCLC. Despite the positive results with CPI + chemo, chemo-free options are still needed for some patients. Preclinical and clinical data in advanced NSCLC indicate that low-dose SBRT may be a potent immunomodulator, enhancing immune response facilitated by CPIs (Demaria et al, 2015; Formenti et al, 2018; Theelen et al, 2019). In a Phase II study, neoadjuvant durvalumab combined with low-dose SBRT (8 Gy × 3) was well tolerated and associated with a major pathologic response (MPR) rate of 53% (Altorki et al, 2021). Given the evidence for atezo antitumor activity in early-stage NSCLC, as seen in LCMC3 (Lee et al, 2020) and IMpower010 (which led to FDA approval of atezo as adjuvant treatment following resection and platinum-based chemo in pts with stage II-IIIA NSCLC, who have PD-L1 expression on ≥1% of tumor cells), NAUTIKA1 now includes a PD-L1+ cohort to explore neoadjuvant atezo with low-dose SBRT. <h3>Materials/Methods</h3> NAUTIKA1 (NCT04302025) PD-L1+ cohort will enroll pts with resectable stage IB-IIIA or select IIIB (T3N2 only) NSCLC (8th edition AJCC TNM staging). Pts must have PD-L1+ status (defined as expression in ≥1% tumor cells by any FDA-approved PD-L1 assay) performed in a Clinical Laboratory Improvement Amendments–certified laboratory. Pts will receive up to 4 cycles of neoadjuvant atezo in combination with low-dose SBRT (8 Gy × 3) in the first cycle, followed by surgical resection and standard-of-care adjuvant treatment. The primary efficacy objective is to evaluate pCR, defined as lack of any viable tumor cells on local pathology review of H&E slides from the lung cancer resection specimen, including all sampled regional lymph nodes. Secondary objectives include investigator-assessed radiographic response, MPR, disease-free survival, EFS, OS, nodal downstaging and circulating tumor DNA clearance. The safety objective includes evaluation of the incidence and severity of adverse events. Exploratory endpoints include correlation of pre- and post-treatment tissue and blood biomarkers with clinical outcome mechanisms of immune escape, as well as evaluation of artificial intelligence–powered digital pathologic response assessment. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD