VELOCITY-Lung substudy-03: A phase 2 study of neoadjuvant domvanalimab (dom)+zimberelimab (zim)+chemotherapy (chemo) or zim+chemo followed by adjuvant dom+zim or zim in patients with resectable stage II-III non-small cell lung cancer (NSCLC).

TPS8121 Background: Management of resectable NSCLC involves surgery with perioperative systemic therapy. Immune checkpoint inhibitors (CPIs) and targeted therapies are now used in the perioperative setting, leading to improved survival outcomes. The combination of dom (anti–T-cell immunoglobulin and ITIM domain [TIGIT]) and zim (anti–programmed death protein 1 [PD-1]) has shown promising antitumor activity with a manageable safety profile in metastatic NSCLC and may provide an opportunity to improve clinical outcomes in the perioperative setting in early-stage, resectable NSCLC. Substudy-03 of the VELOCITY-Lung platform study is evaluating novel perioperative treatment combinations in patients with newly diagnosed, resectable, stage II-III NSCLC. Methods: VELOCITY-Lung (NCT05633667) is an open-label, multicenter, phase 2 platform study with 3 ongoing substudies targeting the different NSCLC patient populations. Key eligibility criteria for Substudy-03 include age ≥ 18 years, histologically/cytologically confirmed stage II, IIIA, IIIB (T[3-4]N2) (per AJCC 8th ed.) squamous or nonsquamous NSCLC considered resectable with curative intent, no prior systemic or CPI therapy or radiotherapy, ECOG PS 0-1, any PD-1 ligand (PD-L1) status, and no actionable EGFR or ALK genomic alterations in patients with nonsquamous NSCLC. Randomization in Substudy-03 will be stratified by disease stage (II vs III) and baseline PD-L1 expression status (≥ 50% vs < 50%). Current treatment groups in the neoadjuvant phase of the preliminary stage are: (A) dom+zim+platinum (Pt)-based chemo or (B) zim+Pt-based chemo for a maximum of 3 cycles; this will be followed by definitive surgery within 6 weeks of completing neoadjuvant treatment. Adjuvant treatment will include: (A) dom+zim or (B) zim and will begin within 12 weeks of surgery. Patients will continue to receive adjuvant treatment until disease recurrence, death, or unacceptable toxicity or to a maximum of 14 cycles. Dosing will be as follows: zim 360 mg intravenously (IV) once every 3 weeks (Q3W) and dom 1200 mg IV once Q3W (up to 3 cycles in the neoadjuvant phase and up to 14 cycles in the adjuvant phase). Pt-based chemo will be based on patient tumor histology (squamous vs nonsquamous). The primary endpoint is pathological complete response rate, defined as the percentage of patients with no residual invasive cancer in resected lung specimens and lymph nodes, assessed by local pathology review. Secondary endpoints include major pathological response rate (percentage of patients with ≤ 10% residual tumor in lung and lymph nodes at surgery), event-free survival, overall survival, and safety. Approximately 31 patients will be enrolled into each treatment group of the preliminary phase. The study is currently recruiting. Clinical trial information: NCT05633667 .