1488 A multicenter phase 2 trial of lifileucel plus pembrolizumab in patients with checkpoint inhibitor-naive metastatic NSCLC: updated results

<h3>Background</h3> Resistance to frontline immune checkpoint inhibitor (ICI) ± chemotherapy presents a challenge in the treatment of metastatic non-small cell lung cancer (NSCLC). Tumor-infiltrating lymphocyte (TIL) cell therapy with lifileucel alone demonstrated an objective response rate (ORR) of 21% in patients with refractory metastatic NSCLC previously treated with an ICI. Integration of TIL cell therapy in frontline regimens may improve long-term outcomes in NSCLC. We report updated efficacy and safety results for lifileucel combined with pembrolizumab in patients with ICI-naive metastatic NSCLC. <h3>Methods</h3> IOV-COM-202 (NCT03645928) is a global, phase 2, multicenter, multicohort, open-label study. Cohort 3A has enrolled patients with ICI-naive advanced or metastatic NSCLC with disease progression, ≥1 resectable lesion for lifileucel manufacturing, and ≥1 evaluable lesion (by RECIST v1.1). Patients received nonmyeloablative lymphodepletion (cyclophosphamide and fludarabine), followed by a single lifileucel infusion, and ≤6 doses of high-dose interleukin-2 (IL-2). Pembrolizumab was administered once before lymphodepletion and continued after lifileucel up to 2 years. Primary endpoints were ORR and safety (incidence of grade ≥3 TEAEs). <h3>Results</h3> As of August 12, 2024, 22 patients had been infused with lifileucel. Patients had a median age of 57 years (range, 30–69) and a median of 1 (range, 0–4) lines of prior systemic therapy. PD-L1 tumor proportion score was &lt;1 in 77.3% (n=17), tumor <i>EGFR</i> status was wild-type (wt) in 63.6% (n=14). Common anatomic sites of tumor resection were lung (45.5%) and lymph node (22.7%). Median lifileucel dose was 22.9×10⁹ cells. At a median follow-up of 25.6 months, the ORR (95% CI) in the <i>EGFR</i>-wt subgroup of interest for further studies was 64.3% (35.1%–87.2%). Median DOR in this subgroup was not reached (NR; 95% CI, 3.7 months–NR). Six responses occurred in 11 patients with <i>EGFR</i>-wt PD-L1–negative disease (54.5%). Five patients had durable and ongoing responses at last follow-up, including 3 patients with PD-L1–negative status (figure 1). For the <i>EGFR</i>-mutation post-TKI (n=8) subgroup, the ORR was 12.5%. TEAEs were consistent with underlying disease and known profiles of pembrolizumab, nonmyeloablative lymphodepletion, and IL-2. Most common grade ≥3 nonhematologic TEAEs were hypoxia (54.5%), febrile neutropenia (45.5%), and hypophosphatemia (31.8%). <h3>Conclusions</h3> In patients with ICI-naive metastatic NSCLC, lifileucel plus pembrolizumab demonstrated robust antitumor activity and durable responses, including in patients with <i>EGFR</i>-wt PD-L1–negative tumors. No new safety signals were observed with lifileucel plus pembrolizumab. These results support further investigation of lifileucel/ICI combination as part of frontline therapy in metastatic NSCLC. <h3>Trial Registration</h3> NCT03645928. <h3>Ethics Approval</h3> This study was approved by the institutional review board at each site and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonization. All patients provided written informed consent.