A phase I trial of intratumoral adenovirus-interleukin-12 (IT-ADV/IL-12) and atezolizumab in metastatic non-small cell lung cancer (NSCLC) progressed on first-line immunotherapy.

Abstract

8551 Background: Interleukin-12 (IL-12) is a cytokine that enhances anti-tumor immunity via interferon-gamma release and has demonstrated synergistic effects with immune checkpoint inhibitors (ICIs) in immunoquiescent tumors. We report results of phase I trial of intratumoral adenovirus-interleukin-12(IT-ADV/IL-12)plus atezolizumab in metastatic NSCLC patients who progressed on prior ICI. Methods: This institutional single-arm, open-label phase I trial enrolled 13 patients with metastatic NSCLC who progressed on ICI from October 2021 to February 2024. First 2 patients received IT-ADV/IL-12 at 5 × 10¹¹ viral particles (vp), while the remaining 11 patients received a reduced dose of 3 × 10¹¹ vp as per protocol. Atezolizumab (1200 mg) was given every 3 weeks for up to 1 year or till disease progression. Endpoints were safety (as per Common Terminology Criteria for Adverse Events v5.0) and disease control rate (DCR), including complete response (CR), partial response (PR), or stable disease (SD) as defined by RECIST v1.1. Results: 12/13 patients were included in analysis (1 patient excluded due to rapid progression before starting atezolizumab). All patients had initial response to prior ICI (4/12 with CR and 8/12 with PR) but later developed resistance. DCR was 50% (6/12), median progression-free survival (PFS) was 2 months, and median overall survival (OS) was 10.5 months. 2/12 (25%) patients were alive at the time of analysis with median follow up time of 22 months. PD-L1 expression did not affect treatment response. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 4 patients, who demonstrated a higher likelihood of treatment response (p = 0.06), with all 4 achieving stable disease (SD). Most common TRAE of any grade was fatigue (4/12, 33%). There were no grade 4 or 5 events, and no treatment discontinuation related to TRAE. Next-generation sequencing results were available in 10/12 patients. The most common mutation was TP53, detected in 9/10 patients. There was no statistically significant association between the presence of TP53 mutation and treatment response. Conclusions: IT-ADV/IL-12 plus atezolizumab was safe, tolerable, and showed promising clinical benefit in metastatic NSCLC with acquired resistance to ICI, without new safety concerns. Presence of TP53 mutation did not impact the treatment response. Study Characteristics Results (n=12) Age (median) years 69 years Female (n) 5 (41.6%) PD-L1<1%>1% 5 (41.6%)7 (58.3%) Sites of progression after IL-12 therapy Local (lung)Distant visceralBrainRegional Lymph node 9 (75%)5 (41.6%)1 (8.3%)6 (50%) IT ADV/IL-12 related Grade 3 adverse events (n)FeverDyspneaHyponatremiaAnemia/leukopeniaPneumonia 21111 Response DCR (n)Progression (n) 6 (50%)6 (50%) Median PFS 2 months Impact of PD-L1 expression on PFS<1%>1% 3.6 months3.29 months(p= .84) Median OS 10.5 months