Association of lymphopenia rescue and CA19-9 levels with overall survival following IL-15 superagonist N-803 and PD-L1 t-haNK chemo-immunotherapy for 3 ^rd line or greater metastatic pancreatic cancer.

Abstract

2542 Background: Lymphopenia and high CA19-9 levels are associated with poor prognosis in pancreatic cancer patients. N-803 (ANKTIVA), an IL-15 superagonist is the first FDA approved molecule with a mechanism of action of rescuing lymphopenia by proliferating lymphocytes (NK and T cells). In QUILT-88, a Phase 2 multi-center study (NCT04390399), participants with 2nd line or greater locally advanced or metastatic pancreatic cancer (mPC) received N-803 and PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cell therapy in combination with low-dose chemotherapy as ≥ 3 rd line therapy. The absolute lymphocyte count (ALC), CA19-9 level, and correlation with overall survival (OS) was assessed. Methods: Patients (n = 84) received low-dose SBRT and low-dose chemotherapy in combination with N-803 and PD-L1 t-haNK cells to orchestrate responses of the innate and adaptive immune system, a paradigm change in the treatment of mPC. The association between OS and ALC < or ≥ median 1.045 x 10 9 cells/L and CA19-9 < or ≥ median 4079.6 U/mL at baseline was assessed. Results: Median OS for 3 rd line patients (n = 43) was 6.2 months (95% CI 5.0 - 7.1;) and for all patients ≥ 3 rd to 6 th line patients (n = 84) was 5.7 months (95% confidence interval [CI] 4.3 – 6.4). OS was positively associated with both higher ALC and lower baseline CA19-9 levels. OS was significantly higher for participants (median OS: 7.1 months) with ALC ≥ 1.045 x 10 9 cells/L and CA19-9 < 4079.6 U/mL than for those participants (median OS: 3.1 months) with ALC < 1.045 x 10 9 cells/L and CA19-9 ≥ 4079.6 U/mL (HR 3.6, p < 0.001). Higher ALC count was associated with prolonged OS over the course of the study. Grade 3 or higher TEAEs occurred in 95% of patients and were largely chemotherapy-associated. Conclusions: The multimodal chemo-immunotherapy protocol to induce immunogenic cell death resulted in OS that exceeded 6 months for both 3 rd and ≥ 5 th line patients, exceeding OS achieved by other therapies in this setting by ~2 months. It is notable that both favorable baseline ALC/CA19-9 and on-study higher ALC was associated with prolonged survival, given N-803’s ability to increase both NK and CD8+/CD4+ T cells, the first FDA approved agent that proliferates lymphocytes in the face of lymphopenia. These findings support further investigation of this novel therapeutic regimen that includes PD-L1 t-haNK, and N-803 that, as an IL-15 superagonist, may be able to overcome lymphopenia and improve prognosis. Clinical trial information: NCT04390399 .