Search

Purpose:Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.Patients and Methods:NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Results:Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9–52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9–11.1 months), and median OS was 32.3 months (95% CI: 20.7—not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3–expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response.Conclusions:Combination nivolumab and temozolomide demonstrated promising activity in NEN.See related commentary by Velez and Garon, p. 691

Evaluation of circulating MDSC. (A) Changes in total MDSC and (B) monocytic (M-MDSC) and granulocytic (G-MDSC) subsets at cycle 1, day 15 (C1D15) compared to screening in the entire patient cohort. (C) Levels of circulating MDSC at screening by clinical response and changes during study treatment compared to screening in partial response (PR, orange) and stable disease (SD, green) patients. Each symbol represents one patient (n = 9). Line indicates mean.

Evaluation of co-inhibitory molecules by patient response. Total T cells at screening and C1D15 were identified as being CD4+ or CD8+ and patients were grouped by best clinical response as partial response (PR) or non-PR. The percentage of each T cell subset expressing (A) PD-1, (B) LAG3, (C) TIM3, and (D) KLRG3 at screening and C1D15 are shown. * p < 0.05.

Evaluation of circulating CD4+ T cell subsets. (A) Changes in regulatory T cells (Tregs) during treatment compared to screening in the entire patient cohort. (B) Changes in levels of circulating CD4+ naïve (CD45RA+ CCR7+), central memory (CM; CD45RA- CCR7+), effector memory (EM; CD45RA- CCR7-), and terminal effector memory (TE; CD45RA+ CCR7-) subsets at screening and cycle 1, day 15 (C1D15) of nivolumab and temozolomide treatment in the entire study cohort. (C) Levels of co-inhibitory molecules PD-1, LAG3, TIM3, and KLRG1 on circulating CD4+ T cells on study treatment compared to screening. Each symbol represents one patient (n = 9). Line indicates mean, *p

Purpose:Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.Patients and Methods:NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Results:Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9–52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9–11.1 months), and median OS was 32.3 months (95% CI: 20.7—not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3–expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response.Conclusions:Combination nivolumab and temozolomide demonstrated promising activity in NEN.See related commentary by Velez and Garon, p. 691

Supplementary Table 1: Most common treatment related adverse events; Supplementary Table 2: Treatment related serious adverse events; Supplementary Table 3: Mass Cytometry (CyTOF) panel; Supplementary Table 4: Mass cytometry gating of immune cell populations; Supplementary Table 5. Representativeness of Study Participants.

Water plot of best response in lung NEN.

Evaluation of circulating CD8+ cell subsets. (A) Changes in levels of circulating CD8+ naïve (CD45RA+ CCR7+), central memory (CM; CD45RA- CCR7+), effector memory (EM; CD45RA- CCR7-), and terminal effector memory (TE; CD45RA+ CCR7-) subsets at screening and cycle 1, day 15 (C1D15) of nivolumab and temozolomide treatment in the entire study cohort. (B) Levels of co-inhibitory molecules PD-1, LAG3, TIM3, and KLRG1 on circulating CD8+ T cells on study treatment compared to screening. Each symbol represents one patient (n = 9). Line indicates mean, *p

Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NENs). We present the results for a phase 2 trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood.NCT03728361 is a nonrandomized, phase 2 study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets.Among all 28 patients with NEN, the confirmed response rate was 9/28 (32.1%, 95% CI: 15.9%-52.4%). Of 11 patients with lung NEN, the response rate was 64% (n=7); there was a significant difference in responses by primary tumor location (lung vs others, p=0.020). The median PFS was 8.8 months (95% CI: 3.9 - 11.1 months), and median OS was 32.3 months (95% CI: 20.7 - NR months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9±13.4% vs. 31.7±14.6%, p = 0.03) and decrease in CD4+ T cells (59.6±13.1% vs. 56.5±13.0%, p = 0.001) after 2 weeks of treatment. LAG-3 expressing total T cells were lower in patients experiencing a partial response (0.18±0.24% vs 0.83±0.55%, p = 0.028). MDSC levels increased during study and did not correlate with response.Combination nivolumab and temozolomide demonstrated promising activity in NEN.

4121 Background: Treatment options are limited in patients with metastatic NEN. Temozolomide (TEM) alone and in combination with capecitabine is active in NEN and has been shown to have immunomodulatory impact. Here we present the final results for the NEN cohort of a phase 2 trial of combination nivolumab and TEM in patients with advanced NEN along with observed peripheral immune changes. Methods: NCT03728361 is a non-randomized, two-cohort, open-label phase 2 trial of nivolumab and TEM in patients with metastatic NEN and small cell lung cancer. The NEN cohort enrolled patients with tumors of any WHO grade, location, and line of therapy; all patients had evidence of progression prior to study. Prior immunotherapy was not allowed. Treatment consisted of nivolumab 480 mg IV on day 1 and TEM 150 mg/m2 on days 1-5 of a 28-day cycle. The primary objective was efficacy measured as response rate (RR) by RECIST v1.1. Secondary objectives were progression free survival (PFS) and overall survival (OS), by the method of Kaplan–Meier. The translational objective was to analyze peripheral blood mononuclear cells (PBMCs) collected at screening (baseline) and on cycle 1, day 15 (C1D15) via mass cytometry. Results: The RR was 36% (n=10/28, 95% CI: 18.6%-55.9%), including 10 patients (36%) with PR, 16 (57%) with SD, and 2 (7%) with PD (Table). The disease control rate was 93%. Responses occurred across all WHO grades; 44% of patients with tumors with Ki-67 >20% had PR. There was a significant difference in ORR by primary tumor location (bronchial vs pancreas vs other, p=0.004). There was no significant difference in response by Ki-67% (p=0.872), or in patients treated as first line (31%) or beyond (40%, p=0.706). The median PFS was 8.9 months (95% CI: 3.9 – 11.1 months), and median OS was not reached (95% CI: 20.7 – NR months). Two immune related SAE’s occurred: myocarditis and diarrhea in one patient each; gr4 toxicities included neutropenia (10%) and thrombocytopenia (7%). Profiling of PBMCs revealed no correlation of baseline MDSC levels with clinical benefit, however significant changes within the T cell landscape, including a decrease in CD4+ T cells (59.6% ±13.08 vs. 56.5% ±13.01, p=0.001) and increase in CD8+ T cells (27.9% ±13.36 vs. 31.7% ±14.57, p=0.03) were observed. Conclusions: Combination nivolumab and TEM demonstrated promising efficacy in patients with NENs; median OS has not been reached. Clinical trial information: NCT03728361. [Table: see text]

4123 Background: LAG-3 is an immune checkpoint present on NK cells, activated T cells and myeloid cells that inhibit T cell responses. Recent evidence demonstrating the safety and efficacy of LAG-3 inhibition has increased interest in this pathway for the treatment of multiple malignancies but the role in NEN is unclear. We present results from correlative peripheral blood mass cytometry (CyTOF) performed in a phase 2 trial (NCT03728361) of the combination of NIVO and TMZ in pts with advanced NEN. Methods: Patients (pts) with progressive NEN of any grade or primary location and any line of therapy were eligible. Small cell lung cancer was excluded. Clinical results from NCT03728361 will be presented in a separate abstract. Study treatment consisted of NIVO 480 mg IV every 4 weeks and TMZ 150 mg/m2 for 5 consecutive days out of a 28-day cycle. Peripheral blood mononuclear cells (PBMCs) were available from 16 out of 28 patients at screening (baseline) and cycle 1, day 15 (C1D15) and analyzed via CyTOF. Antibody labelling was performed using a 37 marker Maxpar Direct Immune Profiling Assay (Fluidigm). Immune cell populations were compared using two sample t-tests between pts with partial response (PR) and non-partial response (non-PR). Results: At screening, no differences were observed in PD-1, TIM3, or KLRG1 positive T-cell populations between pts with PR or non-PR. Patients with a PR had a significantly lower % of LAG-3 expressing T cells (p=0.029). There was a trend towards a lower % CD8+LAG-3+ T cells in pts with PR (p=0.086). At C1D15: The % of CD8+ LAG-3+ T cells were significantly higher in PRs vs. non-PR (p = 0.015). In matched samples comparing T cell populations at screening to C1D15, LAG-3+ CD8+ T cells increased significantly in PRs when compared to non-PRs (p=0.021). Conclusions: The % of LAG-3+ T cell population at baseline associates with non-response to TMZ/NIVO in NENs. Among responders, there was a significant increase in CD8+ LAG-3+ T cells by Day 15 compared to baseline indicating a potential mechanism of immune escape and eventual resistance. Clinical trial information: NCT03728361. [Table: see text]