Background Immune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies of alternatives to glucocorticoids are lacking. We examined whether interleukin-6 blockade by tocilizumab reduced ICI-induced colitis and arthritis. Patients and methods Patients with solid cancer experiencing Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade >1 ICI-induced colitis/diarrhea (n=9), arthritis (n=9), or both (n=2) were recruited and treated with tocilizumab (8 mg/kg) every 4 weeks until worsening or unacceptable toxicity. Patients were not allowed to receive systemic glucocorticoids and other immunosuppressive drugs within the 14-day screening period. The primary endpoint was clinical improvement of colitis and arthritis, defined as ≥1 grade CTCAE reduction within 8 weeks. Secondary endpoints were improvements and glucocorticoid-free remission at week 24; safety; radiologic, endoscopic, and histological changes; and changes in plasma concentrations of C reactive protein, cytokines (IL-6, IL-8, and IL-17), and YKL-40. Results Nineteen patients were available for efficacy analysis; one patient was excluded due to pancreatic insufficiency-induced diarrhea. Patients received treatment with pembrolizumab (n=10) or nivolumab (n=4) as monotherapy or ipilimumab and nivolumab (n=5) combined. Seven patients had been initially treated with glucocorticoids, and two of them also received infliximab. Ten patients continued ICI therapy during tocilizumab treatment. The primary endpoint was achieved in 15 of 19 (79%) patients. Additional one patient had ≥1 grade reduction at week 10, and another patient had stabilized symptoms. At week 24, ongoing improvement without glucocorticoids (n=12), including complete remission (n=10), was noted. Five patients had grades 3–4 treatment-related adverse events, which were manageable and reversible. Conclusions Tocilizumab showed promising clinical efficacy and a manageable safety profile in the treatment of ICI-induced colitis and arthritis. Our findings support the feasibility of randomized trials of immune-related adverse events. Trial registration number NCT03601611.

Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC). Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%. Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events. The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual.

Determining response to therapy for patients with pancreatic cancer can be challenging. We evaluated methods for assessing therapeutic response using cell-free DNA (cfDNA) in plasma from patients with metastatic pancreatic cancer in the CheckPAC trial (NCT02866383). Patients were evaluated before and after initiation of therapy using tumor-informed plasma whole-genome sequencing (WGMAF) and tumor-independent genome-wide cfDNA fragmentation profiles and repeat landscapes (ARTEMIS-DELFI). Using WGMAF, molecular responders had a median overall survival (OS) of 319 days compared to 126 days for nonresponders [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.11–0.79, P = 0.011]. For ARTEMIS-DELFI, patients with low scores after therapy initiation had longer median OS than patients with high scores (233 versus 172 days, HR = 0.12, 95% CI = 0.046–0.31, P < 0.0001). We validated ARTEMIS-DELFI in patients with pancreatic cancer in the PACTO trial (NCT02767557). These analyses suggest that noninvasive mutation and fragmentation-based cfDNA approaches can identify therapeutic response of individuals with pancreatic cancer.

Purpose: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). Patients and Methods: The study was a phase 2 randomized trial with Simon’s optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. Results: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6–47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1–21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3–33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. Conclusions: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.

Considering strong T-cell response from influenza vaccination, we aimed to evaluate ipilimumab, nivolumab, seasonal influenza vaccine, and stereotactic body radiotherapy (SBRT) treatment efficacy in heavily pretreated patients with refractory pancreatic cancer (PC). In a single-center, phase II study (NCT05116917), individuals diagnosed with PC with progressive disease (PD) after gemcitabine- or fluorouracil-containing regimens were enrolled. SBRT (15 Gy) was administered on day 1 of the first cycle. Ipilimumab (1 mg/kg) was administered every 6 weeks and was limited to a maximum of two infusions. Nivolumab (3 mg/kg) was administered every 2 weeks until either PD or unacceptable toxicity, or for a maximum duration of 1 year. The influenza vaccine was administered subcutaneously on the first day of the first cycle. The primary endpoint was objective response rate with a predefined threshold of 15%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. Between 15 November 2021 and 23 May 2023, 19 patients were enrolled and treated. As of data cut-off on 11 November 2023, the median follow-up time was 2.2 months (interquartile range 1.7-4.4 months). No objective responses or stable disease was observed. The median PFS was 1.6 months [95% confidence interval (CI) 1.4-1.8 months], and the median OS was 2.2 months (95% CI 1.8-4.6 months). Treatment-related adverse events were reported in 13 patients (68%), with 3 (16%) experiencing grade 3 or higher events. Combined ipilimumab, nivolumab, influenza vaccine, and SBRT in patients with PC was feasible but did not lead to objective responses, and thus did not satisfy the predefined criteria for expanding to complete accrual.