Nivolumab/Ipilimumab Plus SBRT Shows Antitumor Activity in Refractory Pancreatic Cancer

Stereotactic body radiation therapy (SBRT) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated clinically meaningful antitumor activity with a favorable toxicity profile in difficult-to-treat patients with refractory metastatic pancreatic cancer, although the contribution of SBRT is still unclear, according to data from the phase 2 CheckPAC trial (NCT02866383) published in the Journal of Clinical Oncology.¹

Among the 41 patients who received SBRT plus nivolumab (arm A), the clinical benefit rate (CBR) was 17.1% (95% CI, 8.0%-30.6%); this rate was even higher when SBRT was combined with nivolumab and ipilimumab (n = 43; arm B), at 37.2% (95% CI, 24.0%-52.1%), meeting the threshold for efficacy.

“To our knowledge, this is the first prospective evaluation that demonstrates the clinical benefit and safety of SBRT 15 Gy in combination with nivolumab with or without ipilimumab in pretreated refractory patients with metastatic pancreatic cancer who have a poor prognosis and progressive disease,” the lead study author Inna M. Chen, MD, of Copenhagen University Hospital, and colleagues, wrote in the paper. “…Further translational studies should focus on identifying how nivolumab/ipilimumab concurrently with SBRT augments antitumor activity and facilitates remission.”

Pancreatic ductal adenocarcinoma continues to represent one of the deadliest kinds of cancer. Although immunotherapy approaches have been found to produce durable responses in certain subsets, checkpoint inhibitors have only demonstrated benefits in those with microsatellite instability or mismatch repair deficiency.

Emerging evidence has suggested that the combination of radiotherapy and immune checkpoint inhibitors might result in stronger responses in those with pancreatic cancer that has historically been resistant to immune checkpoint inhibitors.

With CheckPAC, investigators sought to examine the clinical benefits and safety of nivolumab with or without ipilimumab plus SBRT in patients with refractory metastatic pancreatic cancer. To be eligible for enrollment, patients must have progressed beyond frontline gemcitabine or a platinum-containing therapy. They also needed to have a measurable lesion and an ECOG performance status of 0 or 1.

A total of 163 study participants who were enrolled to the trial, which was conducted at Herlev & Gentofte Hospital, and 88 patients were randomly assigned 1:1 to arm A or arm B. Those in arm A were given SBRT at 15 Gy on day 1 to a single primary or metastatic lesion plus nivolumab at 3 mg/kg on day 1 and once every 2 weeks. Those in arm B received SBRT at 15 Gy on day 1 with nivolumab at 3 mg/kg on day 1 and once every 2 weeks and ipilimumab at 1 mg/kg on day 1 and once every 6 weeks.

The primary end point of the trial was CBR, and secondary end points included safety, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), OS rate at 6 months and 1 year, and duration of response.

The median age in arm A was 63 years (range, 37-80) vs 66 years (range, 35-79) in arm B; 53.7% and 51.2% of patients, respectively, were male. In arm A, 51.2% had an ECOG performance status of 0 and 48.8% had a status of 1; these rates were 46.5% and 53.5%, respectively, in arm B. Most patients across the arms had 2 metastatic sites, the majority being in the liver. All patients in arm A had mismatch repair–proficient tumors vs 97.7% of those in arm B.

Notably, 53.7% of those in arm A and 51.2% of those in arm B had received 2 or more prior lines of therapy for advanced disease. In arm A, 95.1% of patients previously received gemcitabine-based treatment and 58.5% received platinum-based treatment; these rates were 88.4% and 62.8%, respectively, in arm B.

Of the 44 patients who were allocated to arm A, 41 received treatment. All 41 patients discontinued treatment, the most common reason being because of progressive disease (n = 37), followed by death (n = 2), toxicity (n = 1), and treatment completion (n = 1).

Additionally, 43 of the 44 patients who comprised arm B received treatment; again, all patients discontinued. In this group, 37 discontinued because of disease progression, 3 did so because of toxicity, 2 each because of death or reinduced SBRT/nivolumab/ipilimumab, and 1 because they completed treatment. Forty-one of those in arm A and 43 of those in arm B were included in the analysis.

At a data cutoff date of May 20, 2021, and with a median follow-up of 4.1 months (95% CI, 3.7-5.8), SBRT plus nivolumab elicited an ORR of 2.4% (95% CI, 0.3%-10.8%) and the median DOR was 4.6 months. Moreover, the median PFS in arm A was 1.7 months (95% CI, 1.6-1.8), and the median OS was 3.8 months (95% CI, 3.1-5.8). The 6- and 12-month OS rates were 29.3% (95% CI, 18.2%-47.1%) and 7.3% (95% CI, 2.5%-21.8%), respectively.

In arm B, SBRT plus nivolumab and ipilimumab elicited an ORR of 14.0% (95% CI, 6.0%-26.5%) with a median DOR with this approach was 5.4 months (95% CI, 4.2–not reached), with 1 patient continuing to respond to treatment at 55 months. Moreover, the median PFS was 1.6 months (95% CI, 1.6-2.8) and the median OS was 3.8 months (95% CI, 2.8-6.5). The 6- and 12-month OS rates were 32.6% (95% CI, 21.2%-50.1%) and 14.0% (95% CI, 6.6%-29.3%).

Only 5 of the 23 patients who experienced clinical benefit across the arms went on to receive subsequent treatment following disease progression. Of the 61 patients who did not experience clinical benefit, 4 patients received gemcitabine-based treatment after progression, 4 received 5-fluorouracil–based treatment, and 1 received immune checkpoint inhibitor combination therapy.

Subgroup analyses revealed that those who achieved clinical benefit with treatment also experienced superior OS. Moreover, those with an ECOG performance status of 1, weight loss of 5% or higher, elevated bilirubin, and modified Glasgow Prognostic Score (mGPS) of 2, experienced worse OS. Notably, elevated bilirubin (HR, 11.02; 95% CI, 4.00-30.38) and a mGPS of 2 (HR, 2.30; 95% CI, 1.18-4.60) were independently linked with a worse OS.

Any-grade adverse effects (AEs) were reported in all patients in arm A and 95.3% of those in arm B; grade 3 or 4 AEs were experienced by 73.2% and 79.1%, respectively. Treatment-related AEs (TRAEs) of any grade occurred in 87.8% of those in arm A and 74.4% of those in arm B; these effects were grade 3 or 4 in 24.4% and 30.2% of patients, respectively.

The grade 3 or 4 TRAEs that were frequently reported included diarrhea (11.6%), fatigue (9.3%), adrenal insufficiency (7%), colitis (4.7%), arthralgia (4.7%), myalgia (4.7%), and increased aspartate aminotransferase levels (4.7%).

One of the 3 patients in arm B who discontinued treatment because of a TRAE experienced grade 4 cardiac arrest secondary to adrenal insufficiency; after receiving high-dose steroids, the patient fully recovered.

“Our study has several limitations. The CheckPAC trial was an open-label study,” the study authors concluded. “The median time from diagnosis to inclusion for both cohorts suggested a highly selected cohort, which may limit the generalizability of our results, and the results may be driven by favorable biology. The mechanism beyond responses and the question whether radiation is the key are still unresolved.”

Reference

1. Chen IM, Johansen JS, Theile S, et al. Randomized phase II study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer (CheckPAC). J Clin Oncol. Published online April 27, 2022. doi:10.1200/JCO.21.02511