Nivolumab With Nab-paclitaxel, Gemcitabine Shows Promise in Pancreatic Cancer

Zev Wainberg, MD

The combination regimen of the PD-1 inhibitor nivolumab (Opdivo) plus nab-paclitaxel and gemcitabine was found to demonstrate encouraging clinical activity and low toxicity levels in patients with metastatic pancreatic cancer, according to results of a study presented at the 2017 Gastrointestinal Cancers Symposium.¹

The treatment led to objective responses or stable disease in 12 of 17 patients in 2 cohorts. One cohort consisted of patients with previously treated disease, and the other comprised patients with no prior treatment for advanced pancreatic cancer. Responses occurred in both groups.

A single case of grade 3 non-autoimmune hepatitis, attributed to gemcitabine, constituted the only episode of dose-limiting toxicity (DLT). No patient in either cohort developed grade 3/4 pneumonitis, reported Zev Wainberg, MD, assistant professor of Medicine at the University of California, Los Angeles (UCLA), and co-director of the UCLA Gastrointestinal Oncology Program.

“These results indicate that full doses of nivolumab and nab-paclitaxel, with or without gemcitabine, are feasible for patients with advanced pancreatic cancer,” Wainberg and colleagues concluded in a poster presentation. “Based on the encouraging results from [the cohort with previously treated patients] the expansion cohort will further investigate the safety and efficacy of nivolumab with nab-paclitaxel plus gemcitabine.”

Several lines of evidence suggested a rationale for combining an immune checkpoint inhibitor with chemotherapy to treat pancreatic cancer. Preclinical studies suggested that chemotherapy-mediated release of antigens might prime the immune system for checkpoint inhibitors.²

A phase Ib study of ipilimumab (Yervoy) and gemcitabine suggested the feasibility of combining a checkpoint inhibitor and chemotherapy in pancreatic cancer.³ Multiple studies demonstrated antitumor activity with immune checkpoint inhibitors and chemotherapy, including nab-paclitaxel.

An ongoing phase I clinical trial program (NCT02309177) is evaluating the safety of nivolumab/nab-paclitaxel in patients with advanced solid tumors, including pancreatic cancer (± gemcitabine), advanced non-small cell lung cancer (± carboplatin), and metastatic breast cancer. Wainberg reported interim data from cohorts of patients with locally advanced or metastatic pancreatic cancer.

During the first part of the study, investigators evaluated nab-paclitaxel 125 mg/m² on days 1, 8, and 15 of a 28-day cycle and nivolumab 3 mg/kg on days 1 and 15 in 6 patients who had received 1 prior chemotherapy regimen. If the regimen was deemed safe, investigators would treat an additional 6 patients who had no prior chemotherapy exposure, using the same doses of nab-paclitaxel and nivolumab plus gemcitabine 1000 mg/m² on days 1, 8, and 15.

Part 2 of the study consisted of safety expansion cohorts of 20 patients with previously treated advanced pancreatic cancer and 14 patients with no prior chemotherapy for advanced pancreatic cancer.

The primary endpoint was the number of patients with DLTs in part 1 and the percentage of patients with grade 3/4 treatment-emergent adverse events (TEAEs) in parts 1 and 2. Secondary endpoints consisted of TEAEs leading to dose reduction or delay or treatment discontinuation, as well as preliminary analysis of efficacy.

Data analysis included 11 patients who had received 1 prior chemotherapy regimen and 6 who had received no prior chemotherapy. In the previously treated group, grade 3/4 TEAEs included 2 cases each of anemia, neutropenia, and pulmonary embolism. In the untreated patients, 2 cases of anemia constituted the only grade 3/4 TEAE.

Median treatment duration was 12.6 weeks among previously treated patients and 15.5 weeks among untreated patients. Nine previously treated patients discontinued nivolumab/nab-paclitaxel, 8 because of progressive disease and 1 because of patient withdrawal. In the untreated group, 1 patient discontinued for “other” reasons.

Two previously treated patients attained partial responses (PRs) with nivolumab/nab-paclitaxel and 4 had stable disease (SD). Of the 6 untreated patients included in the analysis, 3 achieved PRs and the other 3 had SD.

Five previously treated patients had reductions in target lesion length that ranged as high as 60%. Five of 6 previously untreated patients had reductions in target lesion length ranging as high as 59% (including reductions of 50% and 37%).

References

1. >Wainberg ZA, Hochster HS, George B, et al. Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (Gem) in solid tumors: interim results from the pancreatic cancer (PC) cohorts. J Clin Oncol 35, 2017(suppl 4S, abstr 412).
2. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. doi:10.1016/j.immuni.2013.07.012.
3. Kalyan A, Kircher SM, Mohindra NA, et al. Ipilimumab and gemcitabine for advanced pancreas cancer: a phase Ib study. J Clin Oncol 34, 2016(suppl; abstr e15747).