Frontline treatment with ibrutinib plus nab-paclitaxel/gemcitabine did not have a statistically significant benefit in progression-free survival or overall survival compared to placebo plus nab-paclitaxel/gemcitabine in patients with metastatic pancreatic cancer.
Danelle James, MD, MAS
Upfront treatment with ibrutinib (Imbruvica) plus nab-paclitaxel (Abraxane)/gemcitabine failed to demonstrate a statistically significant benefit in survival versus nab-paclitaxel/gemcitabine alone in patients with metastatic pancreatic cancer, according to topline results from the phase III RESOLVE (PCYC-1137) trial released by AbbVie, the developer of ibrutinib, in a press release.1
Complete findings of the trial will be submitted for presentation at an upcoming medical meeting and/or publication, AbbVie announced. The FDA granted ibrutinib orphan drug status in pancreatic cancer in June 2017.
"We continue to evaluate the potential of Imbruvica as a cancer treatment alone or in combination for a variety of cancer types. We are passionately advancing our robust ibrutinib scientific development program to continue to advance cancer standards of care, particularly in areas that have unmet medical need," said Danelle James, MD, MAS, head of clinical science at Pharmacyclics LLC, an AbbVie company.
In the multicenter, double-blind, placebo-controlled, phase III RESOLVE trial (NCT02436668), 424 patients were randomized 1:1 to receive ibrutinib in combination with gemcitabine and nab-paclitaxel (n = 211) or placebo and chemotherapy (n = 213) as first-line treatment for patients with metastatic pancreatic cancer. The primary endpoints were progression-free survival and overall survival; secondary endpoints were safety, overall response rate, clinical benefit response, CA19-9 response, patient-reported outcomes, and rate of venous thromboembolic events.
To be eligible for enrollment, patients had histologically or cytologically confirmed stage IV pancreatic adenocarcinoma, adequate hematologic, hepatic, and renal function, a Karnofsky performance status ≥70, and an ECOG performance status of 0 or 1. Those who received prior lines of therapy, neuroendocrine or acinar pancreatic carcinoma, known brain or leptomeningeal disease, underwent major surgery within 4 weeks of first dose of ibrutinib, history of stroke or intracranial hemorrhage within 6 months prior to enrollment, and treatment with a strong CYP 3A inhibitor were excluded from the trial.
Preclinical data demonstrated activity with ibrutinib plus gemcitabine in this disease, showing antitumor effects versus gemcitabine alone in both orthotopic murine pancreatic cancer cell line grafts and in genetically engineered mouse models.2
In a previous interview withTargeted Oncology, when RESOLVE completed accruing, Margaret Tempero, MD, director, University of California, San Francisco (UCSF) Pancreas Center, and professor of medicine, Division of Hematology and Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, discussed the rationale that led to the investigation of ibrutinib in pancreatic cancer.
“It’s all about reprogramming the immune environment. We are still trying to find out exactly how this is happening,” explained Tempero. “We think the net effect of deactivating the pathway is more active CD8-positive cells in the tumor microenvironment; there may be more than that. It may also be simply reprogramming or immune editing in the microenvironment, so that a T2 environment changes to a T1, which is more tumor suppressive.”
Metastatic pancreatic cancer is one of the most aggressive and deadliest forms of cancer, with an estimated 5-year survival rate of less than 5%.
Ibrutinib currently has indications in various hematologic malignancies, including mantle cell lymphoma, chronic lymphocytic leukemia, Waldenström's macroglobulinemia (WM), small lymphocytic lymphoma, marginal zone lymphoma, chronic graft versus host disease, and in combination with rituximab (Rituxan) for adult patients with WM.