Intra-arterial Gemcitabine Improves OS in Locally Advanced Pancreatic Cancer

Michael Pishvaian, MD, PhD

Treatment with intra-arterial (IA) gemcitabine led to an improvement in overall survival (OS) compared with continued treatment with intravenous (IV) gemcitabine plus nab-paclitaxel (Abraxane) in patients with locally advanced pancreatic cancer following sequential treatment with IV gemcitabine, nab-paclitaxel, and radiotherapy, according to data from the first interim analysis of phase 3 TIGeR-PaC trial (NCT03257033).

Data presented at the 2023 ESMO World Congress on Gastrointestinal Cancer showed that patients treated with IA gemcitabine (n = 23) experienced a median OS of 15.7 months compared with 10.1 months for those who continue with IV gemcitabine and nab-paclitaxel (n = 22; HR, 0.48; 95% CI, 0.20-1.12; P < .08).

“I keep emphasizing [median OS was measured] from the time of randomization [to death], because during the induction phase, which lasted 5.5 months on average for all the patients who reached randomization, all got systemic therapy [before randomization],” lead study author Michael Pishvaian, MD, PhD, said in an interview with OncLive^®. The median OS from diagnosis was approximately 21.5 months in the experimental arm vs approximately 15.5 months in the control arm.

Trans-arterial micro-perfusion (TAMP) was designed to force a drug across the artery wall into the micro-vasculature and into tumor tissue through increased pressure following vessel isolation. This process increases drug concentration to the targeted pathological site by approximately 100 times compared with IV administration.

“Systemic therapy for patients with locally advanced pancreatic cancer has its limitations, and we think, in part, it is because the chemotherapy isn’t effectively delivered to the tumors,” said Pishvaian, who is also the director of Gastrointestinal, Developmental Therapeutics and Clinical Research Programs and an associate professor of Oncology at Johns Hopkins Medicine in Baltimore, Maryland. “The ability to get the chemotherapy to the tumors is limited by the dense fibrotic stroma and by the fact that the tumors are very hypovascularized compared with liver tumors, for example. Giving IA chemotherapy allows the concentration of chemotherapy to be much higher in a way that’s delivered locally to the tumor and the tumor microenvironment.”

The ongoing TIGeR-PaC trial is evaluating the TAMP approach vs traditional IV administration. The study enrolled patients with histologically confirmed pancreatic adenocarcinoma with an initial diagnosis within 6 weeks of consent. Patients were also required to have locally advanced, unresectable disease per National Comprehensive Cancer Network Guidelines and an ECOG performance status of 0 or 1.

Prior treatment for pancreatic cancer, other than up to 1 cycle of gemcitabine plus nab-paclitaxel, was not allowed. Patients were also not permitted to have any evidence of metastatic disease or another active malignancy within 2 years of enrollment, other than cervical cancer in situ, in situ carcinoma of the bladder, or non-melanoma carcinoma of the skin.

During the induction phase, all patients underwent treatment with IV gemcitabine plus nab-paclitaxel for 2 months, followed by stereotactic body radiation therapy, then IV gemcitabine plus nab-paclitaxel for 1 additional month. Patients were then randomly assigned 1:1 to receive 8 infusions of IA gemcitabine over 4 months, or continued treatment with 12 total infusions of IV gemcitabine plus nab-paclitaxel over 4 months. Patients then continued therapy with a choice of gemcitabine plus nab-paclitaxel or capecitabine until disease progression.

OS served as the trial’s primary end point. Secondary end points included OS for the treatment-received and non-surgical populations, progression-free survival (PFS), objective response rate, duration of response, health-related quality of life, degree of peripheral neuropathy, frequency of neutropenia requiring medication for white blood cell stimulation, and tolerability and safety.

The first interim analysis was conducted after 30% (n = 26) of all deaths occurred. Thirteen events occurred in each arm, and 19 patients were alive and still in the study, with data censored as of the February 2023 data cutoff.

The mean age was 65 years (range, 43-85) and 70 years (range, 47-83) in the IA gemcitabine and IV gemcitabine/nab-paclitaxel arms, respectively. The majority of patients in both arms were White (75% and 95%, respectively). The mean tumor size was 6.5 cm (range, 2.5-12.9) in the experimental arm and 6.95 cm (range, 2.8-15.0) in the control arm.

Additional data showed that the median PFS was 14.8 months for patients treated with IA gemcitabine vs 6.7 months for those given IV gemcitabine/nab-paclitaxel (HR, 0.55; 95% CI, 0.21-1.47).

Regarding safety, 61% of patients in the IA gemcitabine arm received all planned treatments at the prespecified dose compared with 18% of those in the IV gemcitabine/nab-paclitaxel arm.

“When you look at all grades of all AEs, there were 65% fewer AEs for patients who received IA gemcitabine,” Pishvaian noted. “In each of the metrics of AEs events, the only categories where IA gemcitabine had a higher AE rate was for abdominal pain and nausea, which were related to the procedure. Both were very transient and of low grade.”

The most common any-grade AEs reported in more than 10% of patients in either arm included neutropenia (21% for IA and 81% for IV), anemia (8% and 48%), thrombocytopenia (4% and 38%), elevated aspartate transaminase (4% and 33%), elevated alanine transaminase (13% and 29%), fatigue (8% and 19%), neuropathy (0% and 19%), dehydration (8% and 19%), hypertension (4% and 14%), hypokalemia (4% and 14%), hypoalbuminemia (4% and 14%), abdominal pain (21% and 0%), and nausea (21% and 0%).

Accrual for the study is ongoing, and results of the second interim analysis are anticipated in 2024.

“This is a first interim analysis for a larger phase 3 study. In the ultimate study, we will want [to randomize] 114 patients; this was a report after only 45 patients had been [randomly assigned],” Pishvaian concluded. “If the data do bear out, it could be interesting and potentially be a new way for patients to get their treatment for locally advanced pancreatic cancer."

Reference

Pishvaian M, Zureikat A, Novelli P, et al. The phase 3 study: targeted intra-arterial gemcitabine vs continuation of IV gemcitabine plus nab-paclitaxel following induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for locally advanced pancreatic cancers (TIGeR-PaC) first interim analysis. Presented at: 2023 ESMO World Congress on Gastrointestinal Cancer; June 28 to July 1, 2023; Barcelona, Spain. Abstract LBA-1.