Intra-Arterial Gemcitabine Showed Promise for Locally Advanced Pancreatic Cancer

First Interim Analysis of the Phase 3 TIGeR-PaC Trial

At the 2023 World Congress on Gastrointestinal Cancers, Michael Pishvaian, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, Maryland, shared results from a phase 3 study evaluating intra-arterial gemcitabine among patients with locally advanced pancreatic cancer.

Data from the first interim analysis demonstrated favorable results with intra-arterial gemcitabine compared to IV gemcitabine plus nab-paclitaxel. Dr Pishvaian stated, "The overall survival was improved with intra-arterial gemcitabine compared to continuation IV gemcitabine and nab-paclitaxel. Similarly, the progression-free survival was also improved and the intra-arterial therapy was better tolerated for the 4 months of randomization period compared to IV gemcitabine and nab-paclitaxel."

Transcript:

My name is Mike Pishvaian. I'm an associate professor in the Department of Oncology at Johns Hopkins University School of Medicine, and it's my pleasure today to present the late-breaking abstract of the TIGeR-PaC study, the first interim analysis. It's a phase 3 randomized study comparing IV gemcitabine nab-paclitaxel with intra-arterial gemcitabine after a period of induction therapy with IV gem-nab-paclitaxel and stereotactic radiation therapy.

The trial was designed because for pancreatic cancer, it's a devastating disease and soon to become the second-leading cause of cancer related death in this country. About 30% to 35% of patients present with locally advanced disease, most of those patients have incurable disease because only about 10% to 15% are rendered R0 resectable with chemotherapy. And so we really need more effective ways to treat those 30% to 35% of patients with locally advanced disease.

Systemic chemotherapy has limited efficacy for pancreatic cancer, and at least in part, it's because the chemotherapy is not very effectively delivered to the tumor itself. Pancreatic tumors are notorious for having a dense fibrotic stroma. They're very acellular and they're very hypovascular compared to, for example, liver tumors, which are much more vascularized. As a result, the transarterial micro-perfusion system has been developed in which a catheter is snaked across the artery that is most proximal to the tumor, and then there are two balloons that are inflated, one proximally and one distally to the tumor. And then therapy such as gemcitabine can be infused through the space in between at a high pressure, leading to a high concentration of the drug in the area of the tumor.

In fact, studies have been done pre-clinically and have shown that the concentration of gemcitabine in the tumor microenvironment is 100-fold greater than for when patients receive it intravenously. The interarterial micro-perfusion system has been tested in a safety dose-escalation study called the RR1 study, in which it was determined that the dose of gemcitabine could be escalated up to 1000 mg/m², which is the standard dose that's used intravenously.

And then there was an R2 observational registry study, and the two studies together enrolled 43 patients. And one observation that came out of those studies is that patients who received the intraarterial gemcitabine, those who had had prior radiation therapy, actually had a much greater survival compared to those who had not had prior radiation therapy. And this is relevant because it's consistent with some of the preclinical data demonstrating that radiation damages the micro-arterials, allowing for the drug to be infused primarily just to the tumor and thus be more effective.

So based on this background, we designed the TIGeR-PaC study, which again is a randomized phase 3 study designed to test the hazard ratio of 0.6 with an 80% power and an alpha level of 0.047. With this design, 114 patients will ultimately need to be randomized. We're presenting the first interim analysis after which 26 death events have occurred, and in this design, 45 patients thus far have been randomized.

The study is built with an induction period where patients all receive 2 months of IV gemcitabine and nab-paclitaxel standard of care, then they receive [sterotactic body radiotherapy] SBRT, then they receive 1 more month of IV gemcitabine plus nab-paclitaxel. And after the induction period, patients are re-imaged, and those who are non-progressors can be randomized into the study portion, the randomization portion of the study, where they can either continue IV gemcitabine and nab-paclitaxel as standard of care or go into the experimental arm on a 1-to-1 randomization.

The experimental arm is intra-arterial gemcitabine delivered once every 2 weeks for up to 8 infusions or 4 months. After the 4 months of the randomization period, patients will then go onto continuation therapy, which we allowed at physician's discretion to be either continuation of IV gemcitabine and nab-paclitaxel, or they can move on to oral maintenance capecitabine. And overall survival, again, is the primary endpoint.

As of the first interim analysis, as I mentioned, 45 patients have been randomized. There have been 26 death events, 13 in each arm. The demographics of the two arms were about the same in terms of gender, size of the tumor, age. And when you look at the actual substudy that was done for the trial, we did a 15 patient pharmacokinetic substudy to look at the levels of gemcitabine in the plasma, to really assess whether gemcitabine is being delivered systemically at lower doses. And consistent with the early clinical data, consistent with the preclinical data, when patients receive IV gemcitabine, they have much higher levels of gemcitabine systemically compared to those who received intra-arterial gemcitabine.

Along those lines, because there's less systemic IV gemcitabine, patients who received intra-arterial therapy also had much fewer adverse events. When you look at adverse events of any grade, there was a 65% lower rate of adverse events for patients who received intra-arterial gemcitabine compared to those who received continuation IV gemcitabine and nab-paclitaxel. Looking specifically at the table of adverse events of all grades, for those who had an adverse event occurring in more than 10% of patients, the only metric, the only adverse event for which there was greater adverse events in the interarterial arm was abdominal pain and nausea that were related to the procedure and were transient and generally very low grade. So overall, the intra-arterial therapy was better tolerated.

In terms of the survival data, with overall survival being the primary end point, at the first interim analysis we showed that intra-arterial gemcitabine led to an improved overall survival, 15.7 months compared to 10.1 months with the continuation IV gemcitabine nab-paclitaxel. Now again, this is from the time of randomization, the 15.7 versus the 10.1 months. Similarly, from the time of randomization, there was a greater progression-free survival for patients receiving intra-arterial gemcitabine of 14.8 months, compared to only 6.7 months for patients who continued the IV gemcitabine and nab-paclitaxel. Because this trial included the induction period, and for all of the patients that were randomized, the 45 patients, the average induction period from diagnosis to the point of randomization was 5.5 months. So when you add that 5.5 months of induction onto the overall survival from the randomization point, the median overall survival for patients who were treated with continuation IV gemcitabine and nab-paclitaxel was 15.5 months compared to 21.5 months for patients who received intra-arterial gemcitabine.

What we've shown in this first interim analysis was that the overall survival was improved with intra-arterial gemcitabine compared to continuation IV gemcitabine and nab-paclitaxel. Similarly, the progression-free survival was also improved and the intra-arterial therapy was better tolerated for the 4 months of randomization period compared to IV gemcitabine and nab-paclitaxel. This was the first interim analysis. We anticipate the second interim analysis will be in 2024, and the final results of the overall study will be reported in 2025. But we hope that this will be an option for patients somewhere down the line in the future if the results continue to pan out. And thank you for your attention.

Source:

Pishvaian M, Lopez C, Zervos E, et al. The phase III 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 cancer (TIGeR-PaC). Presented at the 2023 World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain. Abstract LBA-1