Immunotherapy May Boost Chemo Outcomes in Pancreatic Cancer

Liam Davenport

July 02, 2015

BARCELONA, Spain — Adding a novel immunotherapy to gemcitabine extends survival in patients with pancreatic cancer, particularly those with metastatic disease, and maintains and might improve quality of life, researchers report.

The experimental immunotherapy, known as IMM-101 (under development by Immodulon Therapeutics), is a suspension of heat-killed Mycobacterium obuense that induces CD8+ T-cell responses.

The combination of IMM-101 plus gemcitabine improves outcomes and quality of life, and has a favorable adverse-event profile, according to investigator Angus Dalgleish, MD, professor of oncology at St. George's University of London, United Kingdom.

This finding is particularly important because the patients receiving immunotherapy were older and had more severe disease, which would attenuate its potential impact, he noted here at the 17th World Congress on Gastrointestinal Cancer.

The mode of action of IMM-101 is important. "It wakes up the innate immune response, although it's not a vaccine per se," he told Medscape Medical News. It boosts "the gamma delta cells, and that leads to an awakening of CD8+."

Dr Angus Dalgleish

"It's a bit like a checkpoint inhibitor, but it works in a different way. It takes the brakes off, starting with the innate immune system," he explained.

Interest in IMM-101 was sparked when studies demonstrated that it can reduce the metastatic burden. In fact, before his team conducted this study, "I'd treated some patients with IMM-101," Dr Dalgleish reported.

"I was using the agent in melanoma. We'd done some laboratory research that indicated there was real synergy with gemcitabine, so I started using this in pancreatic patients," he said.

Open-Label Trial

The team conducted a randomized open-label phase 2 trial of gemcitabine with and without IMM-101 in patients with advanced pancreatic cancer at 20 sites in Cyprus, Ireland, Italy, Spain, and the United Kingdom.

Specifically, 110 patients with pancreatic cancer and a WHO score of 0 to 2 were randomly assigned to a combination of IMM-101 plus gemcitabine or gemcitabine monotherapy for a maximum of 12 cycles.

The 75 patients in the combination group received gemcitabine 1000 mg/m² in 3 injections, delivered weekly over 3 weeks, plus a 0.1 mL intradermal injection of IMM-101 10 mg/mL. The 35 patients in the monotherapy group received gemcitabine alone.

Patients completed the cancer-specific European Organization for Research and Treatment of Cancer QLQ-C30, a global health-status scale, and the pancreatic-cancer-specific QLQ-PAN26. A repeated-measures analysis of covariance using least-squares means was used to calculate overall quality-of-life scores.

Median overall survival was better in the combination group than in the monotherapy group, although not significantly (6.7 vs 5.6 months; log rank P = .072). However, in the subgroup of patients with metastatic disease, median overall survival was significantly better with the combination (7.0 vs 4.4 months; P = .009).

Progression-free survival was significantly better with the combination than with monotherapy in the population as a whole (4.1 vs 2.4 months; P = .016) and in the subgroup with metastatic disease (4.4 vs 2.3 months; P = .001).

Kaplan–Meier analysis on an intention-to-treat basis indicated that there was a trend toward improved overall survival with the combination in all patients (hazard ratio [HR], 0.68; P = .075) and in the metastatic subgroup (HR, 0.54; P = .009).

It is worth noting that the number of adverse events was substantially higher with the combination than with monotherapy (1264 vs 477).

However, Dr Dalgleish pointed out that there were twice as many patients treated with the combination as with monotherapy. In addition, mean time in the study was longer for patients in the combination group than in the monotherapy group (5.52 vs 3.80 months), the mean rate of adverse events per month was lower with the combination (3.05 vs 3.59 events), the mean exposure to gemcitabine was longer with the combination (118.7 vs 90.5 days), and the mean rate of adverse events per month of gemcitabine was lower with the combination (4.37 vs 4.59 events).

Quality of life was better with the combination than with monotherapy, and improvements in emotional, cognitive, physical, role, and social functioning were reported.

Radar plots of the QLQ-C30 and QLQ-PAN26 scores suggest that, at weeks 13 and 25, the symptoms experienced by patients in the combination group were similar to those experienced by those in the monotherapy group.

These findings are important not only because IMM-101 is the first immunotherapy agent that can be added to gemcitabine, but because the patients had more severe disease. This is because, as the trial was about to start, a number of less severe patients were diverted to the newly available FOLFIRINOX regimen, Dr Dalgleish reported. Furthermore, of all the trials, this study had the largest percentage of patients older than 65 years.

In addition, there were twice as many patients with a WHO score of 2, indicating severe disease, in the combination group as in the monotherapy group.

"Fate basically contrived to give us a really bad group of patients," he said, which explains why "our gemcitabine survival isn't as good as in some previous studies."

Overall, IMM-101 adds "no extra burden of toxicity at all; if anything, it reduces the side effects of chemotherapy, which has been shown in an another study not presented here," Dr Dalgleish noted.

This makes IMM-101 "even more important, and it's something I would use" as soon as a patient is diagnosed, he said. "The mode of action of IMM-101 means that it can be seen as a 'primer' for other therapies, extending its potential use into other modalities."

Dr Margaret Tempero

However, "you can't overinterpret this trial," cautioned session cochair Margaret A. Tempero, MD, professor of medicine at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

"It could be just chance that this happened," she told Medscape Medical News. "I think that it's hypothesis-generating. To the investigators' credit, they are regrouping and are going to focus just on patients with metastatic disease going forward."

"I think they're still trying to decide on their chemotherapy backbone, but we will have to wait and see," she added. But "it's intriguing, provocative, and encouraging."

One of the striking aspects of the session, which covered treatments for cancer of the pancreas and bile ducts, was the sheer range and variety of novel agents being explored.

"The nice thing about the majority of things being looked at is that they are stromal-based targets. They're in the tumor microenvironment, and many of these strategies can be easily combined," Dr Tempero explained.

"I think we're trawling, if you will, in an area of the tumor that we've never adequately taken seriously," she said. "If we find multiple hits, it's likely that we can add them together with stabilizing chemotherapy to make an even greater benefit."

"I don't see any one thing as driving this train; I see a lot of motion. In fact, many of these [agents] could be catalysts for each other," she concluded.

The authors have disclosed no relevant financial relationships.

17th World Congress on Gastrointestinal Cancer (WCGC): Abstract O-003. Presented July 1, 2015.


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