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The Road to Stroma-Directed and Immunotherapy in Pancreatic Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000473590.44190.6c


BARCELONA, Spain—A mycobacterial product that stimulates the immune system and a drug that enzymatically depletes hyaluronan were highlighted here in presentations on new directions in pancreatic cancer at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

The Phase II trial in patients with tumors high in hyaluronan, the high-molecular-mass polysaccharide found in the extracellular matrix, showed improved response rates and progression-free survival when the anti-hyaluronan agent PEGPH20 was added to gemcitabine/nab-paclitaxel.

And the first positive study of an immunotherapy/chemotherapy combination in first-line treatment of pancreatic ductal cancer showed clinically meaningful extension of overall and progression-free survival with IMM-101, a mycobacterial product, combined with gemcitabine.

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Tumors Rich in Hyaluronan

“Pancreas cancer is notorious for its desmoplastic stroma and fibro-inflammatory action, and hyaluronan is a major component of desmoplastic stroma—a barrier to therapeutic access,” explained Andrew E. Hendifar, MD, Medical Oncology Lead Investigator in the Gastrointestinal Disease Research Group of Samuel Oschin Comprehensive Cancer Center of Cedars Sinai Medical Center in Los Angeles.

Hyaluronan, a highly hydrophilic glycosaminoglycan, can generate a large immobile fluid phase, thus compromising access to the tumor by increasing tumor interstitial fluid pressure, compressing the vasculature, and producing a cell “coat,” he noted. Hyaluronan also signals through receptors on the cell surface.

Pancreas, breast, colon, and prostate cancers have been shown to accumulate high levels of hyaluronan.

Hendifar is lead author of the randomized Phase II HALO-109-202 trial, also known as Study 202, which is investigating the use of PEGPH20 plus nab-paclitaxel plus gemcitabine compared with nab-paclitaxel plus gemcitabine alone in patients with stage IV untreated pancreatic cancer. PEGYPH20 is pegylated recombinant human hyaluronidase, an enzyme that depletes hyaluronan.

In his report on the interim results on the first 146 patients in the study, he noted that PEGPH20 rapidly and sustainably decreases the content of hyaluronan in the tumor, thus inducing re-expansion of blood vessels and increasing intratumoral delivery of chemotherapy.

Patients with high hyaluronan-expressing cancer in this trial saw a statistically significant improvement in the objective response rate with the three-drug combination versus the chemotherapy-alone arm (52% vs. 24%). In contrast, patients with low hyaluronan content did not appear to benefit from PEGPH20, with objective response rates that were similar for both treatments: 37 and 38 percent, respectively.



Progression-free survival doubled in high-hyaluronan patients: 9.2 months with PEGPG20-gemcitabine/nab-paclitaxel versus 4.3 months with gemcitabine/nab-paclitaxel. And the median duration of response was 8.1 months with PEGPH20 versus 3.7 months for gemcitabine/nab-paclitaxel. There was also a trend toward improved overall survival: 12 versus nine months.

The study was halted for a while after the first 146 patients were enrolled due to an imbalance in thromboembolic events in the PEGPH20 group, but enoxaparin was then added for prophylaxis and the study resumed. Hendifar said the trans-ischemic events were manageable in subsequent patients, with enoxaparin given at a dose of 1 mg/kg/day.

He noted that a global Phase III, randomized, double-blind, placebo-controlled trial comparing the same drugs in this patient population is scheduled to start in the first quarter of 2016.

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Discussant: Hyaluronan Localized in Stroma

“We are seeing quite interesting results in progression-free survival with PEGPG20—nine versus four months, roughly, which was significant, but we see only a trend in improved overall survival,” said the Discussant for this session, Volker Heinemann, MD, PhD, Director of the Comprehensive Cancer Center of Ludwig-Maximilians-University in Germany.

“It is important to understand that hyaluronan is glycine that is over-expressed in pancreatic cancer and localized to the stroma,” he said, citing GUT 2013;62-112-120. “If you combine hyaluronidase with gemcitabine you can decrease proliferation, and you can decrease the tumor volume and have a positive effect on overall survival in the mouse model.”

Heinemann noted that the agent was tolerated quite well.

He added that the overall 24 percent response rate in the Study 202 control arm of gemcitabine-nab-paclitaxel is highly consistent with the 23 percent for the gemcitabine-nab-paclitaxel arm in the study reported by Von Hoff et al: NEJM 2013;369:1691-1703.

Progression-free survival rates were also similar in those two studies—4.3 months in Study 202 and 5.5 months in the nab-paclitaxel study—as was overall survival (nine months and 8.5 months). “Of course, the control arm in Study 202 is just 21 patients compared with 431 in the Von Hoff study, so this comparison is to be used in brackets,” Heinemann added.

“But if we look at least at the consistency of the data by themselves, I think we can also appreciate that these response data with regard to objective response give us an overall survival picture that is quite impressive so far.”

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IMAGE Trial Tests Mycobacterial Product

In the other highlighted pancreatic cancer study, the first positive evaluation of an immunotherapy/chemotherapy combination in first-line treatment of pancreatic ductal cancer showed clinically meaningful extension of overall and progression-free survival.

The randomized, open-label Phase II IMAGE (Immune Modulation and Gemcitabine Evaluation) trial combined IMM-101, a mycobacterial product, with gemcitabine (at 1,000 mg/m2) and compared that combination with gemcitabine alone in 110 patients.

Interestingly, the greatest improvements were seen in patients with metastatic disease, said the lead investigator, Angus G. Dalgleish, MD, Professor of Oncology in the Division of Clinical Sciences at St. George's University of London, U.K.

He explained that IMM-101 is a heat-killed mycobacterial product that stimulates innate and adaptive immune response. It is administered intradermally rather than subcutaneously, induces CD8+ cell responses, and reduces metastasis in mouse models.

“In this trial it significantly increased overall survival and progression-free survival, with no incremental toxicity or immune-related toxicities, while maintaining quality of life.” And although not statistically significant, there were improvements in neutropenia and fatigue that are very important in quality of life, he added.

The survival curve shape is very characteristic of immunotherapy, Dalgleish noted.

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Study Specifics

There were 74 patients in the treated arm and 35 controls, all with inoperable pancreatic cancer and WHO performance status of zero to two. Two-thirds of the patients were age 65 or older, and the patients were treated at 20 sites in Europe.



Dalgleish reported median overall survival for all IMM-101-treated patients to be 6.7 versus 5.6 months for controls, a 20 percent increase, whereas median overall survival for metastatic patients was 7.0 months with IMM-101 versus 4.4 months for controls, a 59 percent increase.

Median progression-free survival with IMM-101 was also longer in metastatic patients: For all patients the progression-free survival was 4.1 months for the IMM-101 arm versus 2.4 months for controls—a 71 percent increase—whereas for metastatic patients it was 4.4 months versus 2.3 months—a 91 percent increase.

“Further investigation of IMM-101 with additional immunotherapies such as checkpoint inhibitors is logical,” Dalgleish concluded.

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Discussant: Focus Changing from Stroma

In his discussion of the two trials, Heinemann said research in pancreatic cancer has for some time focused on peritumoral tissue and stroma. “We had understood pancreatic cancer as a tumor that is hypervascular and hyperperfused, and rich in collagen and in inflammatory reactions. The thought was that by reducing the stromal compartment we would improve the vascularity of the tumor, we would be able to deliver chemotherapy to a greater extent, and thereby improve antitumor efficacy.”

This seemed to be born out, he said, with the study by Von Hoff and co-workers of nab-paclitaxel plus gemcitabine versus gemcitabine alone. “At that time, the hypothesis was that nab-paclitaxel was focusing on peritumoral fibroblasts and would eliminate these tumors, and so the combination of gemcitabine plus nab-paclitaxel led to a stromal depletion,” Heinemann explained.

Those authors concluded that this was most likely the cause of an increase in gemcitabine accumulation in tumor cells, a response seen in other trials involving various tumors.

“Now I think all of us were quite shocked to see research—Cancer Cell 2014;25:719-734, Cancer Cell 2014;25:735-747—demonstrating that stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma,” Heinemann said. “In fact, stromal elements induced a decrease in fibroblasts, but on the other hand also caused evolution of undifferentiated pancreatic ductal carcinoma cells.

“This was in contrast to what we had expected, but it was supported by the fact that the INFINITY trial, using the sonic hedgehog (SHH) inhibitor IPI-926, in fact made the tumors more aggressive.”

He said this was supported by later works showing that stromal depletion was associated with shorter survival in mouse models—“We have come a long way in treating pancreatic cancer, from gemcitabine, to targeted therapy, to intensified chemotherapy, and now to stroma- and immune-directed therapy.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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