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Radioimmunotherapy-Chemotherapy Targets Advanced Pancreatic Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000451738.18539.ef


While there is no Food and Drug Administration approved treatment for patients with relapsed pancreatic cancer, results of a randomized Phase Ib study suggest that combining a low dose of radiosensitizing gemcitabine with the experimental radioimmunotherapy (RAIT) regimen of yttrium-90 and clivatuzumab tetraxetan is safe and may have significant activity.

As reported at the American Association for Cancer Research's Pancreatic Cancer: Innovations in Research and Treatment conference, the RAIT-gemcitabine combination, tested in patients with metastatic pancreatic ductal cancer who had at least two prior therapies, more than doubled overall survival among those who received more than one treatment cycle—7.9 months for the combination arm versus 3.4 months for patients receiving the RAIT only.

The 58 patients in the study were treated at the Pancreas Center of Excellence at Virginia Mason Medical Center's Digestive Disease Institute.

A much larger study is now comparing the same RAIT-gemcitabine regimen with gemcitabine alone: The international, double-blind, randomized Phase III “PANcreatic Cancer RadioImmunotherapy Trial-1” (PANCRIT-1) is currently accruing a planned 440 patients with stage IV pancreatic adenocarcinoma who received at least two prior treatments. Both trials are sponsored by Immunomedics.

In the trial reported at the meeting, patients received four-week cycles of 200 mg/m2 of gemcitabine weekly, combined with 6.5 mCi/m2 of 90Y-clivatuzumab tetraxetan weekly in the last three weeks, or 90Y-clivatuzumab tetraxetan alone, once-weekly.

In a news briefing during the conference, lead author Vincent J. Picozzi Jr., MD, Director of the Center, explained that 90Y-clivatuzumab tetraxetan consists of the PAM4 antibody and yttrium-90. There was little survival difference between the two study arms for patients who received only one treatment cycle. Two patients in the combination arm had partial responses, and three patients are still alive up to 15 months after the start of treatment.



Side effects were minimal, Picozzi reported, and the only clinically significant side effect that occurred with any frequency was a reduction in blood counts.

90Y-clivatuzumab tetraxetan, when used with low-dose gemcitabine, is a safe, low-side-effect therapy that can prolong survival for at least some patients with metastatic pancreatic cancer, even when no chemotherapy options exist,” Picozzi said.

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Patient Selection?

Asked her opinion for this article, Celina Ang, MD, a GI cancer specialist at Icahn School of Medicine at Mount Sinai, where she is Assistant Professor of Medicine, Hematology and Medical Oncology, said she considered the improvement in survival (i.e., 7.9 months for the combination treatment versus 3.4 months for RAIT alone) to be clinically meaningful considering that the study regimen was given as third-line therapy in metastatic pancreas cancer.



“However, the favorable outcomes of this study may reflect not only the activity of RAIT and gemcitabine, but also the influence of patient selection,” Ang said via e-mail. “The majority of patients with stage 4 pancreas cancer do not survive long enough to receive more than one to two lines of therapy, and many of those who do are not well enough for further treatment.”

Patients who, despite progression, maintain sufficient functionality to be eligible for a clinical trial and to tolerate multiple doses of study treatment (since a survival benefit was only seen with multiple cycles) probably have a lower disease burden and/or more indolent disease biology, she continued. Moreover, this was a Phase IB study designed to evaluate the safety of adding gemcitabine to RAIT, so although the survival findings are intriguing, they still, of course, need to be confirmed in a larger Phase III study.

In addition, she said, the study design is reasonable given that it was designed to evaluate the safety of adding RAID to gemcitabine and the fact that there is no standard third-line regimen for Stage 4 pancreatic cancer.

The most active regimens in metastatic pancreatic cancer are fluoropyrimidine and gemcitabine-based, she noted, so although the abstract did not specify which types of chemotherapy patients had previously received, it can be assumed that most patients had received and progressed on gemcitabine, making it less likely that re-exposure to gemcitabine monotherapy would be clinically active.

“The ongoing Phase III trial comparing RAIT plus gemcitabine versus placebo plus gemcitabine in chemo-refractory Stage 4 pancreas cancer will be enlightening,” Ang said. “It would also be interesting to see how RAIT plus gemcitabine performs against gemcitabine plus nab-paclitaxel, or against FOLFIRINOX in the first-line setting.”

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‘Don't-Eat-Me’ Signal

Also reported at the meeting, CD47, a “don't eat me” signal co-opted by cancers to evade innate immune surveillance, may be an innovative target for treatment of pancreatic cancer, according to preclinical studies described at the meeting.

CD47 is found on both pancreatic neuroendocrine and pancreatic ductal adenocarcinoma cells. Researchers from Stanford University School of Medicine reported that blocking the CD47 signaling promotes phagocytosis in vitro and eliminates tumors in vivo, indicating that disrupting CD47 may effectively eradicate pancreatic cancer in humans.

The research provides a strong preclinical rationale for testing anti-CD47 therapy in patients with pancreatic cancer, said the first author, Geoffrey W. Krampitz, MD, a doctoral candidate in the laboratory of Irving L. Weissman, MD, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University and the Ludwig Center for Cancer Stem Cell Research there.

Krampitz said the CD47 cell-surface protein is found on most cells and prevents them from being removed by macrophages. Cells lose expression of CD47 as they age or are damaged, leading to their elimination, but pancreatic tumors have co-opted CD47 to help them avoid removal.



The co-moderator of the news conference, Andrew M. Lowy, MD, Professor of Surgery and Director of Surgical Oncology at Moores Cancer Center at the University of California, San Diego, School of Medicine, said the study forms part of a very large grant whose overarching theme is to investigate immune-based therapies, which modulate the immune system's ability to recognize and kill pancreatic cancer.



“I think this is one very exciting avenue,” he said.

© 2014 by Lippincott Williams & Wilkins, Inc.
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