Pancreatic Cancer Meeting Highlights New Aggressive Approaches

Janis C. Kelly

May 20, 2014

NEW ORLEANS — Pancreatic cancer research has picked up the pace, with an urgency sparked by the realization that by 2030 this tumor type will be the second most deadly cancer in the United States (after lung cancer) and will kill more Americans than breast, prostate, or colorectal cancer.

Three new research approaches were highlighted here at a press briefing during the American Association for Cancer Research (AACR) special conference, Pancreatic Cancer: Innovations in Research and Treatment. They include a new panel of pancreatic cancer blood biomarkers for use in a blood test to aid earlier diagnosis, a new monoclonal antibody that "uncloaks" tumors for immune destruction and is about to be tested in humans, and the use of gemcitabine to strengthen the punch of a radioactive antibody. This combination of gemcitabine with a radioactive antibody (clivatuzumab tetraxetan with yttrium-90 [90Y], under development by Immunomedics), prolongs survival for at least some patients with metastatic pancreatic cancer, and is now being tested in an ongoing phase 3 trial.

Blood Test May Reduce the Need for Invasive Testing

Late diagnosis is one reason why fewer than 20% of patients with pancreatic cancer survive for more than 1 year, and only 6% survive for 5 years.

Only about 10% of pancreatic cancers are diagnosed while the disease is still localized, when there is a better chance of treatment.

With the aim of improving the early diagnosis rate, a team lead by Ayumu Taguchi, PhD, MD, is developing a blood test that would identify patients who have cancer from those who have other conditions. The blood test combines the known pancreatic cancer biomarker CA 19-9 (which has limited accuracy) with 3 new pancreatic cancer biomarkers.

"Our current imaging approaches to pancreatic cancer detection are not amenable to use in a widespread screening program. A biomarker-based method could be used much more broadly. The goal of our research was to develop a panel of biomarkers that could be used for diagnosis of early-stage pancreatic cancer," Dr. Taguchi said during a press conference at the meeting. He is assistant professor at The University of Texas MD Anderson Cancer Center in Houston and collaborated on this project with researchers from the Fred Hutchinson Cancer Research Center (Seattle, Washington), the University of California San Francisco, and the University of Utah School of Medicine (Salt Lake City).

The team reported that about 90% of the time, the biomarker panel accurately distinguished individuals with pancreatic cancer from those who were healthy, had chronic pancreatitis, or had pancreatic cysts. Dr. Taguchi suggested that this biomarker panel, which requires validation in larger studies, might greatly reduce the number of patients who would have to undergo extremely invasive pancreatic cancer screening procedures, in part because it had a high negative predictive value (98% ability to determine when a patient had chronic pancreatitis or benign pancreatic cysts rather than early-stage cancer).

The researchers first studied candidate biomarkers plus CA19-9 in a training set of blood plasma samples from 138 patients with pancreatic cancer and 81 controls (52 healthy persons and 29 patients with chronic pancreatitis), then tested the most promising combination in an independent cohort of plasma samples from 42 patients with early-stage pancreatic cancer, 50 healthy controls, 29 patients with chronic pancreatitis, and 14 patients with benign pancreatic cysts.

"We need to further validate our panel using larger numbers of samples collected before diagnosis of early-stage pancreatic cancers. However, we are hopeful that we can develop a panel that will have clinical application," Dr. Taguchi said.

During the press conference, moderator Andrew M. Lowy, MD, professor of surgery at the University of California, San Diego, said, "There is a great need for us to improve therapies for pancreatic cancer and our ability to detect and prevent pancreatic cancer." However, Dr. Lowy cautioned that the biomarker panel would probably not be used for routine mass screening because the incidence of pancreatic cancer is so low that there would likely be too many false-positive results.

Anti-CD47 Antibody Strips the Veil From Pancreatic Cancer Cells

Many types of cancer cells hide behind a scrim of CD47 protein, which renders them less visible to the immune system. Monoclonal antibody Hu5F9 strips away that veil and could potentially make many types of cancer subject to removal by normal immune surveillance processes.

Geoffrey W. Krampitz, MD, described work with Hu5F9 that showed tumor regression in preclinical models of pancreatic neuroendocrine tumors and of pancreatic ductal adenocarcinoma. Dr. Krampitz is 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 School of Medicine and the Ludwig Center for Cancer Stem Cell Research in California.

Hu5F9 appears to be active against the subset of "tumor initiating cells" responsible for tumor development, metastasis, and recurrence, as well as against other tumor cells, Dr. Krampitz said. CD47 is expressed at high levels in many types of cancer and functions as what Dr. Krampitz called a "do not kill" flag to protect cancers from removal by passing macrophages. "Every single cancer we have looked at highly expresses CD47 on its cell surface," Dr. Krampitz said.

The researchers tested the anti-CD47 antibody in 3 lines of research, all of which showed impressive efficacy against pancreatic neuroendocrine cancers and against pancreatic ductal adenocarcinomas.

"One treatment model involved injecting very well-characterized pancreatic cancer cell lines into mice either orthotopically or heterotopically and then treating with anti-CD47. In most of those mice we saw complete elimination of the tumor. In genetic mouse models of pancreatic cancer, colon cancer, and other types of cancer treated with an antibody against mouse CD47, we have seen decreased tumor burden, elimination of metastases, and prolongation of survival. Most important, when we took patients' tumors from the operating room and put them into immunocompromised mice to create a xenograft of a human tumor, anti-CD47 produced complete elimination of tumors, reduction of metastases, and prolongation of survival," Dr. Krampitz said at the press conference.

The studies included tumor samples from 39 patients with pancreatic neuroendocrine tumors (19 of which contained tumor-initiating cells) and from 39 patients with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.

Dr. Krampitz said that anti-CD47 will be further characterized in an upcoming paper. He explained that most cells have CD47 on their surface but lose CD47 expression as they age or become damaged, which leads to their elimination by macrophages. Pancreatic neuroendocrine tumors, pancreatic ductal adenocarcinomas, and many other cancer types appear to have high-jacked that signal in a "false flag" strategy to avoid removal by the immune system. Blocking CD47 apparently makes these cancer cells once more visible to normal immune surveillance.

Clinical safety trials with anti-CD47 are expected to begin later this year."Right now we are looking at the safety profile of anti-CD47 in monkeys," Dr Krampitz said. Toxicity concerns with anti-CD47 include removal of healthy cells (particularly red blood cells) that normally express CD47 to prevent autoimmune removal.

Low-Dose Gemcitabine and Radioactive Antibody

The monoclonal antibody clivatuzumab tetraxetan, weaponized with a dose of radioactive 90Y, targets the MUC5ac protein found on the surface of most pancreatic cancer cells, but not on normal cells. Final phase Ib clinical trial data presented by Vincent J. Picozzi Jr, MD, director of the Pancreas Center of Excellence at the Virginia Mason Medical Center's Digestive Disease Institute, Seattle, Washington, showed that adding a low "radiosensitizing" dose of gemcitabine further softened the pancreatic cancer's cellular defenses and significantly increased treatment impact.

90Y-clivatuzumab tetraxetan with gemcitabine is being tested against placebo with gemcitabine for metastatic pancreatic cancer in the phase III PANCRIT-1 trial. The phase III trial opened in January 2014, and Dr. Picozzi said at the press conference that (on the basis of experience with the phase Ib study), researchers expect rapid accrual and hope to complete the study in 2015.

The phase Ib trial included 58 patients, all of whom had metastatic pancreatic cancer and had received at least 2 prior therapies. All patients received 6.5 mCi/m 90Y-clivatuzumab tetraxetan for 3 weeks, divided into multiple smaller doses per cycle. After randomization, half of the patients (group A; n = 29) also received low-dose gemcitabine (200 mg/m2), weekly for 1 week and then in combination with the radioimmunotherapy for 3 weeks in each cycle. Patients received treatment for up to 9 cycles, with 4-week delays in between.

Twenty-seven of 29 patients in group A received at least 1 cycle of the combination, and 12 patients completed 2 or more cycles of treatment. In the other group (group B), 26 patients completed at least 1 cycle of treatment with the antibody alone, and 11 patients completed 2 or more cycles of treatment.

Median overall duration of survival was similar for patients who completed only 1 treatment cycle (3.9 months for group A and 2.8 months for group B) but was significantly longer with combination therapy among patients who completed 2 or more treatment cycles (7.9 months for group A and 3.4 months for group B; P = .004). Two patients in group A had partial responses by RECIST (response evaluation criteria in solid tumors) criteria, and 3 patient in group A are still being observed 11 to 17 months after the beginning of treatment.

The only clinically significant adverse effects were cytopenias (mainly thrombocytopenia), which were "mostly transient and manageable with infrequent hematologic support and little evidence of increased infection or bleeding," Dr. Picozzi reported.

"We found that 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," Dr. Picozzi concluded.

Time for Pancreatic Cancer Research to Catch Up?

"The projections for deaths from pancreatic and liver cancers are startling," said Lynn Matrisian, PhD, MBA, vice president of scientific and medical affairs at the Pancreatic Cancer Action Network (PCAN), which supported the study that predicted the high rate of pancreatic cancer death by 2030.

"This study is a call to action to the scientific and clinical communities, as well as the population at large, to increase attention, awareness, and ultimately progress in the fight against pancreatic cancer," Dr. Matrisian said.

The PCAN researchers used demographics and changes in the annual percentage of cancer incidence and deaths to estimate future cancer incidence and death rates. Increased numbers of older and minority populations will increase the population likely to be at greater risk for pancreatic cancer. Meanwhile, cancer death rates overall and incidence of other major cancers will decline because of better screening and prevention methods and lower prevalence of smoking and viral infections.

Dr. Matrisian said that historically, pancreatic cancer has been less studied, in part because of less funding and in part because the pancreas is located deep within the abdomen, where it is difficult to access and to visualize by imaging modalities. Furthermore, the dense stromal tissue surrounding and infiltrating many pancreatic tumors impedes both imaging and drug delivery.

PCAN is intensifying efforts to heighten awareness, raise funds for comprehensive private research, and advocate for dedicated federal research to advance early diagnostics, improve treatments, and increase chances of survival, with the goal of doubling pancreatic cancer survival by 2020, Dr. Matrisian said.

The 90Y-clivatuzumab tetraxetan/gemcitabine study was funded by Immunomedics Inc. Dr. Taguchi, Dr. Krampitz, Dr. Picozzi, and Dr. Matrisian have disclosed no relevant financial relationships. Three of the anti-CD47 coauthors are employees of Genentech. Two of Dr. Picozzi's coauthors are employees of Immunomedics.

American Association for Cancer Research (AACR) special conference: Pancreatic Cancer: Innovations in Research and Treatment. Presented at news conference on May 19, 2013.


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