Expert Investigators Discuss Emerging Therapies for GI Cancers

A panel of expert clinical investigators discussed details of several treatments and a dozen patient cases involving gastric, colorectal, and pancreatic cancer¹at a satellite meeting of the 2015 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.²

The audience participated in the discussion via electronic tablets that allowed attendees to respond to poll questions and to present cases for review and comment by the panel of key opinion leaders. In this way, community oncologists were able to gain direct input from top clinical investigators on treatment options for their own patients.

Oncologist and moderator Neil H. Love, MD, first reviewed results of an audience poll that asked, “In the past month, how many times would it have been helpful to have input from a clinical investigator about treatment for a patient in your practice?”

BBI608 for Cancer Stem Cells

Two-thirds of respondents reported that they would have liked such input at least twice in the past month. Each expert speaker also presented information on new and emerging GI cancer treatments and applied this information to the patient cases under review by means of numerous, interwoven group discussions.Cancer stem cells are often able to survive chemotherapy, leading to recurrence and metastasis. In a review of selected ongoing studies of novel targeted agents for gastroesophageal (GE) cancer, Philip A. Philip, MD, PhD, Karmanos Cancer Center, Wayne State University, Detroit, Michigan, discussed BBI608, a compound for treatment of cancer stem cells. BBI608 targets STAT3, beta-catenin, and Nanog, with some preclinical evidence of synergy with paclitaxel.

BRIGHTER is an ongoing phase II trial of BBI608 and paclitaxel in gastric or GE junction cancer versus placebo and paclitaxel (NCT02178956).

Axel F. Grothey, MD, professor of oncology, Mayo Clinic, Rochester, Minnesota, said that his clinic has recognized the importance of the cancer stem cell concept by creating a development program in stem cells. Mayo investigators have learned that cancer stem cell treatment has parallels with approaches used in immunotherapy.

“Stem cells make up a very small part of the tumor,” said Grothey. “Instead of using conventional Response Evaluation Criteria in Solid Tumors (RECIST) standards to control progression, we use immunotherapy-like response criteria, because you might want to allow a little progression of the already committed cells before they regress. Immunotherapy has shown us a different way of thinking about cancer therapy.”

TAS-102 for Colorectal Cancer

Asked how BBI608 exerts its effect on cancer stem cells, Grothey said that the mechanism of action would be published soon in theProceedings of the National Academy of Sciences. Because it involves inhibition of a component of Wnt signaling (STAT3), BBI608 is a unique agent.In a discussion of new treatments for advanced colorectal cancer, Howard S. Hochster, MD, associate director for clinical sciences, Yale School of Medicine, New Haven, Connecticut, reviewed TAS-102, a novel fluoropyrimidine, which has shown promise in the RECOURSE phase III trial. However, when the audience was asked in a poll, “If TAS-102 were accessible to you, would you recommend it for your patients with metastatic colorectal cancer?” more than 60% said, “I am not familiar with TAS-102.”

TAS-102 was originally formulated in 1964, but was not practical to use because its half-life was only about 12 minutes. Researchers have now combined TAS-102 with an inhibitor (tipiracil) of the enzyme that metabolizes TAS-102, thymidine phosphorylase. This modification greatly extends the half-life of TAS-102, providing oncologists with another effective fluoropyrimidine in their options for cancer treatments. In RECOURSE, patients with metastatic colorectal cancer (mCRC) who had received 2 or more prior regimens of treatment with chemotherapy and bevacizumab were given TAS 102 plus best standard care (BSC) or placebo plus BSC. The primary endpoint of overall survival (OS) was met (hazard ratio [HR], 0.68, P < .0001), and TAS-102 toxicity was similar to that seen with placebo.

Pancreatic Cancer Treatments

Commenting on the chances for approval of this novel antimetabolite combination that could be appropriate for use in earlier CRC, or combined with irinotecan, oxaliplatin, and targeted agents, Grothey said that TAS-102 is being reviewed by the US Food and Drug Administration (FDA) with a verdict of likely approval within 6 months.Johanna C. Bendell, MD, director of GI cancer research, Sarah Cannon Research Institute, Nashville, Tennessee, discussed improved treatments for pancreatic cancer that have resulted in average survivals of 10 to 12 months now being seen in trials. In terms of new agents for pancreatic cancer, Bendell cited JAK-STAT signaling inhibition as a novel approach. Janus kinases (JAKs) are a family of kinases that includes JAK1, JAK2, JAK3, and TYK2. JAKs mediate cytokine signaling by activating STAT transcription factors, an inflammatory pathway that is highly active in pancreatic cancer.

&ldquo;This high degree of inflammation is why pancreatic tumors are so hard to treat. It is very difficult to get the chemotherapy drugs or targeted agents to the tumor. Reducing this inflammation could result in improved drug delivery and better antitumor effect,&rdquo; Bendell said.

Bendell described RECAP, a recent phase II study of patients with metastatic pancreatic cancer who were randomized to receive second-line treatment of ruxolitinib with or without capecitabine. Ruxolitinib, a JAK1/JAK2 inhibitor, blocks signaling mediated by many proinflammatory cytokines. The calculated hazard ratio (0.79) for the primary endpoint (OS) was not statistically significant. However, when patients were stratified by the modified Glasgow Prognostic Score (mGPS), a well-characterized clinical measure of inflammation in cancer that combines levels of C reactive protein (CRP) and serum albumin, a significant hazard ratio of 0.49 was achieved by the high inflammation group. On the basis of this result, there are now 2 phase III studies involving ruxolitinib under way, JANUS-1 and JANUS-2, in patients prescreened for moderate or high mGPS score.

Another emerging agent for treatment of pancreatic cancer that focuses on improved drug delivery is MM-398, a nanoliposomal form of irinotecan. Recent positive results from NAPOLI-1, a phase III study in patients with metastatic pancreatic cancer, showed improved OS (HR, 0.67, P = .0122) of MM-398 plus 5-FU/leucovorin compared with 5-FU/leucovorin alone. Approval of MM-398 is anticipated by the end of this year, according to Bendell.

Pembrolizumab, an antiprogrammed cell death-1 (PD-1) antibody recently approved for treatment of metastatic melanoma, is being investigated for efficacy and safety in many other tumor types. Tanios S. Bekaii-Saab, MD, assistant professor of medical oncology, Ohio State University, Columbus, discussed the use of immunotherapy via PD-1 receptor blockade in GI cancer, referring to KEYNOTE-012, a phase IB study of pembrolizumab as a single agent in patients with advanced gastric cancer. Tumor cells can evade response of the immune system to malignancy by overexpressing the PD 1 ligand, PD-L1, on their surfaces to bind the negative co-stimulatory PD-1 receptor expressed on activated T cells, thereby shutting off signals directing the T cells to attack cancer cells. Bekaii-Saab described blocking of PD-1 or PD-L1 as a way to make tumors more detectable by T cells, thereby boosting immunogenic activity and tumor clearance. Patients were screened for PD-L1 expression before enrollment to provide a basis for studying the relationship between PD-L1 expression and clinical outcomes.

&ldquo;The response rate of 33% in mostly refractory patients is quite interesting. PD-L1 levels seemed to be associated with response rate, although the statistical significance is currently borderline,&rdquo; Bekaii-Saab said. &emsp;

References

1. Cases from the Community: Clinical Investigators Provide Perspectives on Actual Patients with Metastatic Colorectal, Gastric, and Pancreatic Cancer. Research To Practice.
2. ASCO Gastrointestinal Cancers Symposium, San Francisco, CA, January 15-17, 2015.