More Hope, And More Demands, For Pancreatic Cancer Pipeline

ASCO reflected diverse lay of the land for the challenging development space, with new drugs coming from Merrimack, Halozyme, Threshold and a range of immunotherapy combinations. Meanwhile, Celgene’s Abraxane appears to be on blockbuster track.

The “dizzying” breadth of development is bringing hope for a better future in the tough-to-treat pancreatic cancer, experts say, but in an increasingly value-conscious environment, new therapies will need to earn their keep with significant impact on overall survival and quality of life.

A June 2 education session at the American Society of Clinical Oncology meeting highlighted the challenges of developing drugs for pancreatic cancer, the variety of new therapies on the way and concerns about costs for patients.

Ohio State University’s Tanios Bekaii-Saab commented that the picture in pancreatic cancer treatment has changed a lot even within the last two to three years, with a “dizzying” number of different strategies in development (see sidebar).

“It’s a fantastic time to be involved in developing trials and the treatment of pancreas cancer,” Bekaii-Saab said.

Given the high unmet need in pancreatic cancer, cost hasn’t been a concern in the space. But with the growth of drug development in the tumor type and increasing awareness of value issues, that could change.

Undeniably, the threat of “financial toxicity” and the need to demonstrate value, particularly with the trend toward doublet and triplet combinations of branded drugs, were underlying themes of this year’s meeting (Also see "Oncology Drug Costs Can Be ‘Financial Toxicity,’ ASCO Told" - Pink Sheet, 5 Jun, 2015.).

Cost “rarely crosses my mind” when making treatment decisions now, Andrew Ko, University of California, San Francisco, said at the ASCO session, but cost-effectiveness “needs to be factored into the decision-making process.”

The introduction of expensive vaccine and cell therapies will spur more discussion about value and cost-effectiveness in pancreatic cancer, according to Neal Meropol, University Hospitals Case Medical Center in Cleveland. Meropol has been involved in ASCO’s value initiatives and is a noted researcher on the topic.

During the pancreatic cancer education session, he cautioned that patients are increasingly feeling the burden of increased costs.

“As a society and as individuals we face in the office who might have co-insurance and might bear some of the burden associated with these therapies, we have to decide, what are we actually willing to pay? What is good value for money?” Meropol asked.

Meropol flagged ASCO’s draft framework for determining value of new cancer therapies, which was released on June 22 (Also see "ASCO Value Framework Presents ‘Net Health Benefit’ Score For Drugs" - Pink Sheet, 22 Jun, 2015.). While he stressed the need for demonstrating value, he also acknowledged that “we haven’t quite come to a consensus, at least in North America, with regard to what is good value for money in terms of treatment costs.”

In pancreatic cancer, there are no long-term survivors with metastatic disease and to make a big impact, we either have to find strategies to cure metastatic disease or to improve the cure rate of micrometastatic disease in the adjuvant setting, he urged.

Established options for first-line metastatic disease are the FOLFIRINOX chemo combination, Eli Lilly & Co.’s Gemzar (gemcitabine) and generics, and the combination of gemcitabine with Celgene Corp.’s Abraxane (nab-paclitaxel).

Meropol noted that ASCO’s 2013 effort to set benchmarks for efficacy for various tumor types suggested that for pancreatic cancer, the OS benefit for those eligible for FOLFIRINOX should be at least 4 to 5 months, and should be 3 to 4 months for those who are gemcitabine-eligible (Also see "Cancer Trials Should Show Minimum 20% Overall Survival Benefit, ASCO Suggests" - Pink Sheet, 25 Apr, 2013.).

Meropol advised setting the bar high for developing new, innovative therapies.

Optimism About New Options

This increasing awareness about value issues offers a backdrop for the development of a large and diverse pipeline for pancreatic cancer, a disease that hasn’t seen as much progress in terms of new drug approvals as other tumor types.

According to the BioMedTracker database, 10 drugs are in Phase III and one NDA has been filed. Merrimack Pharmaceuticals Inc. completed submission of a rolling NDA in April for MM-398, a formulation of irinotecan with nanoliposomal delivery for metastatic pancreatic cancer patients who previously had gemcitabine (Also see "Keeping Track: Kybella, Ixinity, Raplixa Approved; Three 'Complete Responses' Surprise No One" - Pink Sheet, 4 May, 2015.). The filing was based on the NAPOLI-1 Phase III study, in which the triplet combination of MM-398 with 5-FU and leucovorin yielded median overall survival of 6.1 months versus 4.2 months for 5-FU/leucovorin, a statistically significant improvement of 1.9 months. MM-398 is also being tested as a first-line therapy for metastatic pancreatic cancer.

Other drugs now in pivotal testing include Threshold Pharmaceuticals Inc.’s evofosfamide (TH-302), AstraZeneca PLC’s PARP inhibitor Lynparza (olaparib), Incyte Corp.’s JAK inhibitor Jakafi (ruxolitinib) and NewLink Genetics’ HyperAcute pancreas vaccine (algenpantucel-L).

Furthermore, including combination studies, about another dozen candidates are in Phase II or II/III and about three dozen more are in Phase I or Phase I/II, with even more trials coming out of academic settings.

The pipeline includes a range of different modalities, with overlapping and complementary mechanisms of action, including novel cytotoxics like MM-398, stromal depleting agents, signal transduction inhibitors and immunotherapies.

Market Opportunities

There remains a high level of unmet need in pancreatic cancer, making it one of the most pressing areas of drug development.

“With 39,000 deaths per year and a dearth of treatment options, pancreatic cancer could represent a $1B+ U.S. market for any successful new entrant,” Cowen & Company note in its March 2015 Therapeutic Categories Report. But, they note, there have been significant barriers to drug development, including the aggressiveness of the disease, the presence of a dense fibrotic stroma that prevents optimal drug delivery and “a willingness to start Phase III studies on the basis of small, often uncontrolled trials data in selected (more healthy) populations.” That has contributed to a high failure rate.

As UCSF’s Ko noted at the ASCO meeting, from 2000 to date, only two new therapies have been approved by FDA for pancreatic cancer – Astellas Pharma Inc.’s Tarceva (erlotinib) in 2005, which has very modest efficacy in pancreatic cancer, and Celgene Corp.’s reformulated paclitaxel Abraxane in 2013 (following clearance in lung and breast cancers). Abraxane has had wide acceptance in pancreatic cancer, Cowen notes: the indication accounted for about $348 million of the drug’s $848 million in total product sales in 2014 and is on its way to becoming a blockbuster in the disease, analysts concluded. Cowen expects global sales in pancreatic cancer alone will reach $1 billion in 2018.

The FOLFIRINOX chemotherapy combination regimen (oxaliplatin/irinotecan/fluorouracil/leucovorin) demonstrated efficacy in a Phase III study of first-line pancreatic cancer published in 2011, paving the way for adoption as a standard option for patients who can tolerate it.

New therapies offer a survival benefit, but at much higher cost, Meropol said, noting a study presented by Emory University’s Daniel Goldstein and colleagues at ASCO’s 2015 Gastrointestinal Cancers symposium. Including the drug costs as well as expenses related to administration and managing toxicities, gemcitabine monotherapy costs $1,363 per month, whereas adding Abraxane to gemcitabine balloons that expense almost ten-fold to $12,221, much of which is related to the higher cost of the branded drug, according to the study. FOLFIRINOX, which requires administration of growth factors that ratchet up costs, is somewhere in between these two at $7,234, researchers estimated.

Meropol noted that the FOLFIRINOX data show that quality of life is improved with the regimen, whereas such data are not available in the pivotal data for Abraxane in pancreatic cancer.

Despite the disappointments of the past, the field is optimistic for positive change. Ko said that there is a “great likelihood” that MM-398 will be cleared by FDA, becoming the first approved salvage treatment for gemcitabine refractory patients. However, he also asked whether “newer was always better” and questioned how efficacy would compare to other chemotherapy combinations used in this setting.

Threshold’s Phase III hypoxia (low oxygen) activated prodrug TH-302 also holds promise, Ko said. Results in Phase II were compelling enough to start a Phase III study called MAESTRO, which tests TH-302 against gemcitabine in first-line metastatic prostate cancer. The trial, which is being run mainly outside the U.S., is fully recruited.

“If this is a positive study – and we should have a readout I would say sometime in the next 12 months – that would offer yet a third potential option for patients with metastatic pancreatic cancer in the first-line setting,” Ko said.

Ko also called attention to Halozyme Therapeutics Inc.’s stromal depleting agent PEGPH20 (Also see "Deal Watch: ASCO Includes Flurry Of Immuno-Oncology Combo Trial Partnerships" - Pink Sheet, 8 Jun, 2015.). Halozyme presented positive Phase II interim trial data at the ASCO meeting that confirmed the value of hyaluronan, or hyaluronic acid, as a biomarker for this drug (Also see "New AbbVie Collaboration Shows Two-Pillar Strategy Working For Halozyme" - Pink Sheet, 4 Jun, 2015.).

Hyaluronan is a component of the tumor’s infrastructure, and aberrant accumulation creates “a protective network or ‘halo’ that surrounds certain tumors,” including pancreatic cancer, Halozyme explains. The stroma, or halo, contributes to the tumor microenvironment and acts as a barrier to drug delivery of many cancer therapies. Halozyme’s Hylenex (rHuPH20) is already approved to facilitate the administration and effectiveness of other drugs, and PEGPH20 would be an improved pegylated formulation.

Biomarkers have been hard to find in pancreatic cancer, but in those with high level of hyaluronan, “you saw really quite a striking improvement in overall response rate as well as median progression-free survival,” Ko said, though the clinician also noted a higher incidence of thromboembolic events.

While the results for PEGPH20 look promising, Ko also cautioned about development challenges. There might be advantages to remodeling tumor stroma, but also a downside in that the stroma might have protective effects in terms of restraining tumor growth.

“Previous attempts to target the tumor microenvironment, in particular with Hedgehog signaling inhibitors, have proved unsuccessful,” Ko and colleagues noted in an article on pancreatic cancer development in the 2015 ASCO Education Book.

But, Ko told the conference, “stay tuned for [PEGPH20], because that has generated considerable interest.”

Keeping Faith In Immunotherapy

Both Ko and Bekaii-Saab see an important role for a range of immunotherapies in pancreatic cancer going forward.

Through multiple different mechanisms, pancreatic cancer is a very immuno-suppressive disease, so it makes sense to approach it with immunotherapy treatment, Bekaii-Saab said. However, the dense stroma around tumors that characterizes the disease makes it hard to treat.

A range of treatments could be deployed, including checkpoint inhibitors, cancer vaccines, oncolytic virus therapies and CAR-T treatments. Checkpoint inhibitors, including anti-CTLA4 and anti-PD1/L1, have made big in-roads in other diseases, but so far have not worked well as single agents in pancreatic cancer. But they could work better in combination with other immunotherapies, as well as traditional chemotherapy and new targeted treatments, the clinician suggested.

Of the PD-1/L1 sponsors, AstraZeneca PLC appears to be taking the lead in this tumor type, having announced plans to start a study comparing its PD-L1 inhibitor MEDI4736 against its CTLA-4 inhibitor tremelimumab in second-line pancreatic cancer (Also see "AstraZeneca’s Oncology Strategy: It’s All About The End Results" - Pink Sheet, 22 Jun, 2015.).

Among other combination studies, Pharmacyclics Inc. is sponsoring a Phase II/III trial called RESOLVE testing its BTK inhibitor Imbruvica (ibrutinib), which also targets the interleukin-2-inducible T-cell kinase, with gemcitabine and Abraxane in first-line metastatic pancreatic cancer. In collaboration with Bristol-Myers Squibb Co., the Sydney Kimmel Comprehensive Cancer Center is running the Phase II STELLAR study of Aduro Biotech Inc.’s CRS-207, a Listeria vaccine engineered to express mesothelin, with its GVAX Pancreas vaccine, which is modified to secrete GM-CSF, with or without Bristol’s PD-1 inhibitor Opdivo (nivolumab) in second-line metastatic pancreatic cancer.

“I think it’s very important to consider a multi-pronged approach to be able to actually effectively harness the power of the immune system in pancreas cancer,” Bekaii-Saab said.