Pancreatic cancer, recognized as an orphan disease, accounts for just 3% of all new cases of cancers, but is the third leading cause of all cancer-related deaths1,2. Despite recent scientific and clinical progress and the rapid rate of drug development in oncology, pancreatic cancer remains a deadly disease with a five-year survival rate of around 7%.

For advanced stage patients, chemotherapy is the only treatment option. Reformulations of chemotherapeutic agents – Celgene’s Abraxane and Shire/Ipsen’s Onivyde – have shown survival benefits in in first and second-line metastatic pancreatic cancer, respectively, however overall survival following treatment with these agents is less than a year. The poor treatment outcomes for pancreatic cancer are in comparison to few other oncology indications. Recently, immunotherapy has been breaking ground in the treatment of many difficult-to-treat cancers, however, historically immunotherapy has had only limited success in pancreatic cancer.

 

 

Tumor microenvironment plays a key role in pancreatic cancer; these tumors have an impermeable, fibrous, desmoplastic stroma which prevents current chemotherapies from being able to reach tumor cells, making them incredibly hard to treat and resulting in the poor prognosis observed with advanced stages of the disease.  Interestingly, pancreatic cancer tumors have a T-cell rich environment, however, because of the expression and activation of various immune-suppressive pathways in the tumor microenvironment, the immune system is unable to eradicate pancreatic cancer cells.

While immunotherapy has not historically been successful in pancreatic cancer, recent events have brightened the prospects for this mode of treatment in pancreatic cancer. In a first-of-its-kind of decision, on May 23rd, under its accelerated approval scheme, the U.S. FDA approved Keytruda for the treatment of solid tumors exhibiting high microsatellite instability (MSI-H) or mismatch-repair deficiency (dMMR). In addition to being an unprecedented move by the FDA, it is also a giant leap forward for pancreatic cancer treatment; approximately 13-17% of pancreatic cancer patients are thought to have MSI-H or dMMR, making it the first immunotherapy to be approved in the indication3-5. In the clinical study which supported this approval, Keytruda demonstrated 83% ORR in the six evaluable pancreatic cancer patients. Keytruda’s availability for MSI-H or dMMR pancreatic cancer makes it the second non-chemotherapeutic agent (after Tarceva) to be labelled for use in pancreatic cancer.

In another area of immunotherapy development, ARMO Biosciences will present interim results of its Phase III immunotherapeutic agent, AM0010, at the ASCO 2017 meeting. AM0010 is a pegylated interleukin (IL)-10 therapy that is being investigated for recurrent metastatic pancreatic cancer patients. Data indicate that the agent induced de-novo clonal expansion of T-cells, and that immune activation was linked to prolonged survival - an ORR of 16%, DCR of 74%, and MOS of 10 months in the 19 evaluable patients.

The immunotherapy pipeline for pancreatic cancer is diverse, consisting anti-cancer vaccines (such as TLP0-001, GVAX), immune checkpoint inhibitors (such as durvalumab, tremelimumab), and other novel immunotherapies (such as virus-based immunostimulant – ParvOryx).

 

 

It seems the initial failures have provided valuable lessons, as many investigational immunotherapies now are supported by strong clinical trial designs, while others are being studied in novel combinations (with other immunotherapies, other targeted agents, or chemotherapies).

 

References:

  1. American Cancer Society, Key Statistics for Pancreatic Cancer (Last Revised: January 2017)
  2. Pancreatic Cancer Action Network, Pancreatic Cancer Facts 2016
  3. Ahn MS, et al. Infrequent microsatellite instability-high (MSI-H) in pancreatitis and pancreatic cancer specimens. Gastroenterology. 2000; 118 (Issue 4; A1378)
  4. Nakata B, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clinical Cancer Research. 2002; 8(8): 2536-40.
  5. Yamamoto H, et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Research. 2001; 61(7): 3139-44.

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