The Lynx Group

Emerging Targeted Therapies for Advanced Pancreatic Cancer Show Promise

May 2014, Vol 5, No 4

San Francisco, CA—New cytotoxic combinations introduced over the past several years for the treatment of advanced pancreatic adenocarcinoma now constitute the standard of care for the treatment of all stages of the disease. Eileen M. O’Reilly, MD, Gastrointestinal Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, reviewed emerging treatments at the 2014 Gastrointestinal Cancers Symposium.

“There are new opportunities for building on these cytotoxic combinations by the addition of molecularly targeted agents, and there is renewed interest in evaluating a range of immunotherapeutic approaches in pancreas adenocarcinoma,” Dr O’Reilly said.

In 2010, the FOLFIRINOX (leucovorin/fluorouracil/irinotecan/oxaliplatin) regimen was established as a standard treatment option for patients with metastatic pancreatic adenocarcinoma in a randomized phase 3 trial, said Dr O’Reilly.

However, enthusiasm for the FOL­FIRINOX regimen has been tempered by the increased gastrointestinal (vomiting, diarrhea), neurologic (peripheral neuropathy), hematologic (thrombocytopenia, febrile neutropenia), and constitutional adverse events compared with gemcitabine, Dr O’Reilly said, in addition to the need for growth factor support.

The regimen of nab-paclitaxel plus gemcitabine recently received approval from the US Food and Drug Administration for the first-line management of metastatic pancreatic adenocarcinoma based on findings from a randomized phase 3 trial comparing it with single-agent gemcitabine. The nab-pac­litaxel plus gemcitabine combination demonstrated an improved overall survival (OS; 8.5 vs 6.7 months, respectively; P = .015), progression-free survival (5.5 vs 3.7 months, respectively; P = .024), and tumor response (23% vs 7%, respectively). It was also superior on the end point of OS in patients with poor-risk features (ie, Karnofsky performance status of 70-80). This combination, therefore, may be suitable for a broader number of patients than FOLFIRINOX, noted Dr O’Reilly.

New Therapies, Immunotherapies
Multiple targeted-type approaches are being evaluated in pancreatic adenocarcinoma, said Dr O’Reilly. Interfering with hyaluronan in the stroma with the use of pegylated recombinant human hyaluronidase PH20 (PEGPH20) as a stromal degradation agent that facilitates drug delivery is showing promise. PEGPH20 may augment the effects of cytotoxic agents, and has led to late-phase trials of its use in combination with nab-paclitaxel plus gemcitabine or with FOLFIRINOX.

The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib may have benefit in patients with pancreatic adenocarcinoma and BRCA/PALB2 mutation. Early-phase trials have been completed to establish a dosing strategy; veliparib is now being evaluated in a phase 2 study in combination with cisplatin and gemcitabine.

Janus kinase (JAK) inhibition is another potential avenue. Ruxolitinib, a JAK1 and JAK2 inhibitor, combined with capecitabine improved 6-month survival compared with capecitabine and placebo in patients with previously treated pancreatic adenocarcinoma.

Immunotherapeutic approaches include:

  • Combining a Listeria-based vaccine, CRS-207, with a GVAX vaccine, which improved OS in a randomized phase 2 trial
  • Anti-CD40–targeted agents
  • Anti–PD-1, anti–PD-L1, and anti-CTL4–targeted agents
  • Adoptive transfer of chimeric-antigen receptor approaches against mesothelin.

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