Systemic Therapy of Pancreatic Cancer: Better Science, Faster Progress

Oncology (Williston Park). 29(11):821, 826.

Weinberg and colleagues elegantly describe recent advances and future possibilities in the treatment of pancreatic adenocarcinoma.[1] I respectfully disagree with the authors that advances in this area of oncology have been “significant,” especially when considered in relation to developments in other similarly aggressive cancers. Drugs that have been approved over the past 2 decades continue to be nontargeted cytotoxic agents. Moreover, the median survival of patients with metastatic pancreatic cancer remains under 12 months even among clinical trial participants-and is much shorter for the overall population of patients with metastatic disease.[2] While combination therapies delay the worsening of performance status, they do not effectively palliate symptoms in the majority of patients because of the low frequency of objective tumor responses.[3,4] In addition, intermediate- and long-term use of cytotoxic regimens (FOLFIRINOX [fluorouracil, leucovorin, irinotecan, and oxaliplatin], gemcitabine/nab-paclitaxel) is often limited by fatigue and neuropathy.[3,4] Quality of life is a major consideration, and for that reason oncologists adopt various “regimen deviations” to improve tolerance-for example, dropping a drug from FOLFIRINOX or administering gemcitabine/nab-paclitaxel on an every-2-weeks schedule. Our goal in treating metastatic disease must be the sequential use of tolerable regimens in order to maximize exposure to active drugs, an approach that worked in advanced colorectal cancer. The availability of other agents, such as the recently approved liposomal irinotecan, for use after failure on gemcitabine-based treatment, may facilitate that kind of strategy, although the benefit may still be modest.

Undoubtedly we are discouraged by the very limited success in treating pancreatic cancer, a characteristic of pancreatic cancer trials during much of the period from the late 1990s through the early 2000s, when a “gemcitabine plus drug X” testing platform was being used. In those years, popular targets such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)/VEGF receptor were investigated in large clinical trials that demonstrated no benefit except for the very marginal and clinically irrelevant improvement with erlotinib.[5] These trials taught us the futility of single-molecule or single-pathway targeting in a highly molecularly complex and redundant disease, especially when the targets are tested in molecularly unselected patients. Unlike diseases such as lung cancer, in which activating and actionable mutations lead to dramatic outcomes in patient subsets, no actionable mutations have been discovered in pancreatic cancer, except for the very-difficult-to-target KRAS mutations[6,7] that affect the majority of patients. This led the pancreatic cancer research community to reconsider the merits of large randomized trials in which agents are tested with minimal scientific rationale and in unselected patients. A consensus was reached in 2008 on the need to focus on improving our understanding of the biology of pancreatic cancer, on enhancing use of preclinical models, and on testing promising agents in well-designed pilot trials before launching large and expensive studies.[8] This shift in focus largely explains the absence of any national phase III trials in advanced pancreatic cancer for a long time.

Where do we stand now? There is undoubtedly a rapidly growing interest in pancreatic cancer research among basic researchers, which is helped by the willingness of pharmaceutical companies to be engaged with this “stubborn” disease. Positive and timely advances have also been the result of the efforts of advocacy groups, spearheaded by the Pancreatic Cancer Action Network, which engage the public, cancer researchers, and funding agencies. More than before, critical areas of research in pancreatic cancer are being identified and actively pursued. This coincides with intensive efforts to tackle the challenge of targeting mutated RAS, an early carcinogenic event that drives the pancreatic malignant process.

Weinberg and colleagues have nicely described several promising therapies. In the setting of a disease with no targetable kinase overactivity (mutation or amplification) and with plenty of difficult-to-target tumor suppressor gene mutations (eg, p53, SMAD4),[5] the hope is to identify treatment modalities that exploit other aspects of pancreatic cancer biology. Exploiting DNA repair deficiencies, such as BRCA mutations, is an emerging personalized treatment modality that uses currently approved drugs.[9,10] Targeting the dense stroma that characterizes pancreatic adenocarcinoma is moving closer to being a real possibility, with exciting early data on the activity of pegylated hyaluronidase in hyaluronan-overexpressing patients.[11] The stroma has traditionally been described as a barrier to effective delivery of anticancer drugs. However, the biology of the stroma must be carefully evaluated to ensure that stromal targeting does not worsen the cancer by removing elements that have a negative influence on the tumor cells. The failure of targeting the Hedgehog pathway in patients[12] highlighted the perils of undertaking translational research without careful attention to preclinical modeling. Immunotherapy is also being actively pursued, although the antitumor activity of single immune checkpoint inhibitors (eg, programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1] inhibitors) has not yet been demonstrated in this disease. Nevertheless, this class of agents may be very valuable when combined with vaccines (eg, GVAX [granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells]) or agents that perturb the immune and inflammatory components of the pancreatic cancer microenvironment (eg, Bruton tyrosine kinase inhibitors). Trials of such combinations are in progress (ClinicalTrials.gov identifiers: NCT02451982, NCT02362048).

The ultimate benefit to patients will come from a demonstration of clinically worthwhile benefits of new drugs that have been tested in well-designed and adequately powered clinical trials performed in an expedited fashion. Current national figures for participation in clinical trials by patients with pancreatic cancer are exceedingly low.[13] One reason for the low numbers is that the eligibility of patients with advanced disease for participation in clinical trials is often limited to those with favorable performance status (0 or 1 on the Eastern Cooperative Oncology Group [ECOG] scale). Studies must also be pursued in patients with unfavorable performance status (2 or 3 on the ECOG scale) and in the elderly, who represent a sizable percentage of patients with pancreatic cancer. And of course, community oncologists must encourage patients to participate in clinical trials. Also, treatment strategies must address clinical problems that affect quality of life (eg, cachexia) and that interfere with treatment outcome. Drugs such as ruxolitinib (now in phase III clinical trials) may prove useful in this regard: ruxolitinib mitigates cachexia and helps patients feel better, thereby enabling them to receive more treatment. Gemcitabine/nab-paclitaxel and FOLFIRINOX may be described as treatment standards, but in reality they are weak standards. An empirical research strategy of “gemcitabine/nab-paclitaxel plus drug X” or “FOLFIRINOX plus drug Y” that lacks a robust scientific rationale must not be regarded as an acceptable developmental path. Finally, a major limitation on the evaluation of new agents in pancreatic cancer is the ability to access tumor tissue, a challenge because of the paucity of material obtained through diagnostic needle biopsies. There is active research to explore the utility of blood (liquid biopsy) and to improve tissue yield from tumor sampling.[14,15] The reliability of circulating tumor cells or other molecules (eg, free DNA, micro RNAs) in representing the underlying disease is yet to be determined.

Financial Disclosure:Dr. Philip serves on advisory boards for and consults for Celgene, Halozyme Therapeutics, and Merrimack Pharmaceuticals; he receives research support from Celgene, Immunomedics, Incyte, and Momenta Pharmaceuticals.

References:

1. Weinberg BA, Yabar CS, Brody JR, Pishvaian MJ. Current standards and novel treatment options for metastatic pancreatic adenocarcinoma. Oncology (Williston Park). 2015;29:809-20;886.

2. Philip PA, Chansky K, LeBlanc M, et al. Historical controls for metastatic pancreatic cancer: benchmarks for planning and analyzing single-arm phase II trials. Clin Cancer Res. 2014;20:4176-85.

3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.

4. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.

5. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-6.

6. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014; 371:1039-49.

7. Kirsten L, Bryant KL, Mancias JD, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91-100.

8. Philip PA, Mooney M, Jaffe D, et al. Consensus report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment. J Clin Oncol. 2009;27: 5660-9.

9. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132-8.

10. Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495-501.

11. Hingorani SR, Harris WP, Hendifar AG, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized phase II study. J Clin Oncol. 2015;33(suppl):abstr 4006.

12. Lee JJ, Perera RM, Wang H, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci USA. 2014;111:E3091-E3100.

13. Hoos WA, James PA, Rahib L, et al. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol. 2013;31:3312-4.

14. Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nature Rev Clin Oncol. 2013;10:472-84.

15. Krebs MG, Metcalf RL, Carter L, et al. Molecular analysis of circulating tumor cells-biology and biomarkers. Nature Rev Clin Oncol. 2014;11:129-44.