Pancreatic Cancer Starkly Illustrates Challenges of Developing Targeted Therapies

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

A recent study determined that it would take 6.7 years on average to enroll enough patients with pancreatic cancer for the trials that opened in 2011—a tall order considering that the 5-year relative survival rate for those diagnosed with pancreatic ductal adenocarcinoma is only 6%.

The critical need to develop innovative paradigms to test new therapeutic concepts based on molecularly defined subpopulations within a given tumor type has been extensively discussed in the oncology literature over the past several years. While a modest-size subgroup within a common clinical entity such as the proportion of patients with EGFR mutation- positive non-small cell lung cancer may be sufficiently large to conduct a phase III randomized trial to define efficacy, it would surely not be appropriate to design such a study for subgroups within the 2%-5% of patients with metastatic cancers of the stomach or ovary.

The time required to conduct and complete a phase III study for such relatively small populations would certainly be difficult if not impossible to justify from the perspectives of investigators, funding agencies, industry sponsors, the general public and, most importantly, patients who could potentially benefit from the strategy if shown to be of clinical utility.

Yet another example of the daunting challenges of realizing the promises of personalized cancer medicine has been starkly illustrated in recent months in a series of reports about pancreatic cancer.

Researchers have now documented the utility of chemotherapy in general and gemcitabine in particular employed as adjuvant treatment for patients with pancreatic cancer following primary surgical resection.^1,2 In a meta-analysis of nine trials, the administration of chemotherapy in this setting was shown to substantially improve overall survival compared with observation alone.¹ In this analysis, the hazard ratio for survival associated with fluorouracil was 0.65 and for gemcitabine was 0.59, compared with observation until progression.

And, in a most impressive multicenter phase III trial conducted in Germany and Austria, the study population (n = 368) with completely resected pancreatic cancer randomized to single-agent adjuvant gemcitabine experienced 5-year overall survival of 20.7% compared with only 10.4% for patients randomized to observation following surgery.² Even with 10-year follow-up, the gemcitabine-treated population experienced superior survival (12.2% vs 7.7%).

But as exciting as these findings may be, there is a more dramatic point to consider: the unfortunate, distressing fact that the European study was initiated in 1998 and the critically relevant survival outcome was not reported in the peer-reviewed medical literature until 2013—15 years after the initiative began enrolling patients.

Is this an acceptable timeline for any clinically important question in the oncology arena today? By the time this therapeutic question was answered, others have arisen—including whether the use of single-agent gemcitabine employed as adjuvant therapy for pancreatic cancer is even relevant now that alternative strategies have since been shown to produce superior clinical outcomes in the metastatic setting.^3,4

Although the entire clinical trials enterprise in the United States is struggling to enroll enough patients into oncology studies,⁵ the issue is particularly pressing in pancreatic cancer. A recent report about patient accrual in studies examining novel approaches in pancreatic cancer has highlighted what can only be described as a dysfunctional system.⁶ Hoos et al noted that it would take 6.7 years on average to accrue enough patients with pancreatic cancer for the trials that were opened in 2011—a tall order considering that the 5-year relative survival rate for those diagnosed with pancreatic ductal adenocarcinoma is only 6%.

Is this situation due to the lack of availability of appropriate trials for this patient population the length of time required to attain answers, or the failure of the research enterprise to develop strategies that have the realistic potential to change the current overall dismal outlook in this malignancy? Whatever the answer, the current situation can only be described as profoundly distressing.

Therefore, the questions concerning the prospects for pancreatic cancer reverberate: Will it be possible for those leading the development of molecularly based precision medicine to establish strategies to document the utility of novel strategies in pancreatic cancer that will not require 15 years for an answer, that will actively engage patients and both encourage and permit their participation in innovative investigative approaches, and that will hopefully change the projected course of this extremely difficult illness?

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America. maurie.markman@ctca-hope.com

References

1. Liao W-C, Chien K-L, Lin Y-L, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systemic review and network meta-analysis [published online September 12, 2013]. Lancet Oncol. 2013;14(11):1095-1103.
2. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 Randomized Trial. JAMA. 2013;310(14):1473-1481.
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364(19):1817-1825.
4. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine [published online October 16, 2013]. N Engl J Med. 2013; 369(18):1691-1703.
5. Doroshow JH. Timely completion of scientifically rigorous cancer clinical trials: an unfulfilled priority [published online August 19, 2013]. J Clin Oncol. 2013;31(27):3312-3314.
6. Hoos WA, James PM, Rahib L, et al. Pancreatic cancer clinical trials and accrual in the United States [published online August 19, 2013]. J Clin Oncol. 2013; 31(27):3432-3438.