Evaluation of Pancreatic Cancer Clinical Trials and Benchmarks for Clinically Meaningful Future Trials: A Systematic Review.
OBJECTIVE
Progress in the treatment of pancreatic adenocarcinoma has been minimal; it remains the only major cancer type with a 5-year survival rate of less than 10%.


OBJECTIVE
To explore why a large proportion of advanced pancreatic cancer clinical trials executed over the past 25 years have had negative results and to identify benchmarks that could have predicted success.


METHODS
Phase 3 studies of patients with advanced pancreatic cancer were identified by searching clinicaltrials.gov and the scientific literature.


RESULTS
Thirty-two phase 3 studies in 13 675 chemotherapy-naive patients resulted in 3 agents or combinations being considered clinically meaningful. Nineteen agents or combinations (70%) were tested in phase 2 trials preceding the phase 3 trial. In cases with paired phase 2 and 3 results, meeting the primary end point of the phase 2 trial predicted the outcome of the phase 3 trial 76% of the time but proceeded despite phase 2 negative results in 10 cases. We applied criteria for a clinically meaningful result identified by the American Society of Clinical Oncology (ASCO) Cancer Research Committee to these historical cases. Overall, progression-free and 1-year survival of experimental arms was compared with time period-controlled median values of control arms to normalize for the observed increase in response to gemcitabine over time.


CONCLUSIONS
Applying the benchmark of a 50% improvement in overall survival as the primary end point to phase 2 data, or secondary end points of a 90% increase in 1-year survival or an 80% to 100% increase in progression-free survival, showed the greatest ability to predict a clinically meaningful phase 3 trial. Had these criteria been applied to these trials over the past 25 years, more than 11 571 patients enrolled in phase 3 trials that did not meet the primary end point could theoretically have been diverted to earlier-stage trials in an attempt to more rapidly advance the field.
Pancreatic Cancer Action Network, Manhattan Beach, California.
Lola
L
Rahib
Pancreatic Cancer Action Network, Manhattan Beach, California.
Julie M
JM
Fleshman
Pancreatic Cancer Action Network, Manhattan Beach, California.
Lynn M
LM
Matrisian
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
Jordan D
JD
Berlin
D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019985:Benchmarking; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D015996:Survival Rate
D000970:Antineoplastic Agents