The challenge of treating pancreatic cancer inched forward with studies reported at the 2013 ASCO Annual Meeting, though some important studies proved disappointing.
Nab-paclitaxel Improves Overall Survival
In treatment-naive metastatic patients, the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) to gemcitabine improved overall survival vs gemcitabine alone, in MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial), a 151-site international phase III study in which 861 patients were randomly assigned to nab-paclitaxel at 125 mg/m2 followed by gemcitabine, or gemcitabine alone.1
Treatment with the combination extended median overall survival by approximately 2 months—from 6.7 months with gemcitabine to 8.5 months with the combination (hazard ratio [HR] = 0.72; P = .000015), reported Daniel Von Hoff, MD, of the Translational Genomics Research Institute in Scottsdale, Arizona, who presented the main results earlier this year at the Gastrointestinal Cancers Symposium.2
Nab-paclitaxel/gemcitabine was favored in all subgroups. Responses by positron-emission tomography (PET) imaging and CA19-9 correlated with overall survival, he reported at the ASCO Annual Meeting.
Serious life-threatening toxicity was not increased with nab-paclitaxel/gemcitabine, but more grade 3/4 adverse events were observed with the combination—most commonly neutropenia (38% vs 27%), fatigue (17% vs 7%), and peripheral neuropathy (17% vs 1%).
“This is a new standard for the treatment of metastatic pancreatic cancer that could become the backbone for new regimens,” Dr. Von Hoff concluded.
S-1 Outperforms Gemcitabine
Updated findings for the phase III JASPAC-01 trial, also presented at the 2013 Gastrointestinal Cancers Symposium,3 confirmed the overall survival benefit of the oral fluoropyrimide S-1, a drug currently used in Asia but not approved in the United States. In the study of 385 patients, adjuvant treatment with S-1 (80–120 mg/d every 6 weeks for four courses) led to a 46% reduction in mortality, compared to gemcitabine.4
Two-year overall survival was 70% with S-1 vs 53% for gemcitabine (P < .0001 for noninferiority and superiority); median overall survival has not been reached with S-1 but was 25.9 months with gemcitabine. Median relapse-free survival was 23.2 months vs 11.2 months, respectively, with 2-year rates of 49% vs 29%, respectively (HR = 0.67; P < .0001 for superiority), reported Akira Fukutomi, MD, of Shizuoka Cancer Center Hospital.
Chemoradiotherapy Lacks Benefit
Chemoradiotherapy provided no benefit over chemotherapy alone in locally advanced pancreatic cancer, and erlotinib (Tarceva) in the induction phase added no benefit over gemcitabine alone, according to the international phase III LAP 07 study, presented by Pascal Hammel, MD, PhD, of the Hopital Beaujon in Clichy, France.5
LAP 07 compared chemoradiotherapy to chemotherapy in patients with locally advanced pancreatic cancer controlled after 4 months of chemotherapy induction. Dr. Hammel noted that previous prospective studies have provided conflicting results as to the role of front-line chemoradiotherapy, while two retrospective studies found that induction chemotherapy may select for patients who will derive benefit from subsequent chemoradiotherapy. Questions have lingered, therefore, regarding the true benefit of chemoradiotherapy.
The study first randomly assigned 442 patients to gemcitabine alone or gemcitabine plus erlotinib for 4 months of induction chemotherapy; the 269 who achieved disease control were then randomized to an additional 2 months of the previous chemotherapy or to a chemoradiotherapy (54 Gy plus capecitabine [Xeloda]). Patients receiving erlotinib in the first randomization received erlotinib as maintenance after protocol completion while gemcitabine was stopped. The primary endpoint was overall survival.
After a median follow-up of 36 months and 221 deaths, no significant difference was observed in median overall survival between the chemotherapy arm (16.4 months) and chemoradiotherapy arm (15.2 months; HR = 1.03; P = .8295). Median progression-free survival was 11.8 months for chemotherapy compared with 12.5 months with chemoradiotherapy (HR = .9; P = .2161).
“It was clear that to continue the study would not change the final results, and futility was declared at the second interim analysis,” Dr. Hammel announced.
When analyzed according to chemotherapy induction arm, median overall survival was 13.6 months for gemcitabine compared with 11.9 months for gemcitabine plus erlotinib (HR = 1.19; P = .0930). The combination also produced more toxicity. “Erlotinib was not beneficial in locally advanced pancreatic cancer, and it increased the toxicity. There was no advantage to adding erlotinib to better control tumor and thus push a higher rate of patients into the second randomization,” he said.
“In locally advanced pancreatic cancer, the standard of care should remain chemotherapy, with chemoradiotherapy being an option after tumor control by chemotherapy,” Dr. Hammel concluded.
Chemoimmunotherapy Falls Short
In the phase III TeloVac trial, the addition of GV1001, a telomerase vaccine, to standard gemcitabine/capecitabine treatment did not improve overall survival in patients with locally advanced or metastatic pancreatic cancer.6 TeloVac randomized 1,062 patients from 51 centers to one of three treatment arms: gemcitabine/capecitabine alone; sequential gemcitabine/capecitabine followed by GV1001, and, for patients with stable disease at week 8, treatment with gemcitabine/capecitabine; or concurrent administration of gemcitabine/capecitabine plus GV1001.
At a median follow-up of 6.1 months, median overall survival in the GV1001 arms was not significantly different from that derived from chemotherapy alone: 7.89 months for the control arm, 6.94 months for sequential GV1001 treatment (P = .0466), and 8.36 for concurrent GV1001 treatment (P = .6378).
“Overall survival with concurrent [gemcitabine/capecitabine]/GV1001 was not different from that of [gemcitabine/capecitabine] alone, and overall survival with sequential GV1001 was not statistically different from [gemcitabine/capecitabine] alone, as it did not meet the criterion for statistical significance (P < .0175),” said Gary W. Middleton, MD, of the University of Birmingham in the United Kingdom. “The addition of a T-helper epitope vaccine to [gemcitabine/capecitabine] did not improve outcome.” ■
Disclosure: Dr. Von Hoff has been a consultant/advisor for and received honoraria and research funding from Celgene Corporation. Dr. Fukutomi has received honoraria from Lilly and Taiho Pharmaceuticals. Dr. Hammel received financial support from Roche for the study. Dr. Middleton reported no potential conflicts of interest.
References
1. Von Hoff DD, Ervin TJ, Arena FP, et al: Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA 19-9 correlates. 2013 ASCO Annual Meeting. Abstract 4005. Presented June 3, 2013.
2. Von Hoff DD, Ervin TJ, Arena FP, et al: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2013.
3. Uesaka K, Fukutomi A, Boku N, et al: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer (JASPAC-01 study). 2013 Gastrointestinal Cancers Symposium. Abstract 145. Presented January 25, 2013.
4. Fukutomi A, Uesaka K, Boku N, et al: JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer. 2013 ASCO Annual Meeting. Abstract 4008. Presented June 3, 2013.
5. Hammel P, Huguet F, van Laethem J-L, et al: Comparison of chemoradiotherapy and chemotherapy in patients with a locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. 2013 ASCO Annual Meeting. Abstract LBA4003. Presented June 3, 2013.
6. Middleton GW, Valle JW, Wadsley J, et al: A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. 2013 ASCO Annual Meeting. Abstract LBA4004. Presented June 3, 2013.
