The largest adjuvant trial in pancreatic adenocarcinoma, the global phase III APACT trial, evaluated the combination of adjuvant nab-paclitaxel/gemcitabine vs gemcitabine monotherapy in patients with resected pancreatic cancer. Results of the study were reported by Margaret A. Tempero, MD, of the University of California, San Francisco, at the 2019 ASCO Annual Meeting.1 The
Independent assessment had never been used before, and we thought we were introducing more rigor into the trial. Clearly, this is a lesson learned for the field going forward: avoid this endpoint.— Margaret A. Tempero, MD
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primary endpoint of independently assessed disease-free survival did not show a difference with the combination. Disease-free survival by prespecified sensitivity analysis of investigator assessment, however,showed a prolonged disease-free survival, Dr. Tempero reported. Dr. Tempero noted that overall survival data are still immature.
“The primary endpoint of independently assessed disease-free survival was not met, but investigator-assessed disease-free survival appeared to align more closely with the overall survival results,” Dr. Tempero said. Hazard ratios (HR) for disease-free survival were 0.88 (P = .1824) by independent assessment and 0.82 (P =.0168) by investigator assessment. She noted that these results send a message about clinical trial design.
Unusual Trial Design
This trial represents the first time that an independent-assessed disease-free survival endpoint was used in an adjuvant trial for pancreatic adenocarcinoma. And, according to Dr. Tempero, study investigators are now questioning this approach. When asked by an attendee what her recommendations as a trialist would be, based on APACT outcomes, she responded, “It’s simple. Don’t use independent assessment.”
Adjuvant Nab-paclitaxel PLUS Gemcitabine
- The phase III APACT trial evaluated adjuvant treatment with nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with resected pancreatic cancer.
- The primary endpoint, disease-free survival by independent review, was not met. The median disease-free survival was 19.4 months with nab-paclitaxel/gemcitabine vs 18.8 months with gemcitabine (HR = 0.88; P = .1824).
- However, in the prespecified sensitivity analysis of investigator-assessed disease-free survival, a benefit was shown for the combination, with a median disease-free survival of 16.6 months vs 13.7 months for the single agent (HR = 0.82;
P = .0168). - Overall survival data are immature. The interim median survival was 40.5 months vs 36.2 months, respectively (HR = 0.82;
P = .045).
With independent assessment, she now realizes, assessors are not privy to information used by local investigators to determine disease progression, such as postoperative changes, patient-reported pain, and rise in CA19-9 levels. Perhaps because they lacked such information, the independent reviewers in APACT experienced some discordance that needed to be adjudicated, she said.
“We all recognize that clinically, it’s often difficult to distinguish recurrence in the pancreatic bed from postoperative changes. Independent assessment had never been used before, and we thought we were introducing more rigor into the trial. Clearly, this is a lesson learned for the field going forward: avoid this endpoint,” Dr. Tempero suggested.
APACT Details
The hypothesis was that the combination of nab-paclitaxel/gemcitabine would improve outcomes over gemcitabine alone, the standard of care at the time of the trial in patients who underwent resection. In the landmark MPACT trial in metastatic patients, nab-paclitaxel/gemcitabine yielded an absolute 2.1 months of survival time (P < .001).2 After the launch of the APACT trial, gemcitabine plus capecitabine and modified FOLFIRINOX demonstrated survival benefits in the adjuvant ESPAC-43 and PRODIGE 24 trials4 and so became preferred treatments.
The global APACT study enrolled 866 treatment-naive patients (median age, 64 years) who had undergone macroscopic complete resection. Most had lymph-node positive disease (72%) and R0 resections (76%), and all patients showed no evidence of persistent disease.
Patients were randomly assigned to receive, within 12 weeks of surgery, nab-paclitaxel at 125 mg/m2 plus gemcitabine at 1,000 mg/m2 or gemcitabine alone at 1,000 mg/m2 for 6 cycles. The primary endpoint was radiologic disease–free survival, independently assessed without reviewers’ knowledge of clinical circumstances.
Outcomes in Disease-Free Survival
After a median follow-up of 38.5 months, median disease-free survival by independent review was 19.4 months with nab-paclitaxel/gemcitabine vs 18.8 months with gemcitabine (HR = 0.88; P =.1824). The benefit was greatest in patients with moderately differentiated tumors, lymph node–positive disease, R1 resection, and normal CA 19-9 level.
APACT TRIAL
For more information on adjuvant treatment with nab-paclitaxel plus gemcitabine for pancreatic cancer from the APACT trial, see an interview with Margaret A. Tempero, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.
For the prespecified sensitivity analysis of investigator-assessed disease-free survival, a benefit was shown for the combination, with a median disease-free survival of 16.6 months vs 13.7 months for the single agent (HR = 0.82; P =.0168). Overall survival was a secondary endpoint, for which the data are immature. At data cutoff, interim median survival was 40.5 months vs 36.2 months, respectively (HR = 0.82; P = .045).
Grade ≥ 3 treatment-emergent adverse events were reported in 86% of the experimental arm and 68% of the single-agent arm. The most common grade ≥ 3 hematologic and nonhematologic toxicities were for nab-paclitaxel/gemcitabine vs gemcitabine, neutropenia (49% vs 43%) and fatigue (10% vs 3%). Patients in the combination arm also had more peripheral neuropathy, diarrhea, and asthenia.
“Overall survival is encouraging, and longer follow-up will clarify the role for this combination as adjuvant therapy for pancreatic adenocarcinoma,” Dr. Tempero said. “The interim analysis suggests that continued investigation of this regimen in patients with lymph node–positive disease, R1 resection, or an inability to tolerate modified FOLFIRINOX is warranted.” ■
DISCLOSURE: Dr. Tempero is a consultant/advisor for AbbVie, Advance Medical, Astellas Pharma, AstraZeneca, BioPharm Communications, Bristol-Myers Squibb, CPRIT, EcoR1 Capital, Eisai, Ignyta, Immunovia, Merck & Co, Pharmacyclics, Pharmacyte Biotech, and Tocagen; has received honoraria from Oregon Health & Science University; has received travel expenses from AbbVie, AstraZeneca, BioPharm Communications, Bristol-Myers Squibb, Celgene, CPRIT, Eisai, Halozyme, Pharmacyclics, Pharmacyte Biotech, and Tocagen; and has received institutional research funding from Celgene and Halozyme.
REFERENCES
1. Tempero MA, Reni M, Riess H, et al: APACT: Phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine for surgically resected pancreatic adenocarcinoma. 2019 ASCO Annual Meeting. Abstract 4000. Presented June 2, 2019.
2. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.
3. Neoptolemos JP, Palmer DH, Ghaneh P, et al: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicenter, open-label, randomised phase 3 trial. Lancet 389:1011-1024, 2017.
4. Conroy T, Hammel P, Hebbar M, et al: Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine in patients with resected pancreatic ductal adenocarcinomas. 2018 ASCO Annual Meeting. Abstract LBA4001. Presented June 4, 2018.
