The invited discussant of APACT,1 Thomas Seufferlein, MD, PhD, Professor of Medicine at the University of Ulm in Germany, said the updated overall survival data “suggest an improved outcome with nab-paclitaxel plus gemcitabine vs gemcitabine alone…. The combination improves long-term survival and would be a useful addition to the armamentarium in the fight against pancreatic cancer recurrence,” he said, “particularly in patients not being able to receive modified FOLFIRINOX [fluorouracil, leucovorin, irinotecan, oxaliplatin].”
Thomas Seufferlein, MD, PhD
However, he pointed out, “APACT did not meet its primary endpoint of independently assessed disease-free survival, but this endpoint had never been used before in an adjuvant trial of pancreatic cancer.” Despite the statistical lack of disease-free survival benefit, the median overall survival of 41.8 months is “quite impressive,” he said.
Possible Biomarker
In fact, there could be patients whose outcomes are even better—namely, those with high expression of human equilibrative nucleoside transporter 1 (hENT1), which belongs to a family of nucleoside transporters critical to the entry of gemcitabine into cells. This possible biomarker of response was not evaluated.
In the COMPASS study, which evaluated patients treated with nab-paclitaxel/gemcitabine or modified FOLFIRINOX in the advanced setting, hENT1 expression was predictive of response to nab-paclitaxel/gemcitabine, other investigators reported at the 2021 ASCO meeting (P = .0002 in test for interaction).2 In patients receiving gemcitabine/nab-paclitaxel, response rates were 45% for patients with high hENT1 expression vs 21% for those with low-expressing tumors (P = .035), and median overall survival was 9.8 months vs 6.1 months (P = .003), respectively. “It seems high hENT1 expression substantially increases the benefit from this combination,” Dr. Seufferlein commented.
Trials of Other Combinations
He further noted that, as compared to trials of other combinations, the control arm of gemcitabine alone in APACT “fared the best of all the adjuvant trials,” associated with a 5-year survival rate of 31 months. “We don’t know why there is this very high number in the control arm, because R0 resection, T4 tumors, and N1 stages are comparable [for the trials],” he said. He cited ESPAC4 (gemcitabine/capecitabine vs gemcitabine),3 JASPAC 01 (S1 vs gemcitabine [S1 is not relevant to Western populations]),4 and PRODIGE 24 (modified FOLFIRINOX vs gemcitabine).5 The 5-year overall survival rate for APACT of 38% falls between the 28% with ESPAC4 and 48% in PRODIGE, he noted.
Dr. Seufferlein predicted that future treatment of early pancreatic cancer will most likely focus on neoadjuvant or perioperative approaches, based on the first results of SWOG 1505.6 So far, he noted, there is no difference in median overall survival between modified FOLFIRINOX (22.4 months) and nab-paclitaxel/gemcitabine (23.6 months). “In the adjuvant setting it would be advantageous to have more treatment options available, like gemcitabine/nab-paclitaxel—alas, there is no [regulatory] approval.”
DISCLOSURE: Dr. Seufferlein has received honoraria from Servier, Amgen, Bayer Schering Pharma, Celgene, Falk Foundation, Merck Serono, Roche, Sanofi, and Servier; has served in a consulting or advisory role for Servier, Bayer, Celgene, Merck Serono, Roche/Genentech, Cantargia, and Shire; has received research funding from Celgene and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Merck Serono, Roche, Sanofi, and Servier.
REFERENCES
1. Tempero M, O’Reilly E, Van Cutsem E, et al: Phase 3 APACT trial of adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with resected pancreatic cancer: updated 5-year overall survival. 2021 ESMO World Congress on Gastrointestinal Cancer. Abstract LBA-1. Presented June 30, 2021.
2. Perera S, Jang GH, Zhang A, et al: hENT1 gene expression as a predictor of response to gemcitabine and nab-paclitaxel in advanced pancreatic cancer. 2021 ASCO Annual Meeting. Abstract 4011. Presented June 4, 2021.
3. Neoptolemos JP, Palmer DH, Ghaneh P, et al: Comparison of adjuvant gemcitabine plus capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicenter, open-label, randomized phase 3 trial. Lancet. 389:1011-1024, 2017.
4. Uesaka K, Boku N, Fukutomi A, et al: Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388:248-257, 2016.
5. Conroy T, Hammet 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.
6. Sohal D, Duong MT, Ahmad SA, et al: SWOG S1505: Results of perioperative chemotherapy with mFOLFIRINOX versus gemcitabine/nab-paclitaxel for resectable pancreatic ductal adenocarcinoma. 2020 ASCO Annual Meeting. Abstract 4504. Presented May 25, 2020.
