Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Abstract

Purpose: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430).

Methods: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m²) + gemcitabine (1,000 mg/m²) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety.

Results: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events.

Conclusion: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

FIG 1.

CONSORT diagram. Flow diagram results between treatment arms after primary data cutoff (December 31, 2018). ^aCompleted indicates patients who finished all six treatment cycles and received ≥ 2 doses of the study medication during cycle 6. AE, adverse event; Gem, gemcitabine; ITT, intent-to-treat; nab-P, nab-paclitaxel.

FIG 2.

Kaplan-Meier curves of DFS and OS. Kaplan-Meier curves of DFS by (A) independent assessment and (B) investigator assessment (primary data cutoff, December 31, 2018). OS at data cutoffs of the (C) primary analysis, (D) 16-month follow-up (April 3, 2020), and (E) 5-year follow-up (April 9, 2021). OS rates for ≥ 5 years were 38% with nab-paclitaxel + Gem and 31% with Gem. DFS, disease-free survival; Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; OS, overall survival.

FIG 3.

Forest plot subgroup analysis of DFS and OS. At the primary data cutoff (December 31, 2018), prespecified (A) blinded, independent, centrally reviewed DFS and (B) OS. CA19-9, carbohydrate antigen 19-9; DFS, disease-free survival; ECOG PS, Eastern Cooperative Oncology Group performance status, Gem, gemcitabine; HR, hazard ratio; LN, lymph node; nab-P, nab-paclitaxel; OS, overall survival; ULN, upper limit of normal; WNL, within normal limits.