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.

Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?

“…4,5 The study aimed to achieve a DFS improvement from 13.5 months with gemcitabine alone to 18.5 months with nab-paclitaxel 1 gemcitabine (HR, 0.73). 1 At the primary data cutoff, 439 and 571 events had occurred for the independently assessed and investigatorassessed DFS, respectively. Although there was no statistical difference for independently assessed DFS between the two arms, the median investigator-assessed DFS was 16.6 months with nab-paclitaxel 1 gemcitabine versus 13.7 months with gemcitabine alone (HR, 0.82; 95% CI, 0.69 to 0.96; P 5 .02).…”

“…At 5-year follow-up, the median OS was 41.8 and 37.7 months for nab-paclitaxel 1 gemcitabine and gemcitabine (HR, 0.80; 95% CI, 0.68 to 0.95; P 5 .0091), respectively. 1 To better understand these findings, we need to first put this study in a perspective relative to other published randomized adjuvant studies in resected PDAC (Table 1). Surgical resection in pancreatic cancer remains the only potential curative option, but recurrence is high, and 5-year survival with surgery alone is approximately 10%.…”

“…1,4,5 However, the independently assessed DFS with gemcitabine was 18.8 months. 1 The key discrepancy between the two DFS end points was likely a delay in accurately assessing disease recurrence when using blinded radiological modality alone and a greater proportion of patients being censored by independent assessments (approximately 50%) compared with investigator assessment (approximately 34%). Investigators determined recurrence (investigator-assessed DFS) using all clinical information using their expert judgment which in a significant proportion likely preceded the radiological criteria for recurrence, resulting in the data being censored for central review at the time of initiation of subsequent therapy (independently assessed DFS).…”

“…Tempero et al 1 conducted a randomized study (APACT) of nab -paclitaxel + gemcitabine versus gemcitabine alone in treatment-naïve resected patients with pancreas adenocarcinoma (PDAC) with the primary end point of independently assessed disease-free survival (DFS) that was not performed in real time. Despite the proven efficacy of nab -paclitaxel + gemcitabine in the metastatic setting, 2,3 this study of 866 patients did not meet the primary end point and demonstrated a DFS of 19.4 months with nab -paclitaxel + gemcitabine and 18.8 months with gemcitabine alone (hazard ratio [HR], 0.88; 95% CI, 0.73 to 1.06; P = .18).…”

“…In the article that accompanies this editorial, Tempero et al 1 report nab -paclitaxel + gemcitabine did not improve independently assessed disease-free survival as adjuvant therapy in pancreas adenocarcinoma (PDAC) highlighting the challenges in establishing disease recurrence in resected PDAC using radiological modalities alone. As a result, nab -paclitaxel + gemcitabine should be restricted to a narrow subset of patients who are not appropriate for mFOLFIRINOX, who require significant dose/schedule modifications of gemcitabine + capecitabine, who have adequate performance status, and who acknowledge understanding of the regimen's unproven limited benefit in DFS.…”