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A dose-reduction strategy for a commonly used first-line combination in pancreatic cancer resulted in similar survival outcomes but improved tolerability, a randomized phase II study showed.

In patients with stable disease following nab-paclitaxel (Abraxane) plus gemcitabine induction, investigators observed no significant difference in overall survival for those who continued on the combination versus those who switched to alternating cycles of the combination and gemcitabine alone (median 10.4 vs 10.5 months, respectively; HR 0.90, 80% CI 0.72-1.13, P=0.56).

However, the standard approach was accompanied by more treatment-emergent serious adverse events (AEs; 50% vs 33%) and grade ≥3 AEs (71% vs 59%) compared with the alternating approach, reported Frank Kullmann, MD, of the Hospital Weiden in Germany, and colleagues in .

"The results of the ALPACA trial indicate that applying alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles represents a promising, standardized dose-reduction strategy that improves tolerability while maintaining efficacy in patients with metastatic pancreatic cancer," the researchers wrote.

Response rates (54% and 58%) and disease control rates (96% and 98%) were similar across the continuous and alternating treatment groups, respectively, as was median progression-free survival (5.4 vs 5.5 months; HR 0.80, 95% CI 0.58-1.11, P=0.18).

In an , Paula Ghaneh, MD, and Daniel Palmer, MD, PhD, both of the University of Liverpool in England, said that while the results are encouraging, "whether pre-planned dose reduction is superior to the personalized strategies that are currently used for improving tolerance is not completely clear, and, given the limitations in study design" -- the trial was unblinded and had no formal hypothesis on whether the alternating approach would be superior or non-inferior, for example -- "equivalence in efficacy is also unproven."

Ghaneh and Palmer noted that the trial was underpowered to determine meaningful group differences in overall survival and also pointed out that there were imbalances in some important prognostic variables between study groups, such as higher baseline median carbohydrate antigen 19-9 (CA19-9) concentrations in the standard treatment group.

"Nevertheless, ALPACA provides important trial data and lessons for the design of further prospective studies to test dose-reduction approaches, notably in informing sample size calculations to account for dropout and to provide adequate statistical power to show non-inferiority for clinical outcomes," the editorialists wrote.

The was conducted from 2016 to 2021 and enrolled 325 patients with metastatic pancreatic ductal adenocarcinoma, 319 of whom started induction treatment with nab-paclitaxel-gemcitabine. After three induction cycles, 174 patients had stable disease and were eligible for 1:1 randomization, with 167 starting randomized treatment.

At data cutoff, the median treatment duration was 3 months for patients in the continuous treatment group and 3.3 months for patients in the alternating treatment group.

Regarding the study's primary endpoint of overall survival, the authors acknowledged that they could not estimate the hazard ratio with prespecified precision since it failed to reach the required number of overall survival events, and that the assumption of a hazard ratio of 0.87 was not met.

Kullmann and colleagues suggested, however, that it is "clinically relevant" that patients assigned to the alternating treatment schedule had better tolerability of therapy and a reduction in toxicity endpoints.

The most common AEs of any grade were peripheral neuropathy (74% in the continuous group vs 62% in the alternating treatment group) and fatigue (54% vs 52%). Common grade ≥3 treatment-emergent AEs included peripheral neuropathy (21% vs 14%) and infections (20% vs 11%), while rates of treatment-related serious AEs were 14% and 9%, respectively.

"ALPACA might be the first randomized trial to show that proactive dose management of nab-paclitaxel leads to improved tolerability without compromising efficacy," the researchers wrote.

Another limitation cited by Kullmann and co-authors included a high dropout rate prior to randomization.

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