Randomized Phase II Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab as First-Line Treatment in Advanced Pancreatic Cancer: Survival and Cachexia

Abstract

Purpose: This randomized phase-II trial (ClinicalTrials.gov identifier: NCT02767557) compared efficacy of gemcitabine/nab-paclitaxel (Gem/Nab) with or without the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (Toc) for advanced pancreatic cancer (PC).

Methods: A safety cohort received Gem 1,000 mg/m² and Nab 125 mg/m² on days 1, 8, and 15, and Toc 8 mg/kg on day 1 for each 28-day cycle. Participants with modified Glasgow prognostic scores of 1 or 2 were randomly assigned 1:1 to receive Gem/Nab/Toc or Gem/Nab. The primary end point was the overall survival (OS) rate at 6 months (OS6). Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Exploratory end points were cachexia, quality of life, and biomarkers, including the cachexia-promoting protein, growth differentiation factor 15 (GDF15).

Results: Overall, 147 patients were treated, including six safety cohort participants. The median follow-up period was 8.1 months (IQR, 4.2-13.9). OS6 was 68.6% (95% CI, 56.3 to 78.1) for the Gem/Nab/Toc group and 62.0% (49.6-72.1) for the Gem/Nab group (P = .409). OS for Gem/Nab/Toc versus Gem/Nab improved at 18 months (27.1% v 7.0%, P = .001). No differences in median OS, PFS, or ORR were observed. Incidence of grade-3+ treatment-related adverse events (TrAEs) was 88.1% for Gem/Nab/Toc and 63.4% for Gem/Nab (P < .001). Gem/Nab/Toc decreased muscle loss versus Gem/Nab, with median change +0.1013% versus -3.430% (P = .0012) at 2 months and +0.7044 versus -3.353% (P = .036) at 4 months. Incidence of muscle loss was 43.48% on Gem/Nab/Toc versus 73.52% on Gem/Nab at 2 months (P = .0045) and 41.82% versus 68.75% (P = .0062) at 4 months. GDF15 was not changed by Gem/Nab or Gem/Nab/Toc.

Conclusion: Although the primary end point was not met and TrAEs were increased by Toc, increased survival at 18 months and reduced muscle wasting support an anticachexia effect of IL-6 blockade independent of GDF15. Further studies could leverage these findings for precision anticachexia therapy.

FIG 1.

CONSORT diagram. Gem, gemcitabine; Nab, nab-paclitaxel; Toc, tocilizumab.

FIG 2.

Kaplan-Meier curves for (A) OS and (B) PFS. Gem, gemcitabine; HR, hazard ratio; Nab, nab-paclitaxel; OS, overall survival; PFS, progression-free survival; Toc, tocilizumab.

FIG 3.

Summary of TrAEs that occurred in at least 10% of all treated patients. The P value is provided for ≥grade 3 adverse events. Gem, gemcitabine; Nab, nab-paclitaxel; Toc, tocilizumab; TrAEs, treatment-related adverse events.

FIG 4.

Cachexia phenotypes at baseline, 2 months, and 4 months after treatment initiation. (A) Body weight change from patient-reported habitual weight to baseline. (B) SKM mass by age-, race-, and sex-adjusted Z-score. (C) Weight change from baseline to 2 months or 4 months of treatment. (D) SKM change from diagnosis to 2 months or 4 months. (E) Waterfall plot of SKM change from baseline to 4 months. (F) Proportions of patients with loss versus stable/gain SKM at 4 months. (G) SKM change at 4 months versus OS. (H) Plasma GDF15 levels at baseline and after cycle 1. Statistics: (A, C, D) Wilcoxon signed rank test versus 0; Mann-Whitney test between groups. (B) One sample t-test versus 0. Unpaired t test between groups. (F) Fisher's two-sided exact test. (G) Pearson correlation. (H) Grouped two-way ANOVA for time and treatment. *P < .05, **P < .01, ***P < .001, ****P < .0001. Shown are median ±95% CI. ANOVA, analysis of variance; GDF15, growth differentiation factor 15; OS, overall survival; SKM, Skeletal muscle.