Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter AIO phase II trial (LICC)

Carl Christoph Schimanski, Stefan Kasper, Susanna Hegewisch-Becker, Jan Schröder, Friedrich Overkamp, Frank Kullmann, Wolf Otto Bechstein, Matthias Vöhringer, Robert Öllinger, Florian Lordick, Volker Heinemann, Michael Geißler, Armin Schulz-Abelius, Helga Bernhard, Michael R Schön, Richard Greil, Peter Galle, Hauke Lang, Irene Schmidtmann, Markus Moehler, Carl Christoph Schimanski, Stefan Kasper, Susanna Hegewisch-Becker, Jan Schröder, Friedrich Overkamp, Frank Kullmann, Wolf Otto Bechstein, Matthias Vöhringer, Robert Öllinger, Florian Lordick, Volker Heinemann, Michael Geißler, Armin Schulz-Abelius, Helga Bernhard, Michael R Schön, Richard Greil, Peter Galle, Hauke Lang, Irene Schmidtmann, Markus Moehler

Abstract

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) (P = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm (P = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany.

Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.

Keywords: Tecemotide (L-BLP25); colorectal Neoplasms; liver-limited disease; mucin-1 (MUC1); resection of colorectal liver metastases.

© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
CONSORT flow diagram of the LICC trial. * One patient in the tecemotide arm did not receive vaccination but received CP and was included in the ITT and safety population. In the tecemotide arm, one patient had one R2 resected metastasis besides R0 resected metastases and one patient had one RX metastasis besides R0 and R1 resected metastases. These patients were allocated to the “Non-R0” subgroup in the ITT population and were excluded from the PP population. A centralized radiologic review was conducted for 80 patients, which led to the exclusion of 11 patients (n = 7 tecemotide arm, n = 4 placebo arm) with residual disease at baseline from the per-protocol (PP) population. Abbreviations: ITT: intention-to-treat population, PP: per-protocol population
Figure 2.
Figure 2.
Kaplan-Meier analyses of the ITT population. A) Recurrence-free survival. B) Overall survival
Figure 3.
Figure 3.
Kaplan-Meier analyses of the ITT population, according to MUC1 expression. A) RFS MUC1 low B) OS MUC1 low C) RFS MUC1 medium D) OS MUC1 medium E) RFS MUC1 high F) OS MUC1 high
Figure 4.
Figure 4.
Forest Plots for the ITT population. A) Recurrence-free survival and B) Overall survival. P-values are for testing interaction of treatment with subgroup, thus describing difference in treatment effects across subgroups

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