Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome

Abstract

We examined cabazitaxel, a novel next-generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study.Patients and Methods: Patients who have progressed on one or more prior therapies for locally advanced, unresectable, or metastatic disease were eligible, and prior taxane therapy was allowed. Taxane-na€ ve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon's twostage design (10% significance and 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing.Results: Fifty-three patients enrolled in the taxane-na€ ve cohort (Arm A) and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013, to April 8, 2015: median age 61.7 years (range, 35.5-91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A and 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% [95% confidence interval (CI), 17%-42%] and did not meet the prespecified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI, 16%-57%) and surpassed its efficacy target. HER2 amplification or overexpression was associated with improved disease control (P ¼ 0.003), PFS (P ¼ 0.04), and overall survival (P ¼ 0.002). An M2 macrophage signature was also associated with improved survival (P ¼ 0.031).Conclusions: Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation.

Enhancing drug and cell line representations via contrastive learning for improved anti-cancer drug prioritization

“…For GC, 17.8% of drugs (8/45) with higher priority than the highest prioritized FDA-approved drug, docetaxel, have evidence of anti-GC activity (mean priority of 12.8 and 79.4, respectively). Specifically, alvespimycin , cabazitaxel , and exatecan-mesylate (ExM) each achieved positive results in clinical trials 37 – 39 . Furthermore, three additional drugs, including triptolide, exhibited positive, pre-clinical evidence: romidepsin and YM-155 40 , 41 .…”

Transcriptomic analysis of plasma exosomes provides molecular information of response to cabazitaxel treatment in men with metastatic castration‐resistant prostate cancer

“…Recently, it has been shown that cabazitaxel can activate macrophages population in breast cancer and that leads to improvement of immunotherapy 38 . Also in GI cancer, it has been revealed a M2 tumor associated macrophage subpopulation is biomarker of response to cabazitaxel 39 . Finally, in Tramp C1 prostate cancer mouse model, it has been shown that cabazitaxel induces PD‐L1 expression and immunogenic cell death 23 .…”

“…38 Also in GI cancer, it has been revealed a M2 tumor associated macrophage subpopulation is biomarker of response to cabazitaxel. 39 Finally, in Tramp C1 prostate cancer mouse model, it has been shown that cabazitaxel induces PD-L1 expression and immunogenic cell death. 23 For this reason, we looked for components of immune system that are known to have a role in tumor immunity and we found that these are upregulated in nonresponders compared to responders at baseline, which together with the evidence from the mentioned studies indicates that cabazitaxel resistance in prostate cancer patients could be partially due to immunosuppression, which deserves further investigation.…”

Tumor-Associated Macrophages: A Potential Target for Cancer Therapy

“…Similarly, paclitaxel, a chemotherapeutic drug, is showed to rewire TAMs toward tumoricidal phenotypes through activation of TLR4 on TAMs (152). Another clinical phase II trial in metastatic gastric cancer suggested that high infiltration of M2 macrophages in the TME may enhance the sensitivity of cabazitaxel (a novel taxoid) and improve survival (153). The mechanism by which TAMs enhance the efficacy of chemotherapy may be related to the immunogenic cell death (ICD) of neoplastic cells caused by chemotherapeutic drugs (154).…”