Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer

Abstract

Background: Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy.

Patients and methods: Pooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization.

Results: In two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43-109 versus 56 days, 95% CI 43-69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59-177 versus 55 days, 95% CI 40-70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29-0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30-0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88).

Conclusion: This unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy.

Clinical trials number: NCT00401362, NCT00672477.

Keywords: cancer; constipation; methylnaltrexone; mu opioid receptor; opioids; survival.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Enrollment of cancer patients to two placebo-controlled randomized trials (studies: NCT00401362 and NCT00672477) of methylnaltrexone (MNTX) in patients with advanced illnesses treated with regular opioids with opioid-induced constipation.

Figure 2.

(A) Patients (n = 117, blue) treated with methylnaltrexone (MNTX) had a longer median overall survival (OS) compared with patients (n = 112, green) treated with placebo [76 days, 95% confidence interval (CI) 43–109 versus 56 days, 95% CI 43–69; P = 0.033]. (B) In the MNTX arm, patients (n = 72, blue) with response to MNTX (laxation within 4 h after the first administration) had a longer median OS compared with patients (n = 45, green) without a response or treated with placebo (118 days, 95% CI 46–190 versus 58 days, 95% CI 3–113; P = 0.001). (C) Patients (n = 77, blue) with a response to treatment (laxation within 4 h after the first administration) had a longer median OS compared with patients (n = 152, green) without a response (118 days, 95% CI 59–177 versus 55 days, 95% CI 40–70; P < 0.001). (D) In disease other than cancer, patients (n = 62, blue) treated with MNTX had a similar OS compared with patients (n = 72, green) treated with placebo (medians not reached; P = 0.88).

Figure 3.

(A) Patients (n = 117, blue) treated with methylnaltrexone (MNTX) had a longer median overall survival (OS) compared with patients (n = 56, green) treated with placebo without subsequent crossover to MNTX (76 days, 95% CI 43–109 versus 26 days, 95% CI 17–35; P < 0.001). (B) Patients (n = 73, blue) with a response to treatment (laxation within 4 h after the first administration) had a longer median OS compared with patients (n = 100, green) without a response and crossover to MNTX (118 days, 95% CI 46–190 versus 30 days, 95% CI 23–37; P < 0.001). (C) Patients (n = 56, blue) who crossed over from placebo to MNTX had a longer median OS compared with patients (n = 56, green) treated with placebo without subsequent crossover to MNTX (75 days, 95% CI 59–91 versus 26 days, 95% CI 17–35; P < 0.001).