Current advancements in pharmacotherapy for cancer cachexia

ABSTRACT

Introduction

Cancer cachexia is a multifactorial metabolic syndrome associated with a pathophysiology intertwined with increased inflammatory response, anorexia, metabolic dysregulation, insulin resistance, and hormonal alterations, which together generate a negative energy balance in favor of catabolism. The development of therapeutic strategies to treat cancer cachexia has always been related to clinical interventions with increased food intake/supplementation, physical exercise regimens, and/or medication to attenuate catabolism and increase the anabolic response. However, the approval of drugs by regulatory agencies has always been a challenge.

Areas covered

This review outlines the main pharmacotherapy findings in cancer cachexia as well as the ongoing clinical trials that have evaluated changes in body composition and muscle function. The National Library of Medicine (PubMed) was used as search tool.

Expert opinion

The pharmacological therapy for cachexia should be focused on improving body composition, muscle function, and mortality, although none of the compounds used so far was able to demonstrate positive results beyond increased appetite and improvements in body composition. Ponsegromab (GDF15 inhibitor), a new compound that has just entered a phase II clinical trial, is a promising candidate to treat cancer cachexia and may produce exciting results if the study can be conducted as planned.

KEYWORDS:

• Cancer cachexia
• treatment
• pharmacotherapy
• GDF15 inhibitor
• lean body mass
• muscle function
• mortality

Article highlights

• Despite no compound approval from acclaimed agencies, Anamorelin, a ghrelin receptor agonist, received approval at the end of 2020 in Japan for treating cancer cachexia in patients with non-small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer.

• The other pharmacotherapy agents tested so far in cancer cachexia include compounds that are thought to inhibit inflammation, block myostatin, stimulate the orexigenic pathway in the central melanocortin system, activate anabolic androgenic pathways, and present antipsychotic effects. Overall, these compounds have shown inconclusive results in improving body composition, increasing muscle function, and mortality.

• The new candidates to treat cancer cachexia are proposed to work through blocking growth differentiation factor 15 (Ponsegromab) and inhibiting janus kinases (Ruxolitinib).

• There is also another candidate, Alvespimycin, in pre-clinical studies suggested to inhibit chaperone heat shock protein 90, which may progress to testing in clinical trials once we have more robust evidence.

• Despite the pharmacotherapy discussed in this review, cancer cachexia should be treated by tackling several pathways with a multiple strategy approach that includes nutrition intervention, exercise regimens, and pharmacotherapy.

This box summarizes key points contained in the article.

Declaration of interest

S. von Haehling has been a paid consultant and/or received fees for lectures from Bayer, Boehringer Ingelheim, BRAHMS/Thermo Fisher, Chugai Pharma, Grünenthal, Helsinn, Novartis, Pharmacosmos, Respicardia, Roche, Servier, and Vifor. The other authors have no relevant affiliations or financial involvement with any organization or entity that may pose conflict of interest with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.