Novel systemic treatment approaches for metastatic pancreatic cancer

ABSTRACT

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year overall survival rate of 10%, emphasizing the need for more effective therapies, especially in metastatic disease. The immunosuppressive tumor microenvironment, poor vascularization, and dense tumor stroma typical for PDAC are hurdles that need to be overcome by novel drugs. Investigations are moving toward more targeted treatments including immunotherapy and cell-based approaches.

Areas covered

This article reviews emerging drugs in clinical development for metastatic PDAC, focusing on cellular therapies and novel treatments targeting metabolism, tumor stroma, oncogenic pathways and immunosuppression. With immunotherapy and CAR T-cell therapy on the rise in hematological malignancies, the transfer to solid tumors remains intriguing. Multiple exciting clinical trials investigating innovative therapeutic strategies for PDAC are currently ongoing and reviewed herein. ClinicalTrials.gov, conference abstracts and PubMed were searched in August 2021 and assessed for information on ongoing and published clinical studies.

Expert opinion

With many challenges to overcome, the optimal therapy for patients with metastatic PDAC is likely to consist of a combination of different agents. We are slowly moving from entity-dependent approaches to ones more focused on molecular and pathological features. Increasingly personalized treatment plans tailored to each patient may be the future of PDAC therapy.

KEYWORDS:

• Pancreatic cancer
• metastatic
• immunotherapy
• targeted therapy
• cellular therapy
• novel drugs

Article highlights

• Given the low 5-year overall survival rate of 10% for patients diagnosed with PDAC, novel therapeutic approaches are necessary to improve prognosis and quality of life for these patients.

• Investigational drugs targeting metabolism, stroma, and oncogenic pathways are explored in clinical trials, some of them in randomized phase III studies.

• Although immunotherapy has not been established as standard of care for most PDAC patients, novel immunotherapeutic drugs combined with other agents might change that.

• CAR T cells and bispecific antibody armed T cells are under investigation in early clinical trials for PDAC.

• Combination therapies focusing on molecular and pathological features customized to each patient might be the future of PDAC therapy.

This box summarizes key points contained in the article.

Declaration of Interests

V Heinemann: Amgen, Baxalta, Boehringer Ingelheim, Celgene, Lilly, Merck, Roche, Sanofi, SERVIER, Sirtex Medical, Taiho Pharmaceutical (Honoraria); Amgen, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Halozyme, Merck, MSD, Roche, Sanofi, SERVIER, Sirtex Medical (Consulting or Advisory Role); Amgen, Boehringer Ingelheim, Celgene, Merck, Roche, SERVIER, Shire, Sirtex Medical (Research Funding – Institution); Amgen, Bristol-Myers Squibb, Merck, MSD, SERVIER, Shire, Sirtex Medical (Travel, Accomodations, Expenses).

S Kobold: S.K. is inventor of several patent applications filed by the Ludwig-Maximilians-Universität München in the field of immunooncology. S.K. received research support from TCR2 Inc and Arcus Biosciences for work on T cell therapies unrelated to the present manuscript. S.K. received licencing fees from TCR2 Inc as well as honoraria from TCR2 Inc, Novartis, BMS and GSK.

M von Bergwelt-Baildon: Astellas Pharma, Bristol-Myers Squibb, Kite Gilead, Miltenyi Biotec, MOLOGEN, MSD, Novartis, Roche (Honoraria, Speakers’ Bureau, Research Funding, Travel, Accomodations, Expenses).

S Boeck: Celgene, Baxalta, Incyte, Fresenius, AstraZeneca (Consulting or Advisory Role); Celgene, Servier (Honoraria); Celgene, Clovis Oncology, Roche (Research Funding – Institution).

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Conflict of interest

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

Additional information

Funding

S Kobold is supported by grants from the international doctoral program ‘i-Target: Immunotargeting of cancer’ funded by the Elite Network of Bavaria, the Melanoma Research Alliance (grant number 409510), the Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer funded by the H2020 Program of the European Union (Grant 955575.), the Else Kröner-Fresenius-Stiftung, the German Cancer Aid, the Ernst-Jung-Stiftung by LMU Munich<apos;>s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, by the Bundesministerium für Bildung und Forschung, by the Bavarian Ministry of Economical Affairs (M4-award), by the European Research Council Starting Grant (grant number 756017), by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and –SFB- TRR 338/1 2021 –452881907, the Fritz-Bender-Foundation, the José-Carreras Foundation and the Hector Foundation.