Five years after PACIFIC: update on multimodal treatment efficacy based on real-world reports

ABSTRACT

Introduction

The growing body of real-life data on maintenance treatment with durvalumab suggests that immunological markers of the cancer host interplay may have significant effects on the efficacy of multimodal therapy in patients with unresectable stage III NSCLC.

Areas covered

We summarize real-world clinical data regarding this new tri-modal approach and report on potential biomarker landscape.

Expert opinion

The obvious question posed in this context of a very heterogeneous inoperable stage III NSCLC disease is: How can we augment an ability to predict checkpoint inhibition success or failure? Which tools and biomarkers, which clinical metadata and genetic background are relevant and feasible? No single biomarker will ever fully dominate the unresectable stage III NSCLC space, so we advocate multilevel and multivariate analysis of biomarkers. In this particular opinion piece, we explore the impact of PD-L1 expression on tumor cells, neutrophil-to-lymphocyte ratio, EGFR and STK11 mutational status, interferon-gamma signature, and tumor-infiltrating lymphocytes among others.

KEYWORDS:

• Checkpoint inhibition
• durvalumab
• interferon gamma
• PD-L1
• mutational landscape
• non-small cell lung cancer
• tumor-infiltrating lymphocytes
• tumor microenvironment

Article highlights

• Durvalumab reproducibly improves progression-free survival (PFS) and overall survival (OS) in the real-world setting in inoperable stage III NSCLC versus historic cohorts

• Patients with high PD-L1 expression (≥50%) may have a better response on durvalumab maintenance treatment

• Low Neutrophil-to-Lymphocyte ratio initially and just before the start of durvalumab maintenance treatment may be a favorable biomarker

• The tumor mutational landscape affects durvalumab efficacy and toxicity. EGFR mutations are associated with higher toxicity, i.e. pneumonitis, upon durvalumab consolidation. Patients with EGFR mutations do not seem to profit from durvalumab consolidation. STK11 mutations, in certain genomic and histologic contexts, induce primary resistance to immune checkpoint inhibition.

• High cytotoxic T cell tumor infiltration may improve PFS upon durvalumab consolidation

• High Interferon-gamma expression and associated transcriptomic signatures correlate with durvalumab efficacy on OS and PFS

This box summarizes key points contained in the article.

Declaration of interest

F Manapov has received honorarium from Research Institutional Grant from AstraZeneca. L Käsmann has received honorarium from AMGEN, outside the submitted work. C Eze reports receiving consulting fees from Novartis, outside the submitted work. C Belka reports receiving grants or contracts from ViewRay, Brainlab, and Elekta; payment or honoraria from Bristol-Myers, Squibb, Roche, Merck, AstraZeneca, Elekta, and ViewRay; receiving support for attending meetings or travel from Bristol-Myers Squibb, Roche, Merck, AstraZeneca, Elekta, and View Ray; and having a leadership or fiduciary role with ESTRO, all outside the submitted work.

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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.