What to do after immune-checkpoint inhibitors failure in advanced non-small cell lung cancer: an expert opinion and review

ABSTRACT

Introduction

Immune-checkpoint inhibitors (IO) have significantly improved outcomes of patients with non-oncogene-addicted non-small cell lung cancer (NSCLC), becoming the first-line agents for advanced disease. However, resistance remains a significant clinical challenge, limiting their effectiveness.

Areas covered

Hereby, we addressed standard and innovative therapeutic approaches for NSCLC patients experiencing progression after IO treatment, discussing the emerging resistance mechanisms and the ongoing efforts to overcome them. In order to provide a complete overview of the matter, we performed a comprehensive literature search across prominent databases, including PubMed, EMBASE (Excerpta Medica dataBASE), and the Cochrane Library, and a research of the main ongoing studies on clinicaltrials.gov.

Expert opinion

The dynamics of progression to IO, especially in terms of time to treatment failure and burden of progressive disease, should guide the best subsequent management, together with patient clinical conditions. Long-responders to IO might benefit from continuation of IO beyond-progression, in combination with other treatments. Patients who experience early progression should be treated with salvage CT in case of preserved clinical conditions. Finally, patients who respond to IO for a considerable timeframe and who later present oligo-progression could be treated with a multimodal approach in order to maximize the benefit of immunotherapy.

KEYWORDS:

• Immunotherapy
• non small cell lung cancer
• NSCLC
• IO resistance
• second line therapy
• immune checkpoint inhibitor

Article highlights

• Primary and acquired resistance impair long-term clinical benefits in NSCLC patients treated with IO.

• Interval time to treatment failure and entity of progressive disease should orient clinical decisions. Addition of local therapies in case of oligo-progression or chemotherapy in case of widespread progression could be considered as options, with the aim to restore IO efficacy. Patients with early progression may require alternative treatments.

• Combination of immune checkpoints inhibitors with chemotherapy, anti-angiogenic drugs, and novel immune modulators can synergistically enhance IO by regulating the process of the cancer-immunity cycle. However, these synergistic effects remain uncontrollable and unpredictable.

• Retreatment with IO could be considered in case of disease progression after completion of a prior course of IO treatment or after irAEs resolution.

• A normal cancer-immunity relation is a prerequisite for a clinical response to IO. In situ administration of immune regulators could artificially remodel the immune response.

Declaration of interest

The authors have no 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.

Reviewer disclosures

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

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17476348.2023.2268509

Additional information

Funding

This paper was not funded.