In the relentless battle against lung cancer, a formidable adversary that continues to claim more lives worldwide than any other malignancy, the therapeutic landscape has undergone a dramatic transformation in recent years. Advanced-stage lung cancer, often diagnosed when curative surgical options are no longer viable, compels oncologists to rely heavily on systemic therapies. Among these, immune-checkpoint inhibitors (ICIs) have risen to prominence, offering a beacon of hope through their ability to unlock the immune system’s suppressed potential and mediate durable responses. Yet, the clinical journey with ICIs is far from straightforward. Despite their revolutionary impact, the unavoidable emergence of immune-related adverse events (irAEs) or tumor progression frequently forces discontinuation of these lifesaving agents. This clinical impasse has sparked an intriguing avenue of investigation: the rechallenge of ICIs in patients who have previously received these agents but either halted treatment due to toxicity or lack of efficacy.
Lung cancer, notably non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), embodies complex biological heterogeneity and therapeutic resistance mechanisms that challenge the sustainability of immunotherapeutic efficacy. ICIs, which primarily target programmed cell death protein 1 (PD-1), its ligand PD-L1, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), function by releasing the brakes on T-cell activation, thereby amplifying the host’s antitumor immune response. This method is profound in its capacity to generate durable tumor control in a subset of patients, a phenomenon rarely seen with conventional chemotherapy. Nevertheless, the immune system’s activation may overshoot, triggering irAEs that affect various organs and can be severe or even life-threatening, often mandating immunotherapy discontinuation. Additionally, many tumors develop adaptive mechanisms of immune escape, resulting in progressive disease despite ongoing or previous ICI therapy.
Within this context, the concept of ICI rechallenge has gained attention as a potentially viable strategy to reintroduce immune checkpoint blockade after an initial cessation. ICI rechallenge involves restarting therapy with the same or similar agent following a period of interruption — spanning from temporary suspension due to adverse events to treatment after disease progression. This approach is particularly compelling in lung cancer, where treatment options after failure of frontline therapies remain limited, underscoring an unmet clinical need. However, the evidence underpinning rechallenge strategies remains sparse, fragmented, and largely retrospective, especially concerning SCLC, where data are virtually nonexistent.
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Emerging research evaluating ICI rechallenge after irAEs reveals a complex risk-benefit balance. Reintroduction of immune checkpoint inhibitors succeeding immune toxicity carries an inherent risk of recurrence or exacerbation of the adverse event. Yet, selected patients may tolerate rechallenge with manageable safety profiles, and some may experience renewed antitumor responses. The nuances of predicting which patients are suitable candidates for rechallenge are not well defined, with factors such as the type and severity of prior irAEs, timing of rechallenge, and concurrent immunosuppressive therapies influencing outcomes. This ambiguity leaves clinicians navigating treatment decisions without robust, guideline-backed protocols.
In cases of disease progression while on ICI therapy, rechallenge paradigms become even more complex. Tumoral mechanisms of resistance to ICIs encompass alterations in antigen presentation machinery, changes in the tumor microenvironment, and upregulation of alternative immune checkpoints. Whether a rechallenge can overcome these resistance barriers remains to be conclusively determined. Some studies suggest that rechallenge, often in combination with other systemic agents or radiation, may restore sensitivity or provide synergistic antitumor effects. However, optimal patient selection, timing, and combination regimens are yet to be elucidated through prospective clinical trials.
From a mechanistic standpoint, understanding how ICI rechallenge influences the intricate tumor-immune system interplay is critical. The immunological memory established during initial ICI exposure might prime the immune system for enhanced responses upon rechallenge; conversely, adaptive immune exhaustion or irreversible immune senescence could blunt efficacy. Furthermore, rechallenge exposes patients anew to potential irAEs, whose pathophysiology is still being unraveled. Investigations into biomarkers predictive of rechallenge success or toxicity, such as PD-L1 expression dynamics, tumor mutational burden variations, and circulating immune cell profiles, are ongoing but have yet to reach clinical implementation.
Clinical management of ICI rechallenge demands a multi-faceted approach that incorporates meticulous patient assessment and vigilant monitoring. Multidisciplinary teams must weigh the risks of renewed toxicity against the potential for clinical benefit, apply emerging consensus guidance, and engage in shared decision-making. Currently, recommendations emphasize caution in rechallenging patients with prior severe irAEs, advocating for individualized strategies tailored to the patient’s performance status, prior response, and comorbidities. The limited data also suggest that shorter treatment-free intervals and higher grades of prior toxicity correlate with lower rechallenge tolerability.
Importantly, the landscape of ICI rechallenge research in lung cancer is evolving, and several unanswered questions persist. The delineation between irAE-related discontinuation and disease progression as indications for rechallenge is blurred, warranting stratified studies to assess outcomes specifically within these contexts. Defining the optimal timing and sequencing—whether immediate rechallenge or after a washout period—and investigating rechallenge with different checkpoint inhibitors or in combination with targeted therapies constitute key research frontiers. Equally pivotal is the endeavor to elucidate the molecular and immunological underpinnings driving rechallenge responsiveness, which could enable precision immunotherapy.
As the field advances, integration of real-world data with prospective trial evidence will provide critical insights. Large-scale studies and international registries documenting ICI rechallenge experiences, stratified by histologic subtype and prior treatment exposures, are essential to generating robust evidence. Additionally, expanding research to the understudied domain of SCLC and rarer lung cancer subtypes is imperative, given the paucity of data and the aggressive nature of these malignancies.
The implications of successfully implementing ICI rechallenge in clinical practice are profound. It offers the prospect of extending the durable benefits of immunotherapy to a broader cohort of patients who would otherwise face limited therapeutic avenues. Moreover, it introduces an opportunity to refine the therapeutic paradigm towards dynamic and adaptive management post initial ICI exposure. This evolving approach aligns with the overarching goal of personalized oncology, optimizing treatment efficacy while mitigating risks.
In summary, immune-checkpoint inhibitor rechallenge in advanced-stage lung cancer represents a promising yet nascent therapeutic strategy that confronts significant clinical challenges and scientific uncertainties. The emerging body of evidence underscores the imperative for detailed mechanistic studies and rigorously designed clinical trials to establish standardized protocols that maximize patient outcomes. As the oncology community advances this frontier, the integration of immunological insights, clinical prudence, and innovative trial designs will be pivotal.
Through comprehensive reviews and meta-analyses, such as the recent summary by Tang et al., the oncology field is beginning to coalesce data that highlight both the potential and the pitfalls of ICI rechallenge. They provide invaluable guidance on the complex interplay between safety and efficacy, while also identifying critical gaps and future directions. As we stand at this crossroads in lung cancer therapeutics, immune-checkpoint inhibitor rechallenge embodies the intersection of hope, scientific rigor, and the enduring quest to outmaneuver a devastating disease.
Subject of Research: Immune-checkpoint inhibitor rechallenge strategies in advanced-stage lung cancer, focusing on safety and efficacy post disease progression or immune-related adverse events.
Article Title: Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer
Article References:
Tang, LB., Peng, YL., Chen, J. et al. Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01029-7
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Tags: advanced lung cancer treatmentCTLA-4 blockade in cancerdurable responses in cancer treatmentimmune checkpoint inhibitors in oncologyimmune-related adverse events in cancer therapyimmunotherapy challenges in oncologynon-small-cell lung cancer immunotherapyPD-1 and PD-L1 inhibitorsrechallenging ICIs for lung cancersmall-cell lung cancer treatment optionssystemic therapies for advanced lung cancertherapeutic resistance in lung cancer
