Rechallenging Immunotherapy Plus Anlotinib in Lung Cancer

In the relentless battle against advanced non-small cell lung cancer (NSCLC), a groundbreaking retrospective study has shed light on the promising potential of combining immune checkpoint inhibitors (ICIs) with anlotinib as a rechallenge therapy after prior immunotherapy failure. Conducted at the First Affiliated Hospital of Guangzhou University of Chinese Medicine, this investigation provides crucial insights into managing NSCLC patients who lack targetable driver mutations—a group often limited in effective treatment options.

NSCLC, accounting for the majority of lung cancer cases globally, presents formidable challenges in treatment, especially when tumor cells do not harbor actionable genetic alterations. Immune checkpoint inhibitors have revolutionized the therapeutic landscape, harnessing the body’s immune system to attack cancer. However, resistance frequently develops, limiting the long-term efficacy of initial immunotherapy. The innovative approach of rekindling immune responses through rechallenge strategies combining ICIs with antiangiogenic agents such as anlotinib represents a beacon of hope for clinicians and patients alike.

This retrospective analysis focused on a cohort of 14 patients treated between March 2020 and June 2024, all of whom had advanced NSCLC without identifiable driver mutations and experienced disease progression following initial immunotherapy. These patients underwent rechallenge therapy that integrated ICIs and anlotinib, a multi-targeted tyrosine kinase inhibitor known to impede tumor angiogenesis and modulate the tumor microenvironment favorable to immune response.

One of the salient findings from the study was the observed objective response rate (ORR) of 28.6%, a notable indication that nearly a third of patients exhibited measurable tumor shrinkage after rechallenge. Even more striking was the disease control rate (DCR) of 92.9%, suggesting sustained disease stabilization in the vast majority of participants. These metrics underscore a substantial clinical benefit, particularly given the refractory nature of advanced NSCLC cases studied.

The median progression-free survival (PFS) achieved was 11.7 months, a duration that compares favorably to historical benchmarks in this patient population. Further stratification based on programmed death-ligand 1 (PD-L1) expression revealed a significant survival advantage among PD-L1-positive patients, who experienced a median PFS of 13.0 months versus 10.3 months in PD-L1-negative or unknown patients (p = 0.048). This differential highlights the importance of biomarker-driven approaches in tailoring immunotherapy rechallenge protocols.

Equally vital to the evaluation of any cancer therapeutics is the safety profile. Encouragingly, the combination of ICIs with anlotinib was largely well tolerated. Adverse events reported were predominantly mild to moderate, with only a single case (7.1%) of grade 3 toxicity recorded. No treatment-related mortalities were observed, underscoring a manageable safety spectrum that permits continued administration of this therapeutic regimen.

The rationale behind combining ICIs with anlotinib stems from the multifaceted role of angiogenesis inhibitors in disrupting tumor vasculature and enhancing immune cell infiltration. Anlotinib’s inhibitory effects on vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), and platelet-derived growth factor receptors (PDGFR) potentially normalize aberrant tumor vessels, mitigating immunosuppressive barriers and amplifying the efficacy of ICIs.

Mechanistically, the rechallenge approach attempts to overcome acquired resistance mechanisms that blunt initial immunotherapy responses. Tumor heterogeneity, immune evasion tactics, and alterations in the tumor microenvironment pose significant obstacles in therapeutic durability. By introducing an antiangiogenic agent like anlotinib alongside ICIs, the synergy seeks to recalibrate immune surveillance and restore anti-tumor activity.

Notably, the study’s patient population excluded those with targetable driver mutations such as EGFR or ALK alterations, focusing on a subgroup traditionally underserved by targeted therapies. This accentuates the clinical relevance of the findings, as these patients often rely predominantly on systemic chemotherapy or immunotherapy, which yield variable outcomes.

Despite the study’s limited sample size of 14 patients, it provides valuable preliminary evidence supporting the safety and efficacy of ICI-anlotinib rechallenge therapy. The retrospective nature, while inherently imposing certain methodological constraints, does not diminish the translational potential and grounds for larger prospective trials.

Future directions should aim to delineate the optimal sequencing and combination regimens, identify predictive biomarkers beyond PD-L1 to stratify responders, and elucidate resistance pathways to further potentiate the clinical impact. Additionally, integrating comprehensive genomic and immunophenotypic profiling may refine personalized treatment paradigms.

In conclusion, this pioneering research offers a compelling narrative that rechallenging advanced NSCLC patients with ICIs in conjunction with anlotinib holds considerable promise. The observed therapeutic outcomes and tolerability profile advocate for expanded investigations and may ultimately shift therapeutic algorithms to include such combination strategies for patients lacking other targeted options.

As lung cancer continues to claim millions of lives worldwide, innovations like these reinforce the critical need for adaptive, multi-pronged therapeutic tactics. The interplay between immunotherapy and angiogenesis inhibition could herald a new era of improved survival and quality of life for patients grappling with recalcitrant NSCLC. This emerging paradigm exemplifies the relentless pursuit of cancer control, underscoring the dynamic evolution of oncology care.

The integration of real-world clinical data with sophisticated molecular insights holds the key to unlocking the full potential of rechallenge therapies. Collaboration between multidisciplinary teams and ongoing clinical research will be essential to validate and refine these encouraging findings, ultimately expanding the armamentarium against advanced lung malignancies.

The study’s revelations not only kindle hope among clinicians and patients but also emphasize the importance of continually reevaluating and innovating treatment frameworks. As the oncology community embraces the complexities of tumor biology, interventions such as ICIs combined with anlotinib represent strategic strikes against therapeutic resistance.

In sum, the meticulous retrospective evaluation from Guangzhou University of Chinese Medicine serves as a testament to the value of combinational immunotherapy approaches. It propels the discourse forward and sets the stage for transformative advancements in managing advanced NSCLC, a disease historically fraught with therapeutic impasses.

Subject of Research: Safety and efficacy of immune checkpoint inhibitor rechallenge combined with anlotinib in advanced non-small cell lung cancer lacking targetable driver mutations.

Article Title: Safety and efficacy of rechallenge with immune checkpoint inhibitors and anlotinib in advanced non-small cell lung cancer without targetable driver mutations: a retrospective analysis.

Article References:
Chen, X., Wang, K., Liao, Y. et al. Safety and efficacy of rechallenge with immune checkpoint inhibitors and anlotinib in advanced non-small cell lung cancer without targetable driver mutations: a retrospective analysis. BMC Cancer 25, 862 (2025). https://doi.org/10.1186/s12885-025-14209-6

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14209-6

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