Where are we LEAPing with anti-angiogenics and immunotherapy combinations?—reflections from the LEAP-008 study

The definition of effective further-line treatment strategies in patients affected by metastatic, non-oncogene-addicted non-small cell lung cancer (NSCLC) already exposed to immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy remains a highly unmet medical need. Various research and clinical efforts have focused on overcoming ICI resistance by combining such agents with antiangiogenic treatments, aiming at “normalize” tumor vasculature with the potential to synergize with immunotherapy, e.g., by making the tumor more accessible for the immune system (1,2).

To this end, the lenvatinib and pembrolizumab (LEAP) series of clinical trials addressed the efficacy of lenvatinib, an antiangiogenic, multi-targeted small molecule tyrosine kinase inhibitor (TKI), in association with pembrolizumab, a humanized IgG4 directed against programmed cell death protein 1 (PD-1), across multiple tumor types (3). The LEAP-008 study, as part of the series, was a phase III, open-label, randomized clinical trial comparing the activity of pembrolizumab plus lenvatinib vs. docetaxel in patients affected by metastatic NSCLC progressing after immunotherapy and platinum-based chemotherapy (4). The study randomized 422 patients to receive lenvatinib + pembrolizumab (n=185), docetaxel (n=189), or lenvatinib monotherapy (n=48), in a 4:4:1 randomization fashion. The dual primary study endpoints were overall survival (OS) and progression-free survival (PFS), as evaluated by blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints were overall response rate (ORR) and duration of response (DOR); discontinuation rate because of adverse events (AEs); reporting and frequency of AEs; variations in health-related quality of life (HRQoL) and time to true deterioration (TTD). Endpoint assessment based on best response to immediate previous ICI therapy was an exploratory post hoc analysis.

Both co-primary endpoints were not met, with observed median PFS [95% confidence interval (CI)] of 5.6 (4.2–6.5) months vs. 4.2 (3.2–5.2) months and median OS of 11.3 (9.4–13.2) vs. 12.0 (9.6–13.7) months in the lenvatinib plus pembrolizumab and docetaxel arm, respectively. With regard to safety endpoints, there was no significant difference between treatment arms, with any-grade AEs occurring in ~90% of patients in each arm: 91.7% in the lenvatinib-pembrolizumab arm, 91% in the docetaxel arm and 89.4% in the lenvatinib arm. Grade 3–5 events occurred in 55.8% of participants randomized to the lenvatinib-pembrolizumab arm, as compared to 47.5% and 51.1% of patients randomized in the docetaxel ad lenvatinib monotherapy arms, respectively. Quality of life metrics also showed no significant differences across treatment arms.

In summary, while the safety profile remained manageable and consistent with previous experiences, there was no observed clinically meaningful synergistic effect between LEAP in patients with pre-treated advanced or metastatic NSCLC.

The LEAP-008 study is not alone among recent ICI combination trials in NSCLC which have failed to demonstrate benefit in the ICI-pretreated, advanced NSCLC population. Both the SAPPHIRE and the CONTACT-01 phase 3 trials, which evaluated multikinase anti-angiogenic TKIs in combination with ICI in the same population, did not meet their primary endpoint, although in the SAPPHIRE study, median OS was numerically longer with sitravatinib and nivolumab, with respect to docetaxel [12.2 vs. 10.6 months; hazard ratio (HR) 0.86, 95% CI: 0.70–1.05; P=0.144] (5,6). Disappointingly, even blocking angiogenesis with a monoclonal antibody directed against VEGFR2 in combination with ICI did not increase OS as compared to single-agent chemotherapy in the phase 3 SWOG S2302 Pragmatica-Lung trial, even if results of the phase II Lung-MAP S1800A had been encouraging (7).

The phase II SCORPION trial, while not testing the combination of antiangiogenics and immunotherapy directly, but as a sequence, demonstrated encouraging signs of activity with the combination of ramucirumab and docetaxel in NSCLC patients progressing after platinum-based immunotherapy and ICI combination treatment, reaching its primary endpoint with ORR of 34.4% (80% CI: 23.1–47.2%) (8).

Globally, these mixed results demand a closer look at the underlying assumptions for testing this treatment combination in patients with NSCLC progressing on ICI or ICI plus chemotherapy first-line treatment in advanced/metastatic NSCLC.

Indeed, preclinical evidence supporting a potentially synergistic effect of anti-angiogenic treatments and ICI has not been confirmed so far in the NSCLC population, while it has yielded significant results in other tumor types, such as renal cell carcinoma (9) and endometrial cancer (10). However, it should be noted that both the CLEAR study in renal cell carcinoma, and the KEYNOTE-775 study in endometrial cancer, did not enroll patients who had received ICI beforehand. Therefore, comparisons between these settings should be drawn with caution, considering both the different study designs and diverse underlying tumor biology characteristics. Indeed, such synergistic mechanisms are likely not active in malignant neoplasias tout-court, but rather depend on organ and tumor-type specific biological factors which should be ideally dissected in the preclinical setting before starting future clinical trials with such combinations. Indeed, although vessel normalization is thought to facilitate access of ICI and of the immune system to the tumor parenchyma, this has not been specifically tested in different NSCLC preclinical models. Moreover, preclinical and clinical studies failed to provide data on potential predictive biomarkers of lenvatinib + ICI response in NSCLC, potentially diluting any beneficial effects in a subgroup of patients.

Therefore, even though the theoretical principle of antiangiogenic and immunotherapy combinations remains fascinating, clinical data failed to confirm such synergistic effect. Hence, going back “from bedside to bench” would be instrumental to unveil different mechanisms to unleash the full potential of such combinations, or, if such synergism is not confirmed by robust preclinical experiments, spare patients from further clinical trials evaluating combinations that, even if active in other tumors, are not expected to make the field move forward.

As a future perspective in the field, antiangiogenics in the bispecific format, e.g., ivonescimab (11-13), and BNT327 (14) among others, hold promise as potentially more effective tools to target tumor angiogenesis as well as unleashing immune system activation. In particular, ivonescimab is a tetravalent bispecific antibody targeting PD-1 and VEGF, which has been studied in the setting of EGFRm NSCLC progressing after EGFR TKI therapy in the phase III, double-blind, placebo-controlled HARMONi-A study. Encouraging results of the first preplanned interim analysis have shown median PFS of 7.06 vs. 4.8 months for chemotherapy plus ivonescimab vs. chemotherapy and placebo, respectively (11). More recently, the HARMONi-6 phase III randomized, double-blind study investigated the efficacy of ivonescimab plus chemotherapy compared to tislelizumab and chemotherapy as first-line treatment in squamous NSCLC, showing improved mPFS for the experimental arm, with mPFS of 11.1 months (95% CI: 9.9–not evaluable) vs. 6.9 months (5.8–8.6) [HR 0.60 (95% CI: 0.46–0.78); one-sided P<0.0001], respectively (12).

In summary, future trials should incorporate adaptive biomarker platforms, early pharmacodynamic readouts, and carefully stratified patient subsets according to solid preclinical features, which have been elusive so far when investigating the combination of antiangiogenics and ICI in NSCLC. Without such efforts, a quantum leap based on antiangiogenics-based treatments in previously treated advanced or metastatic NSCLC will remain chimera.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-116/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-116/coif). A.M. reports a grant from PharmaMar; and payment or honoraria from Beigene, Sanofi, PharmaMar, and GSK. P.B. reports grants or contracts from Pfizer and Roche; consulting fees from Astrazeneca, MSD, GenMab, Novartis, Beigene, Diaceutics, Pharmacosmos, and PharmaMar; and support for attending meetings and/or travel from PharmaMar and Pfizer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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