Trial Exploring Combined Neoadjuvant Therapy With Pembrolizumab/Lenvatinib + Adjuvant Pembrolizumab in Pat. With NSCLC

The primary aim of this single arm, phase II study is to determine the efficacy of the combination therapy Pembrolizumab/Lenvatinib regarding the rate of major pathological response (MPR-Rate). The investigators expect to improve the MPR-Rate of 20% in Anti-PD1/-PD-L1 monotherapy (observed in recent trials) to a MPR-Rate of 40% with the combination therapy Pembrolizumab/Lenvatinib.

In Tyrol lung cancer is the fourth most incident cancer in women and the second most in men (1). Mortality related to lung cancer is highest in both sex groups, which supports the huge unmet medical need for improved lung cancer therapies in the near future (2). In very recent years, many novel therapies have entered the clinical scene, particular for treatment of non-small cell lung cancer (NSCLC) and many of those drugs target the tumor microenvironment (TME) (3-6). Both, anti-angiogenic-treatment (AAT) and immunotherapy target the TME and have been successfully established as standard therapeutic options in NSCLC (6-9). Recent preclinical studies strongly suggest that AAT and immune-checkpoint-inhibitors act synergistically and first clinical studies also proved an acceptable safety profile (6, 10, 11). However, response and therapeutic efficacy of these approaches is still limited to certain subgroups of patients and therefore the search for biomarker(s) predicting response and/or toxicity for improved patient selection is of utmost importance. This knowledge would definitely allow a more rational and efficient clinical use of these compounds. Neoadjuvant "window of opportunity" trials may offer an important way of answering relevant translational research questions related to optimized (biomarker-driven) patient selection, as they allow sequential tissue sampling during diagnostic work-up and subsequently (after neoadjuvant therapy) upon surgical tumor resection. Most studies investigating immunotherapy combinational approaches mainly focused on the characterization of the immune cell compartment, while the influence on the vascular network as well as on their mutual regulation, particularly in case both compartments are targeted in parallel, has not sufficiently been addressed. Standard neoadjuvant therapy is a mainstay of combinational chemotherapy with high toxicity and complication rates (12, 13). Several recent early clinical trials have shown promising pathologic response rates and good tolerability with neoadjuvant immune-checkpoint antibody therapy (14-16). Recently, neoadjuvant immune-checkpoint antibody monotherapy (ICA) with the PD-1 blocking monoclonal antibody Nivolumab showed high pathological response rates and good tolerability (14). Adjuvant treatment with immune-checkpoint-inhibitors has been shown to be effective and safe in the treatment of early stage melanoma (17, 18). In NSCLC prospective randomized trials with the aim of recapitulating these beneficial effects are ongoing. A high medical need in the adjuvant therapy setting is to select the optimal candidates for therapy and liquid-biopsies drawn during adjuvant treatment offer important opportunities for patients selection: (i) the kinetics of cell-free tumor-DNA (ct-DNA) can be used to monitor remission status and potentially early sense later overt clinical relapse (19-22); (ii) longitudinal assessment of patient-specific tumor alterations may predict therapy recurrence (iii) together with measurements of immune cell populations ct-DNA kinetics might gain insights into the dynamics within the TME during a prolonged period of checkpoint-blockade. Combining these informations might lead to a better understanding of potentially beneficial neo-/adjuvant treatment effects finally leading to relapse-prevention. The present phase II investigator-initiated trial (IIT) investigates the efficacy of the neoadjuvant combination therapy of the PD-1 inhibitor Pembrolizumab with the antiangiogenic kinase inhibitor Lenvatinib (primary endpoint: major pathological response) and how this therapy shapes the TME. Furthermore, the disease kinetics and the effects on cellular and soluble immune-biomarkers will be monitored during an additional adjuvant treatment-phase with Pembrolizumab via liquid-biopsies, multi-dimensional flow cytometry and cytokine quantification. In total 33 patients with early stage NSCLC will be included in this trial. The scientific program provides a comprehensive mapping of the TME prior to and after neoadjuvant intervention using various single cell analysis platforms to depict the composition of the TME. Consecutively collected plasma and blood probes will be analysed and correlated with routine response assessment, TME patterns and the clinical endpoints. In conclusion, the present phase II study aims for identification of potential biomarkers and biomarker combinations relevant for combination therapy of immunotherapy and anti-angiogenic agents in early stage NSCLC.