Dihydropyridinic calcium channel blockers are a subclass of antihypertensive drugs with growing significance in the therapeutic armamentarium. Early studies in the 1990s had aroused certain fears with regard to the safety of the first drugs from this class, since they had a fast onset of action and a short half-life, and thus they were associated with reflex adrenergic activation. New molecules with long half-lives and high lipophilia have shown safety and efficacy in the control of blood pressure, as well as in the reduction of several end points related to hypertension. Moreover, these new molecules, which block special subtypes of calcium channel receptors, provide drugs not only with an action profile that goes beyond the antihypertensive effect, but also with a lower rate of side effects. Therefore, in the light of new studies that include calcium channel blockers alone or in combination, these agents will probably be used even more extensively for the management of hypertension in the following years.

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Purpose/Objective(s): Immunotherapy has been recommended as firstline standard of care in metastatic NSCLC. Radiotherapy coding with immunotherapy could enhance tumor responses via inducing a synergetic immunologic activity. Our preclinical research and retrospective analysis indicated low dose radiation (LDRT) combing with immunotherapy after SBRT had potential synergic anti-tumor effect. This study aims to explore the safety and tolerability of this new combination strategy. Materials/Methods: This is a phase I study includes a dose escalation phase (Ia) and a dose expansion phase (Ib) with at least 29 stage IV NSCLC patients. Eligible patients should be PD-L1 positive (TPS 1%), and has at least 3 extracranial tumor lesions. During phase Ia, patients will receive SBRT (30Gy/3f) to a small lesion, followed by LDRT to a large lesion at 3 dose levels (L1: 2Gy/1f, L2: 4Gy/2f, L3: 10Gy/5f) starting from the first day of SBRT. Sintilimab (200mg i.v., q3w) will start within 7 days after radiation completed until PD, unacceptable toxicities, withdrawal, or reaches a maximum of 24 months. If no DLT occurs with 1 PR in any dose level, will enroll 3 more patients. 20 patients receiving a recommended LDRT dose based on the result of phase Ia will then be enrolled in phase Ib to obtain additional safety and response data. Primary endpoint was safety and tolerability; secondary endpoints include ORR, PFS, and OS. Results: From 4/2019 to 1/2020, the dose escalation phase was completed with no dose limiting toxicities observed. In total, 12 patients were enrolled. Most patients were male (91.7%) with adenocarcinoma (66.7%). 41.7%patients had PD-L1 expression50% (TPS, 22C3). 6patients were enrolled in L1, and 3 in both L2 and L3, separately. The most common toxicity was hypothyroidism (3/10, G1). One patient in L2 experienced G2 radiation-related pneumonitis and one patient in L1 experienced G2 immune-related pneumonitis. No ‡ grade 3 AEs were observed. Until January 1th 2020, 10 patients received at least once tumor assessment. ORR was 70%, including 4/6 patients in L1 and 3/3 patients in L2. One patient in L3 achieved SD. Through immune related biomarkers analysis in peripheral blood samples, we found that the combination therapy increased the number of T-cell clones and TCR diversity, while at the same time decreased the PD-1 expression on CD8+T cell and ctDNA. Conclusion: The combination of SBRT + LDRT+ sintilimab is safe and tolerable. LDRT at 4Gy/2f seems to have better tumor response. This report is the first to document the use of SBRT + LDRT+ ICIs for the fistline treatment of metastasis NSCLC. Clinical trial information: NCT03812549.

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