Metronomic oral cyclophosphamide &amp; low dose nivolumab for advanced hepatocellular carcinoma (HCC).
Authors: Jo-Pai Chen, Tsui-Mai Kao, Fu-Jen Hsueh, Wei-Chen Lu, Wei-li Ma, Hsu Wu, Keng-Man Chiang, Hsing-wu Chen, Sung-Hsin Kuo
Journal: Journal of Clinical Oncology (2021)

e16190 Background: Metronomic oral cyclophosphamide would suppress Treg and low dose nivolumab(0.1 mg/kg biweekly) might be still effective for immunogenic cancers. We try to introduce this regimen for immunogenic advanced HCC. Methods: From 2016 to 2021, 65 advanced HCC patients receiving ICIs in Yun-lin Branch of National Taiwan University Hospital were reviewed. Results: In these patients, 46 failed sorafenib; 35 (54%) HBV infected, 23 (35%) HCV infected, 7 (11%) alcoholism. The objective response rate was 48% (31/65) and disease control rate was 74% (48/65), with favorable toxicity profiles. In 43 nivolumab users, dosage from 0.3 to 3 mg/kg biweekly with 58% in 3 mg/kg; 15 receiving second-line low dose biweekly 20 mg nivolumab with oral metronomic cyclophosphamide 50 mg per day produced response rate 53% (8/15) &amp; clinical benefit 73% (11/15). For this special regimen, in 10 HCV-infected patients, ORR was 70% &amp; DCR was 90%; in 4 HBV-infected patients, ORR was 25%. In 10 with lung/LN metas only, ORR was 80%. 7 receiving bevacizumab, nivolumab, &amp; cisplatin had 57% (4/7) response rate. In 7 atezolizumab users, combined with low dose bevacizumab (100 to 200 mg per 3 weeks) for first-line use, 6 were responders (86%). 19 front-line immunotherapy users had 68% (13/19) response rate (5 bevacizumab &amp; atezolizumab; 4 lenvatinib &amp; pembrolizumab; 2 bevacizumab, cisplatin, &amp; nivolumab; 2 nivolumab with SBRT on MPV); 47 later line users had 38% (18/47) response rate (some receiving nivolumab combined with CT; bevacizumab with nivolumab &amp; CT; sorafenib or regorafenib). 13 patients had MPV involvement (7 responders to immunotherapy-54%): 3 patients, using nivolumab after sorafenib failure, all suffered from rapid progression; 3 patients, receiving front-line SBRT over portal vein tumors and nivolumab, had response rate in 67% (2/3) and 100% clinical benefit; 2 responders to front-line lenvatinib &amp; pembrolizumab (ORR 2/2-100%); 1 responder to front-line bevacizumab &amp; atezolizumab (ORR 1/2-100%; another patient responded to second-line lenvatinb &amp; pembrolizumab); 1 responder to front-line bevacizumab, cisplatin, &amp; nivolumab. Conclusions: In our institution, ICIs combined with metronomic chemotherapy, low dose bevacizumab, multi-targeted VEGFR2 TKI, CT(platinum, anthracycline, and 5-fluorouracil), &amp; SBRT could produce favorable response rates(first line 68%; later line 38%)/clinical benefits and toxicity profiles in advanced HCCs, even in heavily-treated patients, MPV involvement, and fulminant spreading status. Metronomic oral cyclophosphamide &amp; low dose nivolumab, all failing sorafenib, seemed feasible and effective with lower toxicity/cost. Patients with HCV infection or lung/lymph nodes metastasis only seemed to respond better. Immune-modulation mechanisms of metronomic oral cyclophosphamide, nivolumab biologically-effective dose, clinical trial design, &amp; biomarkers research are warranted.