Pembrolizumab in Combination with Bevacizumab and Oral Cyclophosphamide in Heavily Pretreated Platinum-Resistant Ovarian Cancer

Background: Immune checkpoint inhibitors (ICIs) have been widely implemented in the treatment of solid tumors. Although epithelial ovarian carcinoma is considered as scarcely immunogenic, the presence of tumor-infiltrating T lymphocytes (TILs) in the ovarian tumor microenvironment (TME) could increase sensitivity to immune checkpoint inhibitors (ICIs). Combinations of ICIs with chemotherapy, anti-VEGF compounds and PARP inhibitors are under evaluation in ovarian cancer. Recently, a Phase II study evaluated the efficacy of Pembrolizumab in Combination with bevacizumab and oral cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian cancer.Methods: Herein, we present a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pretreated ovarian cancer in the Oncology Unit of Alexandra University Hospital.Results: Median age at diagnosis was 54.5 years (SD; 8.9; range: 44–72). All patients were diagnosed with high-grade serous ovarian carcinoma (HGSC). Initial disease stage was FIGO IIIC (8/10; 80%), IIIB (1/10; 10%) and IIC (1/10; 10%)). Patients were heavily pretreated with a median of 6 (range: 4–9) prior lines of systemic therapy. All patients have experienced disease progression on first-line platinum-based chemotherapy and median PFS to first-line treatment was 20.1 months (95%CI; 11.4 – 28.7). Patients received a median of 4 cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 2-11). ORR was 20% (2/10) with two patients achieving partial response (PR) and two patients achieving stable disease (SD) while disease control rate (DCR) was 40% (4/10). Median PFS was 2.7 months (95%; 0.6 – 4.8) and 6-month PFS rate 20%. Conclusions: Though our data reflect a small population, we here demonstrate that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in platinum-resistant recurrent ovarian carcinoma. This novel combination provides a promising alternative in heavily pretreated patients that have otherwise limited treatment options.

Metronomic oral cyclophosphamide & low dose nivolumab for advanced hepatocellular carcinoma (HCC).

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) & clinical benefit 73% (11/15). For this special regimen, in 10 HCV-infected patients, ORR was 70% & 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, & 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 & atezolizumab; 4 lenvatinib & pembrolizumab; 2 bevacizumab, cisplatin, & 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 & 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 & pembrolizumab (ORR 2/2-100%); 1 responder to front-line bevacizumab & atezolizumab (ORR 1/2-100%; another patient responded to second-line lenvatinb & pembrolizumab); 1 responder to front-line bevacizumab, cisplatin, & nivolumab. Conclusions: In our institution, ICIs combined with metronomic chemotherapy, low dose bevacizumab, multi-targeted VEGFR2 TKI, CT(platinum, anthracycline, and 5-fluorouracil), & 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 & 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, & biomarkers research are warranted.

Unusual Case of Hepatic Sinusoidal Obstruction Syndrome Induced By Low Dose Oral Cyclophosphamide

Hepatic sinusoidal obstruction syndrome (SOS) has been reported in patients receiving high dose intravenous (IV) cyclophosphamide especially as a part of preparative regimen for hematopoietic stem cell transplantation. Hepatic SOS from low dose oral cyclophosphamide has not been reported. Here we present a rare case of hepatic SOS induced by low dose oral cyclophosphamide. A 78-year-old male with history of coronary artery disease status post coronary artery bypass graft (CABG) was initially seen in hematology clinic for evaluation of normocytic anemia. During workup, bone marrow biopsy revealed NK cell large granular lymphocytic leukemia (LGL). He was then started on low dose oral cyclophosphamide 50 mg daily. After 2 months, his dose was reduced to 25 mg daily due to severe neutropenia. He then tolerated cyclophosphamide well and his hemoglobin (Hb) improved from his baseline 8 gm/dl to 12 gm/dl in 4 months. After 6 months of treatment, he was admitted to the hospital for abdominal distension, ascites and 15 pounds weight gain over 3 weeks. Labs most prominent on admission were Hb of 12.5 gm/dL , WBC 5.3 x 103/µL, Platelets 197 x 103/µL, total bilirubin 1.6 mg/dL, aspartate aminotransferase (AST) 89 U/L , alanine aminotransferase (ALT) 35 U/L and alkaline phosphatase (ALP) 283 U/L. Workup of ascites included abdominal paracentesis which revealed serum ascites albumin gradient(SAAG) <1.1 and fluid cytology was negative for carcinoma. Ultrasound of abdomen showed diffuse parenchymal heterogeneity and increased echogenicity of liver with patent hepatic vessels with normal direction of blood flow. Echocardiogram revealed preserved left ventricular systolic function with estimated left ventricular ejection fraction of 60%. He then underwent transjugular liver biopsy which revealed chronic lymphoproliferative disorder of NK cells, prominent centrilobular sinusoidal dilatation and congestion, lobular disarray, cholestasis and sinusoidal fibrosis suggestive of veno-occlusive disease secondary to drug/toxin induced liver injury. The Naranjo adverse drug reaction probability scale indicated a probable relationship between hepatic SOS and cyclophosphamide. Cyclophosphamide was held. Bone marrow biopsy showed the patient was in remission. His liver enzymes are improving and hematologic counts continue to be stable while on observation. High dose of IV cyclophosphamide given as myeloablative therapy in combination of total body irradiation or busulfan (or other agents) in preparation for hematopoietic stem cell transplantation can induce hepatic SOS, which can be severe leading to acute liver failure and death. The diagnosis is usually based on clinical features of tender hepatomegaly, weight gain, ascites and jaundice. Liver biopsy is usually diagnostic. Mechanism of injury is related to direct toxic effects of cyclophosphamide on sinusoidal cells in the liver, causing their necrosis and release into the sinusoids, obstruction and obliteration of hepatic veins. This case demonstrates that hepatic SOS can also be caused by low dose oral cyclophosphamide. Given this rare occurrence, it is prudent for the clinicians to keep an open mind and consider hepatic SOS as a potential side effect even with oral cyclophosphamide. Disclosures Yacoub: Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Roche: Other: Support of parent study and funding of editorial support.