Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC).

Abstract

336 Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.

Immune Checkpoint Blockade Therapy for Hepatocellular Carcinoma: Clinical Challenges and Considerations

“…Durvalumab and tremelimumab combination therapy led to an ORR of 18% and a DCR of 57.5% with 20% of patients had grade 3/4 treatment-related adverse events, showing minimal enhancement of efficacy and increased risk of severe side effect compared to one ICI alone (88). Similarly, tremelimumab plus durvalumab showed an ORR of 20% and a DCR of 60% in advanced HCC with median PFS of 7.8 months (89).…”

Immunobiology of cholangiocarcinoma

“…The median PFS was 3.1 months and OS was 5.5 months, while multiple grade 3/4 treatment-related AEs were reported. 92 Efficacy in this study may have been hampered by inclusion of an unselected BTC population. However, given the increased risk for adverse events and limited efficacy of combination PD-1/CTLA-4 blockade, there is substantial interest in investigating alternative combination immunotherapies.…”

Therapy of Primary Liver Cancer

“…168 Results from an early phase II trial combining tremelimumab and durvalumab demonstrated a safety and a promising antitumor activity both in HCC and BTC. 169 The tremelimumab and durvalumab combination holds great promise in becoming a new first-line treatment for liver cancer.…”