KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib.

Abstract

209 Background: Immunotherapy approaches, including immune checkpoint blockade, have shown initial promising results in HCC. Anti PD-1 therapy with pembrolizumab has demonstrated antitumor activity and manageable safety in multiple cancers. KEYNOTE-224 (NCT02702414), an open label, phase 2 trial assessed the efficacy and safety of pembrolizumab in pts with advanced HCC previously treated with sorafenib. Methods: Eligible pts were age ≥18 y with confirmed HCC, radiographic progression after sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and predicted life expectancy > 3 mo. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, unacceptable toxicity, withdrawal of consent or investigator decision. Response was assessed every 9 wk (RECIST v1.1, central review). Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints included DOR, DCR, PFS, OS, and safety and tolerability. Data cutoff date was Aug 24, 2017. Results: Of 104 treated pts, 23 continued therapy (median follow up 8.4 mo, range 0.4-13.6). Median age of pts was 68y (range 43-87), 21.2% were HBV+, 26% were HCV+, 94.2% were Child Pugh A, 79.8% had PD on sorafenib and 63.5% had extrahepatic disease. ORR was 16.3% (95% CI, 9.8 to 24.9) and similar across subgroups with different etiology. Median time to response was 2.1 mo (range 1.8-4.8) and 94% of responders were estimated to have a response duration ≥6 mo. Best responses were CR in 1 patient (1.0%), PR in 16 (15.4%), SD in 47 (45.2%) and PD in 34 (32.7%); DCR was 61.5%. Median PFS was 4.8 mo (95% CI, 3.4 to 6.6) and median OS (9.4 to NA) was not reached. The 6 mo PFS and OS rates were 43.1% and 77.9%, respectively. Treatment related (TR) AE occurred in 73.1% of pts; fatigue (21.2%) and increased aspartate aminotransferase (12.5%) were seen in ≥10% of pts and grades 3-5 TRAE in 25% including 1 death (ulcerative esophagitis). No cases of HBV/HCV flare occurred; immune mediated hepatitis occurred in 3 (2.9%) pts. Conclusion: Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in pts with advanced HCC previously treated with sorafenib. Safety was generally comparable to that established for pembrolizumab monotherapy. Clinical trial information: NCT02702414.

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

“…Radiofrequency ablation has been shown to increase the frequency of tumor-reactive circulating T cells and T cells specific for recall antigens and autologous NK cell response. 4,13 This phenomenon first was reported in patients with melanoma who were treated with anti-CTLA-4 antibodies and subsequently treated with anti-PD-1 antibodies. 2).…”

“…This result supports a study illustrating that TGF-β signaling diminishes tumor response to PD-1/PD-L1 blockade by excluding CD8-positive effector T cells from the tumor parenchyma. 13 High levels of IFN-γ, IL-10, and CXCL9 have been reported to correspond to PD-L1 elevation in cancer cells and cells from the lymphoid and endothelial lineages. Hence, TGF-β is a potential biomarker for response to PD-1/PD-L1 blockade and may be a crucial contributor leading to attenuated T-cell infiltration in tumors in patients with HCC who do not respond to PD-1/PD-L1 inhibition.…”

“…4,13 Both nivolumab and pembrolizumab recently were given accelerated but not full approval for the treatment of HCC. This adds to the growing body of evidence demonstrating that patients with advanced HCC can benefit from immune checkpoint inhibitors with durable objective responses.…”

“…To the best of our knowledge, this was not mentioned in previous studies with nivolumab or pembrolizumab. 13 One limitation of the current study was that research biopsy was not mandated and archival tissue was used. 18 It was noted that isolated occurrences of immune response not captured by RECIST have been reported in patients with bladder cancer (1.5%; 1 of 65 patients), renal cell cancer (1.8%; 3 of 168 patients), and NSCLC (unquantified; reported in a study with multiple malignancies).…”

Nivolumab in patients with advanced hepatocellular carcinoma and Child‐Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series

“…With advancing stage of liver disease and worsening fibrosis, liver inflammation evolves to local and systemic immunodeficiency, with T-cell dysfunction and recruitment of T-regulatory cells. 38,40 Although the current retrospective series included only patients who were treated with nivolumab, pembrolizumab also has demonstrated efficacy in patients with CPA HCC, 40 and other immune checkpoint inhibitors and combinations currently are being studied in clinical trials. 39,40 The presence of tumor-infiltrating lymphocytes within the liver, along with the upregulation of exhaustion markers, suggest the potential for response to immune checkpoint inhibition with nivolumab and other immunotherapy approaches in patients with HCC who have underlying fibrotic liver disease.…”