Nivolumab in HCC and Pembrolizumab in Tumors with Mismatch Repair Deficiency

Nivolumab in HCC and Pembrolizumab in Tumors with Mismatch Repair Deficiency

Immunotherapy with PD-1 inhibitors has heralded a new age in cancer care. In the Saturday, May 30, Clinical Science Symposium “Immunotherapy for Every Patient: Check Your Enthusiasm,” data were reported on the efficacy of nivolumab in hepatocellular carcinoma (HCC) and pembrolizumab in tumors with mismatch repair (MMR) deficiency. 

Nivolumab Efficacy in HCC

Dr. Anthony B. El-Khoueiry
Data from a phase I/II study presented by Anthony B. El-Khoueiry, MD, of the University of Southern California Norris Comprehensive Cancer Center, indicated that nivolumab may be a promising treatment for patients with advanced HCC (Abstract LBA101). “Nivolumab has manifested a manageable safety profile in the 47 patients evaluated so far,” Dr. El-Khoueiry said. “This is critical because patients with HCC frequently have viral hepatitis and underlying liver cirrhosis.”

Evaluating nivolumab in HCC was a rational choice based on the observation that patients with HCC overexpressing PD-L1 have a poor prognosis. Patients enrolled in the study were required to have histologically confirmed advanced HCC with a Child-Pugh score of 7 or less and not be candidates for curative treatment options. Patients were allowed to have one or more prior lines of systemic therapy that failed, including sorafenib, the current standard of care in advanced HCC.

In this dose-escalation study, patients received 0.1 to 10.0 mg/kg of nivolumab intravenously for up to 2 years. Dose escalation occurred in parallel cohorts based on whether they had hepatitis B (11 patients), hepatitis C (12 patients), or were noninfected (24 patients). Safety was the primary endpoint of the study.

Out of 47 patients evaluable for safety at the time of the interim analysis in March 2015, 41 patients had Child-Pugh scores of 5. Eighty-three percent of patients had extrahepatic metastases or vascular invasion, 75% had prior systemic therapy, and 68% had prior sorafenib.

A maximum tolerated dose was not defined. Drug-related adverse events (AEs) occurred in 68% (32 patients), with 19% reporting grade 3/4 AEs. All-grade AEs reported included aspartate aminotransferase increase (AST; 19%), lipase increase (17%), rash (17%), alanine aminotransferase increase (ALT; 15%), amylase increase (15%), and pruritus (13%). The grade 3/4 AEs reported in 5% or more of patients included elevations in AST (11%), ALT (9%), and lipase (9%).

Currently, 17 patients remain on study. Thirty patients discontinued treatment—26 because of disease progression, two because of drug-related AEs, and two because they had a complete response (CR).

Response was measured using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Of 42 patients evaluable for response, CR was reported in two patients (5%) and partial response (PR) in six patients (14%) for an overall objective response rate of 19%. “Responses were seen across all three cohorts of patients, and responses were durable,” Dr. El-Khoueiry said. Preliminary 1-year overall survival (OS) was 62%. These responses were much higher than those seen with sorafenib, the current standard of care, Dr. El-Khoueiry said.

Dr. El-Khoueiry concluded that with a manageable safety profile, nivolumab produced durable responses and has so far shown an encouraging 12-month OS.

“The response rate of 19% and the prolonged duration of response and stable disease are encouraging and offer the potential promise of a novel treatment modality for hepatocellular carcinoma,” he said.

Discussant Lawrence Fong, MD, of the University of California, San Francisco, agreed. “This study shows that nivolumab has clinical efficacy without significant toxicity. For this disease with limited treatment options, nivolumab shows that patients can achieve a durable response.”

The study has dispelled concerns of using immune checkpoint inhibitors in a disease associated with viral infections, Dr. Fong said. Nivolumab now needs to be evaluated in randomized clinical trials for patients with HCC. 

Pembrolizumab Efficacy in Tumors with MMR Deficiency

Dr. Dung T. Le
 Dung T. Le, MD, of the Sidney Kimmel Comprehensive Cancer Center, reported data from a phase II study that showed that tumors with genetic MMR defects respond substantially better to therapy with the PD-1 inhibitor pembrolizumab compared with tumors proficient in MMR (Abstract LBA100).

The study evaluated the efficacy and safety of 10 mg/kg of pembrolizumab administered intravenously every 2 weeks in three cohorts of patients: 25 with MMR-deficient colorectal cancer (CRC); 25 with MMR-proficient CRC; and 21 with MMR deficiency across different cancers.

The co-primary endpoints of the study were immune-related progression-free survival and overall response rate at 20 weeks. Because there were no differences in immune-mediated and RECIST 1.1 responses, Dr. Le presented results for RECIST responses.

Data were presented from a January 2015 data cutoff, released online May 30, 2015, in New England Journal of Medicine. For the primary endpoint, objective response rate was 62% for MMR-deficient CRC, 0% for MMR-proficient CRC, and 60% for MMR-deficient non-CRC. Disease control rates (CR + PR + stable disease) were also high for patients with MMR-deficient tumors: 92% for MMR-deficient CRC, 16% for MMR-proficient CRC, and 70% for MMR-deficient non-CR.

Dr. Le indicated that responses were durable and in some cases began with the first dose of pembrolizumab. Median progression-free survival and OS were not reached for patients with MMR-deficient CRC and were 2.3 months and 5.0 months, respectively, for patients with MMR-proficient CRC.

Dr. Le indicated that previous studies in lung cancer and melanoma had suggested tumors with a high mutational burden were more likely to respond to therapy with PD-1 inhibitors. MMR deficiency is associated with a high degree of mutational burden, she said. Indeed, she showed data from whole-exome sequencing in which MMR-deficient tumors had an average of 1,700 somatic mutations per tumor compared with 70 somatic mutations in MMR-proficient tumors.

“Clinical benefit was noted across tumors with mismatch repair deficiency, including cancers of the colon, uterus, stomach, prostate, duodenum, and bile ducts,” Dr. Le said. She noted that based on these data, KEYNOTE 164 would be initiated with the expansion of cohorts with MMR deficiency.

Discussant Neil Howard Segal, MD, PhD, of Memorial Sloan Kettering Cancer Center, added that the study provided compelling evidence for the efficacy of pembrolizumab, which can potentially change the treatment for patients with MMR-deficient CRC.

Dr. Segal provided the rationale of the emergence of neoantigens in tumors with high mutational burden, each representing a potential immune target. He highlighted previous studies that demonstrated a numerical threshold of mutational burden within a tumor for an effective immune response—for melanoma it was more than 100 mutations, and for NSCLC it was more than 178. “This study demonstrates that the principle may also apply in CRC,” he said. “The study supports studying pembrolizumab in the front-line setting for MMR-deficient metastatic CRC.”

Watch the session: Visit the ASCO Virtual Meeting website.