Advanced Age Presents No Barrier to Successful Nivolumab Treatment in HCC

June 30, 2017

Conference | ESMO Gastrointestinal Cancers Congress

Ignacio Melero, MD, PhD

Durable responses and improved long-term survival were demonstrated with nivolumab (Opdivo) that were not altered by the age of patients with advanced hepatocellular carcinoma (HCC) across all age groups of patients participating in the CheckMate 040 trial, according to a subanalysis of data presented at the 2017 ESMO World Congress on Gastrointestinal Cancer (WGI). Nivolumab, an antibody targeting the PD-1 receptor that restores T-cell mediated antitumor activity, was well-tolerated by younger and elderly patients who showed similar safety profiles.

The analysis presented at WGI was done at a median follow-up of 12.9 months, and stratified patients by age; 142 (54.2%) patients were aged <65 years, 89 (34.0%) were aged 65 to < 75 years, 120 (45.8%) were ≥65, and 31 (11.8%) patients were aged ≥75 years.

Similar responses to nivolumab were observed, where objective response rates (ORR) of 16.9% in patients younger than 65 years compared to 16.7% in patients 65 years and older were reported. The patients were further stratified into sorafenib-naïve and sorafenib-experienced cohorts. Patients who were sorafenib-naïve had an ORR of 21.1% for patients younger than 65 years, and an ORR of 19.0% for patients older than 65 years. Patients who were sorafenib-experienced had an ORR of 15.4% for patients younger than 65 years and an ORR of 21.1% for patients older than 65 years.

CheckMate 040 was the first study to demonstrate that a PD-1 inhibitor was effective in patients with HCC; nivolumab was administered to 262 patients with HCC having a median age of 63.0 years (range, 19-83); 80 (30.5%) patients were sorafenib-naïve and 182 (69.5%) were sorafenib-experienced. Nivolumab was administered intravenously at doses ranging from 0.1 mg/kg to 10 mg/kg every 2 weeks for up to 2 years. The primary endpoints were safety and tolerability and ORR according to RECIST v1.1 criteria by blinded independent central review (BICR).

Patient baseline characteristics that differed between patients <65 years and ≥65 years included Barcelona clinic liver cancer (BCLC) stage, where 90% versus 64% of patients were stage C, and extrahepatic metastases, which were present in 71% versus 64% of patients, respectively. More young patients (69%) had received surgical resection compared to older patients (55%). Older patients (49%) were more often HBV- or HCV-uninfected compared to younger patients (32%).

The best overall response with nivolumab in patients aged >60 years, 65 to <75 years, and ≥75 years included complete responses (CRs) in 3 (2%), 1 (1%), and 0 patients, respectively. Partial responses (PRs) were also reported in 21 (15%), 15 (17%), and 4 (13%) patients, respectively. Stable disease was achieved by 35%, 38%, and 42% of patients and progressive disease occurred in 42%, 35%, and 32% of patients, for each respective age group.

The disease control rates were 53% in patients <65 years, 56% in patients aged 65 to <75, and 62% in patients aged 75 and older.

The responses were durable; the median duration of response was 19.35 months (range, 2.5 to 32.8+), not reached (NR; range, 4.2 to 16.6+), and 12.46 (range, 3.2 to 16.6+) months in the respective age groups.

Overall survival (OS) was prolonged following nivolumab in the oldest patients. The 18-month OS rates were 47% for patients >60 years, 47% for patients 65 to <75 years, and 57% for patients ≥75 years. The median OS was 16.6 months (95% CI, 13.8-20.2), 17.0 months (95% CI, 14.2-20.7), and 19.9 months (95% CI, 10.4-28.6), respectively.

Notably, patients across all age groups demonstrated a reduction of target lesions.

“To date, there are few data on the response to nivolumab in elderly patients. It is important to know the nivolumab response in this population because treatment options are limited in hepatocellular carcinoma, which is often diagnosed at an advanced age; in addition, younger patients with HCC are living to well beyond the age of 65 years and will probably progress on standard-of-care first-line treatment with sorafenib,” Ignacio Melero, MD, of the Centro de Investigación Medica Aplicada (CIMA) and Clínica Universitaria (CUN) at the Universidad de Navarra, Spain said in his presentation.

Among the overall CheckMate trial population, sorafenib-naïve patients demonstrated an ORR of 20% and an 18-month OS rate following nivolumab of 57%. In sorafenib-experienced patients, the ORR was 15%, and 18-month OS rate was 44% with nivolumab treatment.

Older patients did display a longer time to response (TTR) than younger patients; median TTR was 2.7 months in patients aged <75 years and 3.6 months in patients ≥75 years.

“The safety profile of nivolumab in elderly patients with HCC is generally consistent with the results previously reported in the overall population, encompassing all age groups,” said Melero.

Treatment was discontinued for 89% of patients >60 years, for 82% of patients 65 to <75 years, and for 84% of patients ≥75 years. In the respective age groups, 80%, 64%, and 77% discontinued treatment due to disease progression, respectively, and 4%, 8%, and 3% of patients discontinued due to treatment related adverse events (TRAEs). One death occurred in a patient in the 65 to <75 years age group.

Grade 3/4 TRAEs were reported in 20% of all patients <65 years and in 23% of all patients ≥65 years. Grade 3/4 treatment-related ALT/AST elevations were reported in 3%/4% of patients <65 years and in 4%/7% of patients ≥65 years.

“Hepatic safety events were comparable in patients less than 65 years and 65 years and older,” Melero said. “Currently, CheckMate 456, a phase III study evaluating nivolumab as a first-line therapy in patients with advanced HCC, is ongoing.”

Reference Melero I, El-Khoueiry A, Yau T, et al. Efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma analyzed by patient age: a sub-analysis of the CheckMate 040 study. [ESMO WGI Abstract O-008] Ann Oncol. 2017;28(suppl_3).

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