Results
Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.
Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.
The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.
Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.
Discussion
Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.8,9
Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.10 The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.11 This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.12
The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.13,14
Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.15