Salvage Ipilimumab plus Nivolumab after Anti-PD-1/PD-L1 Therapy in Advanced Hepatocellular Carcinoma

Abstract

Combination anti-PD-(L)1/CTLA-4 blockade is approved in patients with hepatocellular carcinoma (HCC) in the first-line setting or after sorafenib, but whether this treatment has efficacy after prior anti-PD-(L)1 therapy is unknown. We performed a multicenter retrospective review of patients with advanced HCC treated with ipilimumab plus nivolumab after prior anti-PD-(L)1 therapy, excluding patients with prior anti-CTLA-4 treatment. Of the 32 patients who met our inclusion criteria, prior anti-PD-(L)1 regimens included atezolizumab plus bevacizumab (50%, n=16), other anti-VEGF plus anti-PD-(L)1 combinations (31%, n=10), and anti-PD-(L)1 monotherapy (19%, n=6). The median number of prior systemic therapies was two (range 1-8). The objective response rate (ORR) with ipilimumab plus nivolumab by RECIST 1.1 was 22% (1 CR (3%), 6 PR (19%), 8 SD (25%), 16 PD (50%), and 1 NE (3%)), and objective response was associated with improved PFS and OS. Immune related adverse events were reported in 13 patients (41%), with no new safety signals. This study demonstrates that ipilimumab plus nivolumab has efficacy in patients with HCC who have received prior anti-PD-(L)1 therapy, suggesting that failure to respond to prior PD-(L)1 blockade should not preclude treatment with salvage ipilimumab plus nivolumab. Prospective studies are needed to define the optimal sequence of therapies.

Two Cases of Advanced Hepatocellular Carcinoma Who Responded Well to the Combination of Durvalumab Plus Tremelimumab After Disease Progression During Atezolizumab Plus Bevacizumab Therapy Under Bevacizumab Withdrawal

“…The efficacy of drug sequencing from ICI to ICI with regimens including Atezo/Bev has been reported previously [ 14 ], with the response rate for nivolumab plus ipilimumab reported to be 16-30% in RECIST 1.1 and the rate of immune-related adverse events required systemic corticosteroid treatment reported to be 10-12% that included the Atezo/Bev regimen [ 15 - 17 ]. Tremelimumab, which has the same CTLA-4 inhibitory effect as ipilimumab, is also expected to be effective and safe.…”

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

“…Median OS and PFS were 9.2 and 2.9 months, respectively. The treatment was associated with irAEs, including pneumonitis and colitis/esophagitis (13% each), followed by autoimmune hepatitis (9%), rash (9%), arthritis (3%), and myocarditis (3%) [97]. Thus, these studies demonstrated that nivolumab and ipilimumab could provide a clinical benefit in patients resistant to sorafenib and other PD-(L)1 inhibitors.…”

Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress

“…Thus far, there have been studies indicating that the combined use of ipilimumab and nivolumab may be efficacious and well-tolerated following prior ICI-based combination therapies. This underscores the need for prospective clinical assessments of this treatment sequence [105,106] (Table 2).…”