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The recent approval of nivolumab in combination with ipilimumab demonstrates the utility of dual immunotherapy for patients with hepatocellular carcinoma.
Arriving after several negative phase 3 trials testing single-agent immune checkpoint inhibitors (ICIs), the recent approval of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) demonstrates the utility of dual immunotherapy for patients with hepatocellular carcinoma (HCC).
“This [approval] solidifies the role of immunotherapy-based combinations in the field,” said Anthony B. El-Khoueiry, MD, lead author of the CheckMate 040 study (NCT01658878) that led to doublet’s approval on March 10, 2020, for patients with HCC who received prior sorafenib (Nexavar) therapy. “We have seen single-agent PD-1 antibodies like pembrolizumab [Keytruda] and nivolumab show activity in small phase 1 and phase 2 studies and [subsequently] receive accelerated approvals, but when it came to phase 3 studies, these agents did not meet primary end points with statistical significance.”
Motivated by the hypothesis that concurrently administering more than 1 ICI could lead to greater anticancer activity than single-agent immune checkpoint blockade, investigators planned and subsequently initiated several studies to test this supposed synergy. CheckMate 040 was among these clinical efforts and evaluated the efficacy of nivolumab and ipilimumab, a CTLA-4 inhibitor, in cohort 4 (n = 49). Patients received the ICIs at 1 mg/kg and 3 mg/kg, respectively, every 3 weeks for 4 cycles, followed by 240 mg of nivolumab every 2 weeks until disease progression or unacceptable toxicity.1
The overall response rate (ORR) was 33% (95% CI, 20%-48%), with 4 complete responses (CRs) and 12 partial responses (PRs). The duration of response with the immunotherapy doublet ranged from 4.6 months to more than 30.5 months and 31% of responses lasted at least 24 months, outperforming nivolumab monotherapy, which was assessed in cohorts 1 and 2 (Table).1
Table. Efficacy Data from the CheckMate 040 Trial1
“When we look at the efficacy data from [cohort 4], the results are really quite striking. There was a complete response rate of 8%. These patients not only responded to the combination [but also had] complete responses that were quite durable,” said El-Khoueiry. “[These results] build on the single-agent activity that’s been seen [and affirm] that immunotherapy-based combinations may potentially show very promising activity.”
ICI Monotherapy Approvals
The FDA cleared nivolumab monotherapy for use in this setting in September 2017 based on efficacy data from a subset of 154 patients with HCC from cohorts 1 and 2 of CheckMate 040 who either progressed on sorafenib or were unable to tolerate the tyrosine kinase inhibitor. Patients received nivolumab at 3 mg/kg every 2 weeks. Findings indicated that treatment with the ICI induced a 14% ORR, with a 2% CR rate and a 12% PR rate by blinded independent central review per RECIST 1.1 criteria.1
In November 2018, single-agent pembrolizumab gained approval for patients with HCC who have been treated with sorafenib based on results from the KEYNOTE-224 trial (NCT02702414). Participants in the single-arm study received pembrolizumab intravenously at 200 mg every 3 weeks. Pembrolizumab demonstrated a 17% ORR among 104 patients, including a 1% CR rate and a 16% PR rate by blinded independent review per RECIST 1.1 criteria.2
The Search for Activity in the Front Line
Building upon the efficacy of single-agent ICI therapy in HCC has proved challenging. Data from the phase 3 CheckMate 459 trial (NCT02576509) of frontline nivolumab versus standard-of-care (SOC) sorafenib in 1009 patients with unresectable HCC, did not meet statistical significance for improved overall survival (OS; HR, 0.85; 95% CI, 0.72-1.02; P = .0752). Although CheckMate 459 missed its primary end point of OS, findings trended toward an OS benefit with the PD-1 inhibitor.3
Meanwhile, pembrolizumab monotherapy fell short of reaching a prespecified benchmark for statistical significance compared with placebo as second-line therapy for patients who previously received sorafenib, according to findings from the phase 3 KEYNOTE-240 trial (NCT02702401). The study enrolled 413 patients who were randomized to receive best supportive care plus either pembrolizumab or placebo. The OS for pembrolizumab therapy had an HR of 0.78 (95% CI, 0.611-0.998; P = .0238).4
The lackluster performance of ICI monotherapies in phase 3 investigations has since prompted an interest in immunotherapeutic combinations: “It was important to build on [these] data by [conducting] studies of combination therapies,” said El-Khoueiry, chair ofthe Clinical Investigations Support Office at the University of Southern California Norris Comprehensive Cancer Center and director of clinical translation at the Southern California Clinical and Translational Science Institute, both in Los Angeles.
The phase 3 CheckMate 9DW study (NCT04039607) is currently recruiting 1084 patients with advanced HCC who have not received prior systemic therapy, who will be randomized to the combination of nivolumab plus ipilimumab or either SOC sorafenib or lenvatinib (Lenvima).
Although the ICI doublet received an accelerated approval as a second-line therapy, results from the CheckMate 9DW trial will elucidate whether or not nivolumab and ipilimumab have efficacy in an earlier stage of disease, according to El-Khoueiry.
Novel Combinations Could Become SOC
The dual ICI approach is among a number of immunotherapeutic combinations under investigation as first-line treatment of HCC, particularly those that pair an ICI with VEGF inhibition.
On May 29, 2020, the FDA approved the combination of atezolizumab (Tecentriq), a PD-L1 inhibitor, with bevacizumab (Avastin), a VEGF inhibitor, for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy.5
The decision was based on findings from the phase 3 IMbrave150 study (NCT03434379), in which the combination was compared with sorafenib as frontline therapy for 501 patients.
At a median follow-up of 8.6 months, the median progression-free survival was 6.8 months with atezolizumab and bevacizumab versus 4.3 months with sorafenib. The median OS was not estimable among the 336 patients evaluable in the combination arm and 13.2 months in the sorafenib group (n = 165; HR, 0.58; 95% CI, 0.42-0.79; P <.001).6
“There was a 42% reduction in the risk of death with atezolizumab and bevacizumab,” El-Khoueiry said. The approval of the regimen, he noted, “would move the immunotherapy- based combination approach to the frontline setting.”
Updated IMbrave150 results, presented at the 2020 Gastrointestinal Cancers Symposium, showed that the median time to deterioration (TTD) was better among patients who were treated with the doublet therapy compared with patients who received sorafenib. The median TTD was 11.2 months with the combination versus 3.6 months with sorafenib (HR, 0.63).
This advantage extended to the TTD of physical functioning (median TTD, 13.1 vs 4.9 months; HR, 0.53; 95% CI, 0.39-0.73) and role functioning, which favored atezolizumab and bevacizumab (9.1 vs 3.6 months; HR, 0.62; 95% CI, 0.39-0.73). The dual immunotherapy approach also delayed the TTD in patientreported loss of appetite, fatigue, pain, and diarrhea.7
Other activity in the field includes regimens that combine PD-1/PD-L1 inhibition with multikinase inhibitors, El-Khoueiry said. The combination of pembrolizumab with lenvatinib, which inhibits VEGF and other kinases implicated in pathologic angiogenesis, is being explored in the phase 3 MK-7902-002/E7080-G000-311/LEAP-002 study (NCT03713593). The trial will compare the doublet with single-agent lenvatinib in an estimated 750 patients with advanced HCC.
In July 2019, the FDA granted the combination a breakthrough therapy designation for patients with newly diagnosed, advanced, and unresectable HCC that is not amenable to locoregional treatment. The classification was based on positive interim findings from the single-arm, phase 1b KEYNOTE-524/Study 116 (NCT03006926) of pembrolizumab and lenvatinib in 104 patients with HCC.8
Additionally, the combination of atezolizumab and cabozantinib (Cabometyx), which inhibits VEGF and other kinases, is under evaluation versus sorafenib in the phase 3 COSMIC-312 study (NCT03755791).
Investigators are seeking to recruit 740 patients with advanced disease who have not received prior systemic therapy.
Patients who are not randomized to the doublet regimen or sorafenib will receive cabozantinib monotherapy. Investigators will interpret the data from this arm to compare the efficacy of single-agent cabozantinib with sorafenib.
The phase 3 HIMALAYA trial (NCT03298451) is evaluating the efficacy of combining durvalumab (Imfinzi), which also targets PD-L1, and tremelimumab, which is directed at CTLA-4, in patients with unresectable, advanced HCC who have not previously received systemic treatment and are ineligible for locoregional therapy versus sorafenib. The study is also testing singleagent durvalumab in this patient population. In January 2020, the FDA granted orphan drug status to the combination.9
As HCC specialists spearhead studies designed to answer the question of whether or not immunotherapeutic combinations are a key to unlocking greater efficacy in HCC, strategies for optimal sequencing remain elusive due to the highly active nature of these investigations.10
“There are a lot of questions about how to best sequence these agents because of the shifting data in the field,” El-Khoueiry said. He noted that if the combination of atezolizumab and bevacizumab becomes the dominant regimen in the first-line setting, “there are very little data on what to use after [this regimen] and how to sequence the agents. This is a challenge in the field, and we need to generate more data, whether from clinical trials or real-world evidence.