A phase 2 study is underway to evaluate the safety and efficacy of the pembrolizumab and quavonlimab coformulation in combination with lenvatinib as treatment of patients with advanced hepatocellular carcinoma.
A phase 2 study is underway to evaluate the safety and efficacy of the pembrolizumab (Keytruda) and quavonlimab (MK-1308A) coformulation in combination with lenvatinib (Lenvima) as treatment of patients with advanced hepatocellular carcinoma (HCC), according to a poster displayed as part of the ESMO World Congress on Gastrointestinal Cancers 2021.1
As a leading cause of cancer-related death around the world, investigators have long sought to make advances in the treatment landscape of advanced HCC, including the introduction of immunotherapy. Although immunotherapies have improved clinical outcomes, there is still a high mortality rate associated with the disease, underscoring an unmet medical need for new treatment strategies.
Based on the phase 1/2 open-label, multicohort CheckMate 040 clinical trial (NCT01658878), in which the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated a promising objective response rate and durable responses with tolerable safety, it’s now known that the use of PD-1/PD-L1 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors administered both alone and in combination regimens can be effective.2 Further, lenvatinib, a multikinase inhibitor, was introduced in the frontline setting of advanced HCC and achieved antitumor activity when used in combination with pembrolizumab in a phase 1b study (NCT03006926).3 These studies served as the basis for the MK-1308A-004 study (NCT04740307).
The coprimary end points of the study’s safety lead-in phase are safety, tolerability, and determining the recommended phase 2 dose of lenvatinib in combination with quavonlimab. For the efficacy expansion phase of the study, the coprimary end points include safety and objective response rate (ORR) per RECIST v1.1 by blinded independent central review. The secondary end points explored in the study include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and time to progression (TTP), all assed per RECIST v1.1 and by BICR, and assessed by modified RECIST v1.1.1
As exploratory end points, the study is assessing all the efficacy defined by DOR, DCR, PFS, and TTP in patients with advanced HCC who have not received prior systemic treatment in addition to time to deterioration and change from baseline according to the global health status/quality of life scales (EORTC Quality of Life Questionnaire Core 30 [QLQ-C30] and EORTC Quality of Life Questionnaire HCC 18 [QLQ-HCC18]), health utilities according to EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L), and molecular biomarkers.
MK-1308A-004 is designed as a multicenter, single-arm, open-label, phase 2 study. Between 6 to 20 patients will be included in the safety lead-in phase and of those included, approximately 10 will be eligible for the dose-limiting toxicity (DLT) evaluation then assigned to a dose level.
At dose level 0, patients will be treated with pembrolizumab 400 mg plus quavonlimab 25 mg given intravenously (IV) every 6 weeks (Q6W) plus lenvatinib administered at 8 mg for those with a bodyweight of <60 kg or 12 mg if their body weight is 60 kg or higher. At dose level -1, patients receive equivalent doses of pembrolizumab plus quavonlimab as those treated at dose level 0, but, lenvatinib is administered at 4 mg in those with a bodyweight <60 kg or 8 mg for those with a bodyweight or 60 kg or above. Given patients tolerate dose level 0 well, the efficacy expansion phase will be opened to between 100 and 104 patients with advanced HCC. Treatment during the efficacy expansion phase will consist of pembrolizumab 400 mg plus quavonlimab 25 mg plus lenvatinib 8 mg for those with a bodyweight below 60 kg and 12 mg for those with a bodyweight of 60 kg or higher.
Those eligible for enrollment are adults aged 18 years or older with radiologic, histologic, or cytologic confirmed disease who have no history of systemic therapy, and have measurable disease per RECIST v1.1, are Child-Pugh class A, have an ECOG performance status of 0 or 1, and have BCLC stage C or stage B disease. Patients are also required to have adequate organ function. The protocol allows for patients with past or ongoing hepatitis C virus infection or controlled hepatitis B virus infection given they meet all other inclusion criteria.
Prior locoregional therapy to the liver, prior systemic chemotherapy, and treatment with investigational agents are grounds for exclusion from the study. Individuals will also be excluded if they present with esophageal or gastric bleeding lasting more than 6 months, bleeding of thrombotic conditions, use of factor X inhibitors or anticoagulants, had major surgery to the liver 4 or fewer weeks after the first dose of study treatment, have active autoimmune disease requiring systemic therapy, or were diagnosed with immunodeficiency or are receiving steroidal therapy within 7 days of the first dose of study treatment.
The follow-up strategy for MK-1308A-004 is to administer quavonlimab for up to 2 years and lenvatinib is administered until disease progression or unacceptable toxicity, however, the therapy may be discontinued if patients achieved a confirmed complete response after 4 doses. Posttreatment follow-up will include assessments of safety, disease status, and survival status.
During the study, responses will be assessed by imaging of the chest, abdomen, and pelvis every 9 weeks or more. This will continue until disease progression, withdrawal of consent by the patient, the occurrence of death, or by sponsor decision. The efficacy analysis will include all patients treated in the study who start at dose level. To determine the ORR and DCR, the exact binomial method proposed by Clopper and Pearson will be used. Further, the study will use the Kaplan-Meier method to determine the DOR, PFS, TTP, as well as overall survival.
To assess adverse events (AEs), study participants will be monitored as the study goes on and during follow-up. AEs will be graded based on the Common Terminology Criteria for Adverse Events, v5.0. In terms of patient-reported outcomes (PROs), patients are assessed prior to dosing of study treatment, at AE evaluation, at the end of treatment, and during the 30-day safety follow-up.
Safety is assessed in all treated patients who received 1 or more doses of the study combination.A set population comprised of patients who received at least 1 dose of treatment and completed a least 1 PROs assessment will be included in the PROs analysis
MK-1308A-004 is currently recruiting patients for the safety lead-in phase in centers on the east and west coast of the United States, as well as in South Korea, Switzerland, and Taiwan. The same countries with the addition of China, Italy, Japan, and Spain, will be recruiting patients for the efficacy expansion phase.
1. Li D, Cheng A, Lim H, et al. Pembrolizumab/quavonlimab coformulation in combination with lenvatinib in advanced hepatocellular carcinoma: phase 2 trial in progress. Presented at: ESMO World Congress on Gastrointestinal Cancer 2021 – Virtual; June 30-July 3, 2021. Abstract P-135.
2. Yau T, Kang Y, Kim T, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi: 10.1001/jamaoncol.2020.4564
3. Finn R, Ikeda M, Zhu A, et al. Phase Ib Study of Lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020; 10;38(26):2960-2970. doi: 10.1200/JCO.20.00808.