Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma (GOING)
Status:
Recruiting
Trial end date:
2023-12-01
Target enrollment:
Participant gender:
Summary
Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein
kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2),
oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour
immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver
in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation.
Regorafenib has shown in clinical trials an acceptable benefit-risk across different tumor
types, including colorectal cancer (CRC), GastroIntestinal Stromal Tumors (GIST) and HCC.
The most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib
are pain, hand-foot skin reaction (HFSR), asthenia/fatigue, diarrhea, decreased appetite and
food intake, hypertension, and infection.
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody to the programmed death
(PD)-1 receptor, blocking the interaction with PD-ligand (PD-L)1/PD-L213 and restoring
T-cell-mediated antitumor activity. Nivolumab was evaluated in second-line the CheckMate 040
Study (Escalation and Expansion cohort.
In both cohorts of the CheckMate 040 Study, the safety profile was acceptable and there were
no reported nivolumab-related deaths. In the dose-expansion cohorts from the Phase 1/2
CheckMate 040 Study, 65% of patients had treatment-related adverse events (TRAEs) of any
grade 18% with Grade 3 or 4 TRAEs with fatigue, pruritus, and rash being the most common.
Elevation of aspartate transaminase (AST) and alanine transaminase (ALT) were the most
frequent Grade 3-4 TRAEs. AST/ALT elevations, however, were generally asymptomatic and
readily managed.
For this reason, the rationale of this Phase I/IIa trial is to optimize the action of
regorafenib and nivolumab but bearing in mind the potential impact of the drug-interaction
and enhancement of the severity and/or frequency of adverse events. Thus, regorafenib will be
administered as monotherapy during the first 2 cycles (each cycle is 3 weeks on plus 1 week
off) of treatment to enhance T cell trafficking and infiltration into the tumor bed to
increase the benefits of anti-PD-PD-L1, specific stimuli while emitting Damage-associated
molecular patterns (DAMPs), followed by regorafenib plus nivolumab to impact step 7 of the
cancer immunity cycle described by Chen.
The anti-PD-L1 effect under hypoxia was evaluated by Noman et al in a tumor model and they
postulated that the abrogated myeloid-derived suppressor cells (MDSC)-mediated T cell
suppression is achieved in part by modulating the cytokine production (IL-6 and IL-10).
Specifically, hypoxia could promote immunosuppression by reducing the cytotoxic efficacy of
immune cells, by increasing the peri-tumoral immunosuppressive cell populations infiltration
of and priming the expression of immunosuppressive cytokines.
Current options for first line are sorafenib and atezolizumab-bevacizumab. Lenvatinib has
been shown to be non-inferior to sorafenib, but it is less frequently used and its toxicity
profile mandates a stringent selection of patients. Sorafenib shares some molecular targets
with regorafenib, but this has specific action against VEGFR-2, VEGFR-3, Tie-2, PDGFR,
FGFR-1, c-Kit, RET and p38-alpha7. Both are antiangiogenic as bevacizumab, but while
bevacizumab is limited to the VEGF pathway, they act on several additional target involved in
cancer progression. Atezolizumab and nivolumab target the PD1 checkpoint but acting at
different levels: PD-1 receptor for Nivolumab and PD-L1 for Atezolizumab. This implies a
difference and if resistance to one of the antibodies emerges during treatment, the use of
the other one may overcome such key event leading to treatment failure.
The aim of this study is to do a sequential treatment combining regorafenib, second- line
treatment in hepatocellular carcinoma (HCC) with anti PD-1 to enhance the outcome of patients
based on the synergy between both drugs.