Lenalidomide to Reverse Drug Resistance After First-line Treatment of Advanced HCC

Overview

The ORR of the lenvatinib combination (lenvatinib combined with PD-1 inhibitor) was largely similar to that of the "A+T" combination (bevacizumab and atelelizumab). The disease control rate (DCR) for the combination of lenvatinib was 88%, demonstrating the efficacy of lenvatinib in combination with immunotherapy. However, progression to second-line therapy after first-line treatment for advanced HCC still faces many challenges. In our clinical practice and review of the literature, we focused on lenalidomide showing some efficacy in second-line treatment of advanced HCC. Lenalidomide is a new generation derivative of thalidomide, which has dual anti-angiogenic and immunomodulatory anti-tumor effects. Lenalidomide may have the potential to reverse drug resistance and increase the efficacy of synergistic immune-targeted therapy. Based on the preliminary data of its effectiveness in the second-line treatment of advanced HCC alone or in combination with TKI, we propose to conduct a prospective, exploratory, single-arm, open, multicenter phase II clinical study of advanced HCC PD-1 inhibitor in combination with lenvatinib after progression of first-line treatment, to initially evaluate the efficacy and safety of this regimen.

Advanced primary hepatocellular carcinoma (HCC) has entered a new phase of clinical research and patient outcomes with the continued availability of new targeted agents and immune checkpoint inhibitors. More notable are lenvatinib in combination with PD-1 inhibitor regimens and the data that continue to emerge from these studies. The 2020 ASCO GI published the Study117, a phase Ib clinical study of lenvatinib in combination with Nivolumab for the first-line treatment of unresectable hepatocytes. The study was an open phase Ib study that enrolled 30 patients, 17 with BCLC- stage B and 13 with BCLC- stage C. In the ITT population, the median age of patients was 70 years (range: 36-81 years) and 24 (80%) were male. 28 patients with ECOG performance status of ECOG 0 and 1 patient with ECOG 2 were enrolled. Enrolled patients received lenvatinib 12 mg (weight ≥60 kg) or 8 mg (weight \<60 kg) orally once daily and in combination with Nivolumab 240 mg intravenously once every 2 weeks. The study results were impressive, with an investigator-assessed overall complete remission rate of 10% CR, a partial remission rate of 66.7% PR, an objective remission rate of 76.7% ORR, and a disease control rate of 96.7% DCR. The ORR of the lenvatinib combination (lenvatinib in combination with PD-1 inhibitor) was generally similar to that of the "A+T" combination (bevacizumab and atelelizumab). The disease control rate (DCR) for the lenvatinib combination was 88%, indicating the efficacy of lenvatinib in combination with immunotherapy. However, there are still many challenges in progressing to second-line therapy after first-line treatment for advanced HCC. The first is the limited efficacy of second-line treatment options recommended by NCCN guidelines. The RESORCE study showed that single-agent regorafenib after sorafenib failure treated patients with Child-Pugh class A liver function had a higher mOS (10.6 months vs. 7.8 months) and mPFS (3.1 months vs. 1.5 months) than the placebo group. the CELESTIAL study showed that single-agent cabozantinib for patients previously treated with sorafenib in patients with HCC who were eligible for progression after at least first-line systemic therapy, 707 patients were randomly assigned in a 2:1 ratio to receive either cabozantinib (60 mg, QD) or placebo. OS was significantly longer in the cabozantinib group (10.2 months vs. 8.0 months, P=0.005). mPFS was 5.2 months vs. 1.9 months, respectively (P\<0.001); ORR was 4% and \<1%, respectively (P=0.009). A randomized, double-blind, placebo-controlled, global phase III clinical study of advanced HCC patients with elevated AFP after first-line failure of sorafenib enrolled 292 HCC patients with failed sorafenib and baseline AFP ≥ 400ng/ml who were randomized to receive either Ramucirumab (8mg/kg) or placebo in a 2:1 ratio. Compared with placebo, ramolutumab improved patients' mOS (8.5 months vs. 7.3 months, P=0.019 9) and mPFS (2.8 months vs. 1.6 months, P\<0.0001) and reduced the risk of death by 29%; while ORR was 4.6% and 1.1%, respectively (P=0.115 6).The CheckMate-040 study \[ 7\] opened a phase II study of a dual immune combination therapy strategy with Nivolumab in combination with Ipilimumab) for the second-line treatment of advanced HCC, enrolling patients with advanced HCC intolerant or progressing on sorafenib therapy, with 33% (16/49; 95% CI 20 to 48) responding to immune combination therapy; BICR was assessed according to RECIST v1.1 criteria, with 8% (4 /49) achieved CR and 24% (12/49) PR; DOR ranged from 4.6 months to 30.5 months, of which 88% lasted at least 6 months, 56% at least 12 months, and 31% at least 24 months. However, all of the above studies were done after failure of sorafenib alone, and there are no effective treatment options for progression beyond targeted combination immunotherapy. Due to the higher ORR of lenvatinib in combination with PD-1 antibody and the absence of risk of lethal bleeding, lenvatinib in combination with PD-1 antibody for advanced hepatocellular carcinoma is used by most physicians in real-world applications in China with good results, but there is no effective second-line treatment option for patients who fail lenvatinib in combination with PD-1 antibody, so our study explores whether lenalidomide can reverse lenvatinib patients who are resistant to lenvatinib in combination with PD-1 antibodies. The phase II clinical study by the Brown University Oncology Group showed that lenalidomide was used as second-line treatment for advanced hepatocellular carcinoma, with 6 of 40 patients (15%) having a partial response and 2 patients (5%) having progression-free survival of 36 and 32 months, respectively, with a median progression-free survival of 3.6 months and a median overall survival of 7.6 months. Lenalidomide is safe and effective in the treatment of patients with Child-Pugh A and B cirrhosis \[8\]. A study in Taiwan found lenalidomide to be active in patients with advanced HCC with a good safety profile. The remission rate of advanced HCC progressing on lenalidomide monotherapy with sorafenib was 13% and the disease control rate was 53%. the 6-month progression-free survival rate was 9.1%. Median progression-free survival and overall survival were 1.8 months and 8.9 months, respectively. Early AFP response was significantly associated with higher disease control (76% vs 22%, P=0.001) and longer progression-free survival (P=0.020) . A study showed that apatinib combined with lenalidomide for advanced primary hepatocellular carcinoma improved treatment outcome and quality of life, with an overall effective rate of 89.7% vs 79.6% in the apatinib combined with lenalidomide treatment group compared to the apatinib alone group, respectively (P\<0.01), while reducing the incidence of proteinuria, hypertension, hand-foot syndrome, diarrhea, and malaise. Lenalidomide, a new generation derivative of thalidomide, has dual anti-angiogenic and immunomodulatory antitumor effects . Lenalidomide binds to its substrate CRBN and forms a copolymer with ubiquitinase E3, which degrades lymphocyte development-related tumor factors IKZF 1 and IKZF 3 through ubiquitination. degradation of IKZF 1 inhibits the binding of downstream substrate IRF4 to Myc and its expression, thus achieving antitumor effects; degradation of IKZF3 factor promotes the proliferation of effector T cells and NK cells and induces the secretion of anti-tumor factors such as IFNγ by effector T cells and NK cells. The degradation of IKZF3 factor can promote the proliferation of effector T cells and NK cells, and can induce the secretion of anti-tumor factors such as IFNγ by effector T cells and NK cells. Recent studies have confirmed that lenalidomide can reverse PD-1 inhibitor resistance, and a study from the group of Cang Yong at the University of Science and Technology Shanghai found that PD-1 inhibitors require CD28 co-stimulatory receptors to promote CD8+ T cell activity and cytotoxicity. However, during depleted T cells and immune senescence, CD28 expression is frequently inactivated leading to PD-1 inhibitor resistance, which limits the antitumor efficacy of PD-1 immunotherapy. This study shows that lenalidomide restores the antitumor activity of cd28 -deficient CD8+ T cells after PD-1 resistance. Lenalidomide can target CRBN ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and release paracrine interleukin-2 (IL-2) and intracellular Notch signaling that are required to activate CD8+ T cells in tumors and inhibit tumor growth via PD-1 blockade. The findings suggest that PD-1 immunotherapy of solid tumors in a CD28- T cell infiltration-rich state could benefit from a combination of lenalidomide reversal of drug resistance. In view of the above, we believe that lenalidomide may have the potential to reverse drug resistance and increase efficacy with synergistic immune-targeted therapy. Based on its preliminary efficacy data in second-line treatment of advanced HCC alone or in combination with TKI, we propose to conduct a prospective, exploratory, single-arm, open, multicenter phase II clinical study of advanced HCC PD-1 inhibitor in combination with lenvatinib after progression to first-line therapy plus lenalidomide to preliminarily evaluate the efficacy and safety of this regimen.