Editor's Note: The treatment of advanced hepatocellular carcinoma (HCC) has entered the era of targeted and immunotherapy, with combined regimens becoming the first-line standard. More combination therapies are still under exploration. At the recently concluded 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the CheckMate 9DW study announced positive results for the dual immunotherapy of anti-PD-L1 and anti-CTLA-4, positioning this "double star" regimen as a potential first-line treatment. Additionally, the conference revealed results from the first Phase II clinical trial of an immune checkpoint inhibitor (ICI) combined with a tyrosine kinase inhibitor (TKI) as a second-line treatment following failure of first-line immunotherapy. Chinese researchers also reported on a Phase I clinical trial of a specific autologous armored-CAR-T cell therapy.Nivolumab Combined with Ipilimumab vs Lenvatinib or Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: Initial Results from the CheckMate 9DW Study
Background: PD-L1 inhibitors have become the standard of care (SOC) for first-line treatment of unresectable hepatocellular carcinoma (uHCC), showing better efficacy compared to sorafenib (SOR). However, patient prognosis remains poor, necessitating alternative therapies with long-term benefits. The CheckMate 040 study showed that nivolumab (NIVO) + ipilimumab (IPI) as second-line treatment for HCC patients who had received SOR had clinically meaningful efficacy and manageable safety, leading to accelerated approval in the US. Here, we report the preliminary results from the pre-specified interim analysis of the Phase III, open-label, randomized clinical trial CheckMate 9DW, which evaluates the efficacy and safety of NIVO + IPI versus lenvatinib (LEN) or SOR as first-line treatment in treatment-naïve HCC patients (NCT04039607).
Methods: Adult HCC patients who had not received prior treatment, were unsuitable for curative surgery or local-regional therapy, had a Child-Pugh score of 5-6, and an ECOG performance status score of 0-1 were enrolled. Patients were randomized (1:1) to receive either NIVO 1 mg/kg + IPI 3 mg/kg every three weeks (up to four cycles), followed by NIVO 480 mg every four weeks, or LEN 8 mg or 12 mg daily, or SOR 400 mg twice daily until disease progression or unacceptable toxicity. NIVO treatment was administered for up to two years. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST v1.1.
Results: A total of 668 patients were randomized to the NIVO + IPI group (n=335) or the LEN/SOR group (n=333); of the 325 patients treated in the LEN/SOR group, 275 (85%) received LEN.
After a median follow-up of 35.2 (range, 26.8–48.9) months, the median OS was 23.7 months for the NIVO + IPI group compared to 20.6 months for the LEN/SOR group (HR 0.79; 95% CI: 0.65-0.96; P=0.0180). The 24-month OS rates were 49% (44%-55%) and 39% (34%-45%) for the NIVO + IPI and LEN/SOR groups, respectively. The ORR was higher in the NIVO + IPI group (36% vs. 13%; P < 0.0001); complete responses (CR) were observed in 7% of the NIVO + IPI group compared to 2% in the LEN/SOR group. The median DOR was 30.4 months for the NIVO + IPI group versus 12.9 months for the LEN/SOR group.
Grade 3/4 treatment-related adverse events (TRAEs) occurred in 41% and 42% of the NIVO + IPI and LEN/SOR groups, respectively; serious TRAEs occurred in 28% and 14%; and discontinuation rates were 18% and 10%, respectively.
Conclusion: NIVO + IPI demonstrated statistically significant OS benefits, higher ORR, and more durable responses compared to LEN/SOR for treatment-naïve uHCC patients, with manageable safety profiles. These results support NIVO + IPI as a potential new first-line standard treatment for advanced HCC.
Phase II Study of Regorafenib Plus Pembrolizumab in Advanced Hepatocellular Carcinoma Patients Previously Treated with Immune Checkpoint Inhibitors
Background: The optimal second-line treatment for advanced HCC patients who progress after initial ICI therapy remains undetermined. Regorafenib is approved for use after sorafenib in advanced HCC. This study primarily evaluated the efficacy of regorafenib combined with pembrolizumab in advanced HCC patients who had progressed after initial ICI therapy.
Methods: Patients aged 18 and older, with Child-Pugh class A, BCLC stage B or C, and ECOG PS of 0 or 1, received oral regorafenib 90 mg daily (3 weeks on/1 week off) and intravenous pembrolizumab 400 mg every 6 weeks. Regorafenib’s daily dose could be increased to 120 mg after the first 4-week cycle if tolerated. Pembrolizumab dose reduction was not allowed. Patients were divided into two cohorts based on prior ICI treatment: cohort 1 = atezolizumab + bevacizumab; cohort 2 = any other ICI regimen (alone or combined). The primary endpoint was ORR by independent central review (RECIST 1.1).
Results: 95 patients from 8 countries were included; cohort 2 had more favorable disease characteristics. The most common prior ICIs in cohort 2 were durvalumab (30%), NIVO (30%), IPI (22%), and pembrolizumab (19%).
With a median follow-up of 7.1 months, cohort 1 had shorter median treatment durations (including interruptions/delays) than cohort 2 (11.0/9.4 weeks vs. 21.4/24.1 weeks). ORR was 5.9% in cohort 1 and 11.1% in cohort 2; stable disease (SD) rates were 48.5% and 63.0%. Median PFS was 2.8 months for cohort 1 and 4.2 months for cohort 2. OS was not reached in either cohort.
Overall, 56% of patients experienced grade 3 TEAEs, and 5% experienced grade 4 TEAEs; drug-related grade 3 and 4 TEAEs occurred in 37% and 3% of patients, respectively. One patient in cohort 1 experienced a grade 5 drug-related TEAE (cardiac arrest). The most common drug-related TEAEs were hand-foot skin reaction (39%), fatigue (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarker assessment of paired biopsy tissues showed decreased macrophage and angiogenesis RNA markers during treatment.
Conclusion: This is the first prospective trial evaluating kinase inhibitors plus ICIs as second-line therapy following first-line ICI therapy in HCC patients. Regorafenib combined with pembrolizumab showed moderate efficacy as second-line therapy. The safety profile was consistent with each drug’s known safety. The optimal treatment for advanced HCC patients progressing after first-line ICI therapy remains an unmet need.
Phase I Study of Specific Autologous Armored-CAR-T Cell Therapy C-CAR031 in Patients with Advanced Hepatocellular Carcinoma
Background: Glypican-3 (GPC3) is overexpressed in HCC but rarely in healthy tissues. Targeting GPC3 with chimeric antigen receptor (CAR) T cells offers a promising option for treating advanced unresectable HCC. C-CAR031 is an autologous CAR-T cell therapy targeting GPC3, equipped with a dominant negative TGF-β receptor II. This report covers the safety and preliminary efficacy of C-CAR031 in advanced HCC patients.
Methods: This first-in-human, open-label dose-escalation trial used an accelerated titration with an i3+3 design. GPC3-positive advanced HCC patients who failed first-line systemic therapy received standard lymphodepletion followed by a single intravenous infusion of C-CAR031. Primary endpoints were safety and tolerability; secondary endpoints included pharmacokinetics and preliminary efficacy. Adverse events (AEs) were graded by CTCAE 5.0, cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were evaluated by ASTCT 2019 criteria, and objective responses were assessed by investigators using RECIST 1.1.
Results: As of January 5, 2024, 24 patients received C-CAR031 across four dose levels (DLs). All patients had BCLC stage C HCC, with 83.3% (20/24) having extrahepatic metastases. The median number of prior treatment lines was 3.5 (range: 1-6), with 95.8% (23/24) having received ICIs and TKIs.
All patients were evaluable for safety. No dose-limiting toxicities or ICANS were observed. CRS was observed in 91.7% (22/24) of patients, with only 1 (4.2%) experiencing grade 3 CRS. The most common ≥grade 3 AEs were lymphopenia (100%), neutropenia (70.8%), thrombocytopenia (37.5%), and elevated transaminases (16.7%). At DL4, 1 patient (4.2%) experienced grade 4 myelosuppression, and 1 patient (4.2%) had grade 3 interstitial pneumonia due to grade 3 CRS. All AEs were reversible.
22 patients were evaluable for efficacy. Tumor reduction was observed in 90.9% of patients, including both intrahepatic and extrahepatic lesions, with a median reduction of 42.2% (range: 3.4%-94.4%). The disease control rate was 91.3%, and the ORR was 56.5%; at DL4, the ORR was 75.0%.
Conclusion: The study shows that C-CAR031 has manageable safety characteristics and encouraging anti-tumor activity in heavily pretreated advanced HCC patients.
References:
- Peter Robert Galle, Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. J Clin Oncol 42, 2024 (suppl 17; abstr LBA4008)
- Anthony B. El-Khoueiry, et al. International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI). J Clin Oncol 42, 2024 (suppl 16; abstr 4007)
- Qi Zhang, Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 42, 2024 (suppl 16; abstr 4019)
