This patient population has had low survival rates with available treatments.
Hepatocellular carcinoma (HCC) and bile duct cancer (cholangiocarcinoma) are the 2 primary types of adult primary liver cancer, with HCC at approximately 75% of liver cancers. HCC, the sixth most common cancer and the third leading cause of cancer-related deaths worldwide, typically develops in individuals with chronic liver disease caused by hepatitis virus infection or cirrhosis.1
With current treatment options, 5-year overall survival (OS) is generally low for patients with liver cancer2:
• OS (all stages): 17%
• OS (early stage, nonmetastatic): 31%
• OS (local metastasis): 11%
• OS (late stage, distant metastasis): 3%
Current treatment options include surgery, transplant, radiation, chemotherapy, and targeted therapy. However, recent clinical trials have demonstrated potential new options for patients with liver cancer. For example, in patients with unresectable HCC, a combination of the VEGFR2- targeted inhibitor rivoceranib (Apatinib; Elevar Therapeutics, Inc) and the PD-1 inhibitor camrelizumab (AiRuiKa; Jiangsu Hengrui Pharmaceuticals Co, Ltd) demonstrated a statistical improvement in both progression-free survival (PFS) and OS.
CARES-310 Phase 3 Trial
The phase 3 CARES-310 trial (NCT03764293) included 543 patients with unresectable HCC. The median age was 58 years, most patients were men (84%), and most were Asian (83%). The dosing was camrelizumab at 200 mg intravenously (IV) every 2 weeks plus rivoceranib at 250 mg orally once daily vs sorafenib (Nexavar; Bayer) 400 mg orally twice daily. At a median follow-up of 7.8 months, the trial results demonstrated a median PFS of 5.6 months with the combination vs 3.7 months with sorafenib (HR, 0.52; 95% CI, 0.41-0.65; P < .0001). At a median follow-up of 14.5 months, the median OS was 22.1 months with camrelizumab plus rivoceranib compared with 15.2 months with sorafenib (HR, 0.62; 95% CI, 0.49-0.80; P < .0001).3 The objective response rate (ORR) in the camrelizumab plus rivoceranib group was 25% compared with 6% in the sorafenib group (P < .0001), whereas the median duration of response (DOR) was 14.8 months vs 9.2 months, respectively, with a median time to response of 1.9 months and 3.7 months.
Toxicities are a notable source of concern with the camrelizumab plus rivoceranib combination. In CARES-310, grade 3 or greater treatment-related adverse events (TRAEs) occurred in 81% of patients treated with the combination vs 52% in those treated with sorafenib. Serious TRAEs were reported in 24% and 6%, respectively. TRAEs that led to discontinuation occurred in 24% of patients in the combination group and 4% in the sorafenib group, and dose reductions occurred in 47% and 32%, respectively.3
Elevar Therapeutics has stated that the FDA has accepted a new drug application for rivoceranib in combination with camrelizumab as a frontline treatment for patients with unresectable HCC and has set a Prescription Drug User Fee Act date of May 16, 2024.4
There are 2 types of bile duct cancer: intrahepatic bile duct cancer and extrahepatic bile duct cancer. Risk factors for bile duct cancer include primary sclerosing cholangitis, chronic ulcerative colitis, bile duct cysts, or infection with a Chinese liver fluke parasite.1
There are 2 clinical trials underway studying novel targeted anti-HER2 drugs, and there are promising results in the treatment of HER2-positive biliary tract cancers in pretreated patients with advanced disease.
HERIZON-BTC-01 Phase 2b Trial
Zanidatamab (ZW25; Zymeworks Inc) is an investigational bispecific monoclonal antibody that targets 2 distinct HER2 epitopes. From September 2020 to March 2022, the phase 2b HERIZON-BTC-01 trial (NCT04466891) enrolled 87 patients with locally advanced or metastatic HER2-amplified biliary cancers across 32 sites in Asia, Europe, North America, and South America. Patients received zanidatamab at an IV dose of 20 mg/kg every 2 weeks.
Of 80 patients who were treatment refractory, an ORR of 41.3% (95% CI, 30.4-52.8) was reported. On central review, partial responses were recorded in 32 patients (40%), as was 1 complete response (1.3%). Another 22 patients (28%) had stable disease, leading to a disease control rate (DCR) of 69%. Investigator-assessed responses were similar overall but showed more complete responders. The median DOR per central review reached 12.9 months, and the median time to response was 1.8 months. The median PFS was 5.5 months, whereas the median OS data were not mature. The OS rate at 9 months was 70%.
Zanidatamab had a manageable and tolerable safety profile with AEs that included mostly low-grade diarrhea and infusion site reactions that were reversible. Serious TRAEs were reported in 8.8%, and 2.5% stopped treatment owing to drug-related toxicity. Grade 3 or greater TRAEs occurred in 19%, and no deaths were deemed related to treatment.5-7
SGNTUC-019 Phase 2 Trial
The phase 2 SGNTUC-019 trial (NCT04579380) included 30 pretreated patients with HER2-positive biliary tract cancer. All patients received at least 1 dose of oral tucatinib (Tukysa; Seagen Inc) and IV trastuzumab-dttb (Ontruzant; Organon). The median follow-up was 10.8 months.
Participants had a median age of 68.5 years, 50% were men, and most were Asian (77%). Patients had a median of 2 prior lines of therapy for their metastatic disease, with most (60%) having been initially diagnosed with stage IV disease. The median PFS and OS were 5.5 months (90%; 3.9-8.1) and 15.5 months (90%; 6.5-16.7), respectively. One complete response (3.3%) was observed in the trial, along with 13 partial responses (43.3%), with a median time to response of 2.1 months and a DOR of 6.0 months (90% CI, 5.5-6.9). There were also 9 cases of stable disease (30%) following treatment with the combination, yielding a DCR of 76.7%. Overall, 70% of patients had some degree of reduction in tumor burden. Grade 3 or greater TRAEs included nausea, decreased appetite, and cholangitis in 3 patients (10%); diarrhea, anemia, increased alanine aminotransferase and aspartate aminotransferase levels in 2 patients (6.7%); and fatigue, hyponatremia, increases in blood creatinine, COVID-19, and abnormal hepatic function in 1 patient each (3.3%).6,7
These clinical trials show promise in the potential to expand treatment options for patients with liver cancer, which has historically been a disease with limited treatment options and low 5-year survival rates. As opportunities for treatment expands, further data may begin to shed light on precision medicine approaches for treatment of this patient population.
1. Liver and bile duct cancer. National Cancer Institute. Accessed August 7, 2023. https://www.cancer.gov/types/liver
2. Liver cancer: your chances for recovery (prognosis). Saint Luke’s Cancer Center. Accessed August 7, 2023. https://www.saintlukeskc.org/health-library/liver-cancer-your-chances-recovery-prognosis
3. Bassett M. Novel combination boosts survival in unresectable liver cancer. MedPage Today. July 28, 2023. Accessed July 28, 2023. https://www.medpagetoday.com/hematologyoncology/othercancers/105686?xid=nl_mpt_Oncology_update_2023-08-01&eun=g1549746d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Automated%20Specialty%20Update%20Oncology%20BiWeekly%20TUESDAY%202023-08-01&utm_term=NL_Spec_Oncology_Update_Active
4. Elevar Therapeutics announces FDA acceptance for filing of new drug application for rivoceranib in combination with camrelizumab as a first-line treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics, Inc. July 17, 2023. Accessed August 29, 2023.https://elevartherapeutics.com/2023/07/17/elevar-therapeutics-announces-fda-acceptance-for-filing-of-new-drug-application-for-rivoceranib-in-combination-with-camrelizumab-as-a-first-line-treatment-for-unresectable-hepatocellular-carcinoma/
5. Harding JJ, Fan J, Oh DY, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi:10.1016/S1470-2045(23)00242-5
6. Nakamura Y, Mizuno N, Sunakawa Y, et al. Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): a phase 2 basket study. J Clin Oncol. 2023;41(suppl 16):4007. doi:10.1200/JCO.2023.41.16_suppl.4007
7. Ingram I. Novel anti-HER2 drugs ‘impressive’ in advanced biliary cancer. MedPage Today. Updated June 4, 2023. Accessed July 29, 2023. https://www.medpagetoday.com/meetingcoverage/asco/104830
About the Author
Douglas Braun, PharmD, RPh, CPH, CSP, is the senior pharmacy director at the American Oncology Network, LLC, in Fort Myers, Florida.