Emerging Therapies and Precision Medicine Offer Promising Results in Hepatocellular Carcinoma and Biliary Tract Cancer

Hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) are challenging malignancies, with rising incidences and poor survival outcomes. Traditionally, treatment options have been limited and prognosis has remained poor, particularly for advanced-stage disease. However, recent innovations in therapeutic approaches are transforming the treatment landscape for HCC and BTC.

Hepatocellular Carcinoma

HCC, the most common form of primary liver cancer, often occurs in the context of chronic liver disease, particularly cirrhosis and hepatitis B or C infections.¹ HCC is a significant global health challenge due to its rising incidence and poor prognosis.

Previously, sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals) was the only systemic therapy option for patients with advanced disease. However, recent advances have brought new hope for patients through innovative therapies, improved diagnostic techniques, and precision medicine approaches.

One of the recent advancements in HCC treatment is the use of targeted therapy combinations. For example, since the success of the IMbrave150 trial (NCT03434379), the combination of atezolizumab (Tecentriq; Genentech), a PD-L1 inhibitor, and bevacizumab (Avastin; Genentech), an anti-VEGF antibody, has become a preferred first-line systemic treatment regimen for advanced HCC. The median progression-free survival (PFS) was 6.8 months with combination therapy compared with 4.3 months with sorafenib, whereas the safety profile remained consistent.2 Overall survival (OS) rate at 12 months was 67.2% with the combination therapy and 54.6% with sorafenib.² In addition, tremelimumab-actl (Imjudo; AstraZeneca), an anti–CTLA-4 antibody, in combination with durvalumab (Imfinzi; AstraZeneca), an anti–PD-1 antibody, can also be used as a preferred first-line systemic treatment regimen for patients with unresectable HCC, based on findings from the HIMALAYA study (NCT03298451).³ The median OS for tremelimumab in combination with durvalumab was 16.43 months compared with 13.77 months for sorafenib.3 Overall, findings from these studies showed improvements in OS compared with traditional therapies such as sorafenib.

The LEAP-002 study (NCT03713593) evaluated the effectiveness of combination lenvatinib (Lenvima; Eisai, Merck), a multikinase inhibitor, with pembrolizumab (Keytruda; Merck), an anti–PD-1 antibody, in first-line HCC.⁴ Although the lenvatinib and pembrolizumab combination did not meet the coprimary end points of PFS and OS, it demonstrated a median OS of 21.2 months, one of the longest among first-line treatments in phase 3 trials.⁴ In turn, this may provide a new treatment option for patients.

There have also been recent advancements in diagnostic techniques for HCC. For example, liquid biopsies are revolutionizing early detection and monitoring. Circulating tumor DNA and specific microRNAs have emerged as biomarkers for early diagnosis, prognosis, and assessment of treatment response.⁵ With the number of clinical trials for HCC on the rise and new developments in treatment options, there will be much to come in the treatment landscape and sequencing of these treatment options.

Biliary Tract Cancer

BTC is an aggressive malignancy associated with poor survival outcomes. Although the disease is relatively rare, it has a high incidence of morbidity and mortality, with cholangiocarcinoma (CCA) being the most common. The disease can be categorized into intrahepatic, perihilar, and distal CCA, each with distinct inflammation, genetic mutations, and environmental factors.^6,7

For many years, the combination of gemcitabine and cisplatin has been considered the standard first-line therapy for advanced biliary cancer. This regimen remains the standard of care (SOC), providing improvement in survival benefits. Over the past few years, there have been developments and advancements in biliary cancer management. One of the most significant advancements in biliary cancer treatment is the introduction of immunotherapy. In the TOPAZ-1 trial (NCT03875235), the addition of durvalumab to SOC significantly improved OS in patients with advanced biliary tract cancer.⁸ Patients treated with the combination therapy experienced a median OS of 12.8 months compared with 11.5 months with chemotherapy alone, with a tolerable safety profile.⁸ Based on the results, the combination of cisplatin, gemcitabine, and durvalumab is recommended as the preferred first-line treatment for unresectable and metastatic biliary tract cancer.⁸ Of note, the combination of pembrolizumab, gemcitabine, and cisplatin is also a preferred first-line treatment regimen based on findings from the KEYNOTE-966 study (NCT04003636). The KEYNOTE-966 study findings showed an overall median survival of 12.7 months for the pembrolizumab group compared with 10.9 months in the placebo group.⁹

Approximately 40% of patients with biliary cancer carry genetic alterations, such as NTRK gene fusions, RET gene fusions, IDH1 mutations, or FGFR2 fusions, that could be targeted through precision medicine.¹⁰ Due to this prevalence, molecular analysis is recommended to be performed prior to or during first-line therapy to identify treatment options as early as possible in advanced disease.

More recent targeted therapy options in this setting include FGFR2 inhibitors. Pemigatinib has been approved for patients with FGFR2 fusion–positive CCA who have experienced progression after more than 1 line of systemic therapy. Futibatinib, a highly selective FGFR2 inhibitor, has shown clinical efficacy in patients with CCA who have been previously treated.¹¹

When it comes to novel targeted therapies in BTC, in the HERIZON-BTC-01 trial (NCT04466891), zanidatamab (ZW25; Zymeworks, Jazz Pharmaceuticals), a bispecific HER2-targeted antibody, has demonstrated early efficacy in patients with HER2-positive BTC. In findings from clinical trials, zanidatamab achieved a median OS of 18.1 months in patients with tumors overexpressing HER2 (immunohistochemistry score of 3+). This therapy, combined with standard chemotherapy, is currently being evaluated in phase 3 clinical trials to further determine its safety and efficacy.¹²

Conclusion

The treatment landscape of HCC and BTC has seen significant advancements with the introduction of novel combination therapies and precision medicine approaches. As research continues to evolve, the future of HCC and BTC management looks increasingly promising, with the potential for further improvements in survival outcomes and quality of life for patients.

REFERENCES

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