Mitesh J. Borad, MD

Although first-line treatment options for advanced hepatocellular carcinoma (HCC) include lenvatinib (Lenvima) and sorafenib (Nexavar), targeted therapies alone or in combination have demonstrated improved overall survival (OS) in some clinical trials. Mitesh J. Borad, MD, program leader of the Gene and Virus Therapy Program in the Department of Oncology (Medical) at the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, compared first-line systemic approaches in a presentation during the 2023 National Comprehensive Cancer Network Annual Conference in Orlando, Florida.¹

Sorafenib gained approval in 2008 based on findings from the SHARP study (NCT00105443).² In the double-blind, placebo-controlled trial, 602 patients with advanced HCC who had not received systemic therapy were randomly assigned to receive 400 mg of sorafenib twice daily vs placebo.² The trial was stopped after a planned interim analysis showed a statistically significant advantage in OS for patients who had received sorafenib. Investigators concluded that median survival and time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than those who received placebo.²

Similarly, in a study (NCT00492752) conducted in the Asia-Pacific region, patients with HCC who had not received previous systemic therapy and had Child-Pugh class A liver disease were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period.³ Patients in the treatment arm demonstrated an OS of 6.5 months (95% CI, 5.56-7.56) vs 4.2 months (95% CI, 3.75-5.46) for patients who received placebo (HR, 0.68; 95% CI, 0.50-0.93; P=.014).

“In both of these studies, there was improvement in overall survival ranging from 2 to 3 months,” Borad said. “There was some improvement in progression-free survival [PFS], and response rates were modest even though there was some improvement, ranging from 2% to 3% in these studies.”

The next kinase inhibitor to gain approval, lenvatinib, gained approval based on efficacy findings from the REFLECT study (NCT01761266).⁴ REFLECT was a noninferiority trial with a primary end point of OS and secondary end points of efficacy and other safety end points. Investigators reported an OS of 13.6 months in the treatment arm (95% CI, 12.1-14.9) vs 12.3 months with sorafenib (95% CI, 10.4-13.9), demonstrating noninferiority of lenvatinib to sorafenib (HR, 0.92; 95% CI, 0.79-1.06).

Borad noted similar toxicities between the 2 agents based on their similar mechanisms of action, with somewhat higher instances of hypertension and palmar-plantar erythrodysesthesia for sorafenib compared with lenvatinib.⁴ Cases of hypothyroidism were greater for lenvatinib vs sorafenib.

Immune Checkpoint Inhibitors

The IMbrave150 study (NCT03434379) evaluated atezolizumab (Tecentriq) and bevacizumab (Avastin) vs sorafenib in 501 patients with unresectable HCC who had not previously received systemic therapy.⁵ The patients were randomly assigned 2:1 (336 patients in the treatment arm vs 165 patients in the control arm).

At 12 months, the OS rate was 67.2% (95% CI, 61.3%-73.1%) in the atezolizumab-bevacizumab arm vs 54.6% (95% CI, 45.2%-64.0%) in the sorafenib arm. Investigators reported the PFS was 6.8 months (95% CI, 5.7-8.3) and 4.3 months (95% CI, 4.0-5.6), respectively (HR, 0.59; 95% CI, 0.47-0.76; P<.001).5 They concluded that the combination of atezolizumab and bevacizumab led to better OS and PFS outcomes compared with sorafenib. Response rates in the treatment arm were 27% to 33% compared with the control arm, which were 12% to 13%.

“This is quite remarkable given that these are patients [with advanced metastatic disease],” Borad said. “What will be important in immunotherapy, of course, is not these initial responses but how durable they are in patients who are 1-, 2-, and 3-year survivors.” Regarding autoimmune toxicities in immunotherapies, “the ones to look out for would be toxicities in the liver, so AST [aspartate transferase] and ALT [alanine transaminase] elevations that occur during the course of treatment are important, especially in the first few months, in order to intervene in a timely manner,” Borad said.

Dual Checkpoint Inhibition

The use of dual checkpoint inhibitors has also been explored, Borad said. The phase 3 HIMALAYA study (NCT03298451) evaluated the efficacy and safety of durvalumab (Imfinzi) and tremelimumab (Imjudo) vs sorafenib in patients with no prior systemic therapy for unresectable HCC.⁶ The combination demonstrated a significant improvement in OS compared with sorafenib in the front line.

A total of 1171 patients were randomly assigned to receive the combination of durvalumab plus tremelimumab (n=393), durvalumab alone (n=389), or sorafenib alone (n=389). Those enrolled within the trial were randomly assigned to 300 mg of tremelimumab for 1 dose plus 1500 mg of durvalumab every 4 weeks, 1500 mg of durvalumab every 4 weeks, 400 mg of sorafenib twice daily, or 75 mg of tremelimumab plus 1500 mg of durvalumab every 4 weeks.

Patients who received durvalumab and tremelimumab showed a significant improvement in OS vs sorafenib (HR, 0.78; 96% CI, 0.65-0.92; P=.0035). Additionally, patients treated with durvalumab monotherapy demonstrated a noninferior OS vs sorafenib (HR, 0.86; 96% CI, 0.73-1.03).

The median OS was reported as 16.4 months (95% CI, 14.2-19.6) with durvalumab/tremelimumab, 16.6 months (95% CI, 14.1-19.1) with durvalumab, and 13.8 months (95% CI, 12.3-16.1) with sorafenib. The median follow-up was 16.1 months in the durvalumab/tremelimumab arm, 16.5 months in the durvalumab arm, and 13.3 months in the sorafenib arm.

To conclude, Borad said that “both sorafenib and lenvatinib still remain clinically available options for a subset of patients. The combination [of] atezolizumab and bevacizumab or durvalumab and tremelimumab are more contemporary options given their superiority over sorafenib and lenvatinib. And lenvatinib and durvalumab could be considered single-agent therapies.”

References

1. Borad MJ. Updates in the management of hepatobiliary cancers. Presented at: 2023 National Comprehensive Cancer Network Annual Conference; March 31-April 2, 2023; Orlando, FL.

2. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

3. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7

4. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

5. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

6. Abou-Alfa GK, Lau G, Kudo M, et al; HIMALAYA Investigators. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):1-12. doi:10.1056/EVIDoa2100070