Novel Combinations Flood the Frontline Treatment Landscape in Advanced HCC

Combinations of checkpoint inhibitors and VEGF TKIs, as well as dual checkpoint blockade, are affording patients with advanced hepatocellular carcinoma (HCC) greater potential for disease control and deep, long-lasting responses, underscoring the need for biomarkers of response to combination regimens and single-agent TKIs, the latter of which still play a role for select populations, according to Anthony El-Khoueiry, MD.

“For long time, sorafenib [Nexavar], the multitargeted tyrosine kinase inhibitor [TKI], was the only standard therapy for advanced HCC based on 2 international trials that showed its superiority compared with placebo in previously advanced and untreated HCC patients,” said El-Khoueiry, an associate professor of clinical medicine at the Keck School of Medicine, USC Norris Comprehensive Cancer Center, in a virtual presentation during the 2021 HCC-TAG Conference.

Sorafenib led to a median overall survival (OS) of approximately 10 months, and it was not until 2017 that an agent showed comparable activity in the frontline setting. In the phase 3 REFLECT trial, lenvatinib (Lenvima) was found to be noninferior to sorafenib as frontline therapy in patients with unresectable HCC, eliciting a median OS of 13.6 months vs 12.3 months with sorafenib (HR, 0.92; 95% CI, 0.79-1.06).¹

Of note, lenvatinib demonstrated a doubling in progression-free survival (PFS; 7.4 vs 3.7 months; HR, 0.66; 95% CI, 0.57-0.77; P <.00001) and almost a tripling in objective response rate (ORR) compared with sorafenib (24.1% vs 9.2%; odds ratio, 3.13; 95% CI, 2.15-4.56; P <.00001).

Real-world [utilization of lenvatinib] reflect the data reported in the REFLECT study, said El-Khoueiry, which has been inclusive of patients with Child-Pugh B disease and main portal invasion.

“If a patient has preserved liver function but contraindications to checkpoint inhibitors, we would treat with single-agent sorafenib or lenvatinib based on level 1 evidence,” said El-Khoueiry. “A patient with well-preserved liver function with bevacizumab [Avastin] contraindications, such as recent bleeding, recent arterial thrombotic events, or risk of perforation, will likely be treated with single-agent TKIs.”

“For patients with Child-Pugh B liver disease or poor performance status, single-agent sorafenib may be a reasonable option given that it has safety data and some single-arm efficacy data in Child-Pugh B disease,” added El-Khoueiry.

In terms of combinations, the pairing of atezolizumab (Tecentriq) and bevacizumab demonstrated an unprecedented improvement in OS in patients with locally advanced or metastatic HCC in the phase 3 IMbrave150 trial. According to an updated data set from the study presented during the 2021 Gastrointestinal Cancers Symposium, the combination, which has been heralded as the new frontline standard of care in this population, led to a median OS of 19.2 months vs 13.4 months with sorafenib (HR, 0.66; 95% CI, 0.52-0.85; P =.0009). The 18-month survival rates were 52% and 40%, respectively.²

The median PFS was 6.9 months vs 4.3 months, respectively (HR, 0.65; 95% CI, 0.53-0.81; P = .0001). The 18-month PFS rates were 24% vs 12%, respectively.

Moreover, the disease control rate (DCR) was 74% with the combination vs 55% with sorafenib, and 56% vs 28% of patients had an ongoing response at the time of data cutoff, respectively.

“Regarding follow-up systemic therapy, a higher proportion of patients in the sorafenib arm had 1 or more later lines of therapy, and 26% of patients had immunotherapy as a subsequent line of therapy. Despite that, the OS difference remained quite significant,” said El-Khoueiry.

“If a patient with advanced HCC has well-preserved liver function and no contraindications to bevacizumab or checkpoint inhibitors, the current standard of care is the combination of atezolizumab and bevacizumab,” added El-Khoueiry.

Another combination that has been evaluated in the frontline setting is lenvatinib (Lenvima) plus pembrolizumab (Keytruda). In a phase 1b study (NCT03006926) of 100 patients, the combination led to an ORR of 36% and a DCR of 88%.³ The median PFS was 8.6 months, and the median OS was 22.0 months.

The combination has since been taken forward into the phase 3 LEAP-002 trial in which 750 patients with Child-Pugh A advanced HCC will be randomized to lenvatinib once daily plus 200 mg of intravenous (IV) pembrolizumab every 3 weeks or lenvatinib plus placebo.

Pembrolizumab has also been paired with regorafenib (Stivarga) and, in a phase 1b study (n = 31), showed an ORR of 26% and a DCR of 90%.⁴ However, regorafenib was given at a dose of 120 mg, leading to a high rate of treatment interruptions and dose modifications. When investigators evaluated a lower dose of 80 mg of regorafenib, a lower rate of treatment interruptions and dose modifications were seen.

The combination of atezolizumab and cabozantinib (Cabometyx) has also garnered significant interest as a potential frontline combination and is under study in the phase 3 COSMIC-312 (NCT03755791) trial. In the study, approximately 740 patients with Child-Pugh A advanced HCC will be randomized to 40 mg of cabozantinib once daily plus 1200 mg of IV atezolizumab every 3 weeks, 400 mg of sorafenib twice daily, or 60 mg of cabozantinib once daily.

In terms of dual immunotherapy approaches, combined PD-1 and CTLA-4 inhibitors reside at the forefront of research because they elicit complementary but distinct mechanisms that affect the immune microenvironment, explained El-Khoueiry.

To that end, the phase 3 CheckMate 9DW trial (NCT04039607) is evaluating the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) vs sorafenib or lenvatinib in patients with Child-Pugh 5 or 6 advanced HCC. In the phase 2 CheckMate 040 trial (n = 50), the combination of nivolumab at a dose of 1 mg/kg and ipilimumab at a dose of 3 mg/kg led to a median OS of 22.8 months, an ORR of 32%, and a DCR of 54% in a sorafenib-pretreated population.⁵

Durvalumab (Imfinzi) plus tremelimumab is also under study in the frontline setting in the phase 3 HIMALAYA trial (NCT03298451). In the trial, patients with Child-Pugh A advanced HCC will be randomized to 1 of 4 arms: durvalumab alone, durvalumab plus tremelimumab (regimen 1), durvalumab plus tremelimumab (regimen 2), or sorafenib alone. In the phase 2 Study 22 trial, the combination of 300 mg of tremelimumab and 1500 mg of durvalumab elicited a median OS of 18.73 months, an ORR of 24.0%, and a DCR of 45.3% in a sorafenib-pretreated population.⁶ 

In conclusion, El-Khoueiry stated, “biomarkers are needed and may allow for a more tailored approach where we may be able to spare patients exposure to unnecessary toxicity or hopefully to select the best combination for a patient.”

References

1. Cheng AL, Finn RS, Han KH, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35(suppl 15):4001. doi:10.1200/JCO.2017.35.15_suppl.4001
2. Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(suppl 3):267. doi:10.1200/JCO.2021.39.3_suppl.267
3. Zhu AX, Finn RS, Ikeda M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2021;38(suppl 15):4519. doi:10.1200/JCO.2020.38.15_suppl.4519
4. El-Khoueiry AB, Kim RD, Harris WP, et al. Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(suppl 4):564. doi:10.1200/JCO.2020.38.4_suppl.564
5. Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564
6. Kelley RK, Sangro B, Harris WP, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol. 2020;38(suppl 15):4508. doi:10.1200/JCO.2020.38.15_suppl.4508