Clear Efficacy Benefit Not Shown With Atezolizumab/Bevacizumab Versus Lenvatinib in Unresectable HCC

Utilizing a network meta-analysis to compare multiple studies looking at atezolizumab (Tecentriq) and bevacizumab (Avastin) compared to Lenvatinib (Lenvima) researchers did not find direct evidence, but their exploratory analysis suggests that the benefit of the combination therapy is not statistically significant for patients with unresectable hepatocellular carcinoma (HCC), according to results presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting.¹

Looking at the phase 3 IMbrave 150 trial (NCT03434379), phase 3 REFLECT trial (NCT01761266), phase 3 SHARP trial (NCT00105443), and the Asia-Pacific arm of the SHARP trial, researchers found that the estimated median hazard ratio (HR) for the combination of atezolizumab and bevacizumab compared to lenvatinib was .81 (95% CrI: 0.61, 1.08; posterior P = .078) for overall survival (OS). When looking at progression-free survival (PFS), the median HR was 0.99 (95%CrI: 0.76, 1.28; posterior P = .454) between atezolizumab and bevacizumab compared to lenvatinib.

According to the researchers, this was similar to results observed in another analysis that showed an OS HR of .63 (95% CI: 0.32-1.25) and PFS HR of .91 (95% CI: 0.23-3.65) when comparing atezolizumab and bevacizumab and lenvatinib in this patient population.²

The results from the network meta-analysis presented at ASCO fell within the Bayesian range of equivalence, according to researchers. This range was defined as the upper limits of credible intervals greater than or equal to 1 for both OS and PFS results. Moreover, the results among all observed studies were subject to a high degree of uncertainty when compared in the network meta-analysis.

The network meta-analysis was based on a de novo systematic literature review that identified evidence for licensed therapies in the first-line setting of treatment for patients with unresectable HCC. Data from the IMbrave 150 trial was supplemented from clinical cut-off data from August 31st, 2020, while HRs for OS and PFS was taken from a multivariable analysis that adjusted imbalances in baseline prognostic covariates from the REFLECT trial. Model selection was based on deviance information criterion and all analyses were conducted in the Bayesian generalized linear model framework.

The IMbrave150 trial ultimately resulted in improved OS and PFS for patients with unresectable HCC on atezolizumab and bevacizumab compared to those patients on sorafenib (Nexavar).³ Researchers saw an OS of 12 months in 67.2% (95% CI: 61.3-73.1) of patients on the combination arm compared to 54.6% (95% CI: 45.2-64.0) on sorafenib. Median PFS was also higher in the combination arm at 6.8 months (95% CI: 5.7-8.3) compared to 4.3 months (95% CI: 4.0-5.6) in the monotherapy arm. The HR for disease progression or death in both groups was .59 (95% CI: 0.47-0.76; P < 0.001).

In the REFLECT trial, researchers looked at lenvatinib compared to sorafenib in patients with unresectable HCC and found a median OS of 17.6 months for lenvatinib versus 17.8 months for sorafenib (HR .90; 95% CI: 0.62-1.29) among 954 patients in a global trial. Moreover, Lenvatinib showed a statistically significant improvement over sorafenib with 7.2 months vs. 4.6 months PFS, respectively.⁴

Previously, sorafenib was the first-line treatment for patients with unresectable HCC but these recent results have shown meaningful results for lenvtainib and the combination of atezolizumab and bevacizumab as a first-line option. However, these data presented at ASCO did not indicate which treatment had a statistically significant advantage over the other, thus, researchers consider this an exploratory analysis. This analysis was done in the absence of a head-to-head analysis of the combination and monotherapy and wanted to compare the efficacy of first line treatments for patients with unresectable HCC.

_References

_{1. Trueman D, Liu Y, Lucero M, et al. The comparative efficacy of atezolizumab and bevacizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Abstract presented at: 2021 American Society of Clinical Oncology Annual Meeting.; June 8-11, 2021; virtual. e16151. doi: 10.1200/JCO.2021.39.15_suppl.e16151}

_{2. Vogel A, Saborowski A. Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev. 2020 Jan;82:101946. doi: 10.1016/j.ctrv.2019.101946}

_{3. Finn RS, Qin S, Ikeda M, et al. IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745}

_{4. Yamashita T, Kudo M, Ikeda K, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020 Jan;55(1):113-122. doi: 10.1007/s00535-019-01642-1}