The positive outcomes that lenvatinib (Lenvima) demonstrated as first-line therapy for patients with hepatocellular carcinoma (HCC) are confirmed in an independent assessment conducted as part of the pivotal, international phase III REFLECT trial.
The independent imaging review (IIR) supports the tumor assessments that clinical investigators performed for the primary analysis using modified Response Evaluation Criteria in Solid Tumors (mRECIST), Riccardo Lencioni, MD, reported at the 2018 International Liver Cancer Association (ILCA) Annual Conference in London, United Kingdom.
A blinded central panel of about 25 radiology experts assessed the scans according to mRECIST and RECIST v1.1 criteria, said Lencioni, who is a professor of radiology at the University of Pisa School of Medicine in Italy and an honorary professor of interventional oncology at the Miami Cancer Institute in Florida.
In August 2018, the FDA approved lenvatinib as a first-line therapy for patients with unresectable HCC based on data from REFLECT, which randomized 954 patients to lenvatinib or sorafenib (Nexavar). The trial met its primary endpoint of OS noninferiority; the median OS by investigator review with lenvatinib was 13.6 months compared with 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06).1
Lenvatinib also proved to be superior to sorafenib for median progression-free survival (PFS) and time to progression (TTP).
In comparing the results based on the reviewers’ assessments, Lencioni and colleagues found that PFS and TTP data produced similar Kaplan-Meier curves for conclusions that clinical investigators reached using mRECIST and that IIR investigators developed using mRECIST and RECIST v1.1 criteria. The results diverged when it came to objective response rates (ORRs). Clinical investigators reported ORRs of 24.1% for lenvatinib and 9.2% for sorafenib per mRECIST. The IRR investigators assessed the ORRs at 40.6% and 12.4% for lenvatinib and sorafenib, respectively, by mRECIST and at 18.8% and 6.5%, respectively, by RECIST v1.1.
The major differences in the assessments were in classifying partial responses (PRs). Clinical investigators reported PR rates of 23% and 9% for the lenvatinib and sorafenib arms, respectively, by mRECIST. By contrast, IIR investigators found PRs of 38% and 12% for lenvatinib and sorafenib, respectively, by mRECIST and 18% and 6% by RECIST v1.1.2
Nevertheless, “the relative ORR in favor of lenvatinib over sorafenib was preserved,” Lencioni and colleagues wrote in their conference poster.
In discussing the assessments during a presentation at the ILCA meeting, Lencioni said the mRECIST criteria allowed IIR panel “to fine tune and be more accurate in the measurement of the responders.” He said some cases are straightforward to assess, while PRs are more complex.
Lencioni said the mRECIST criteria were developed to improve upon standard RECIST in 2 areas: incorporating HCC-specific refinements for assessment of tumor lesions for progression and developing the concept of “viable tumor” for target lesion measurement for response.
“mRECIST was developed to fix some inconsistences of standard RECIST and in doing so address the unique complexity of this malignancy,” he said.
He said the progression changes were designed to prevent overdiagnosis. These were in the areas of ascites/pleural effusion, portal vein thrombosis, infiltrative-type lesions, porta hepatis lymph nodes, lesions treated with prior locoregional therapy, and new lesions.
The response changes were designed to recognize areas of the tumor affected by therapy. “This allows tumors that manifest significant necrosis to be assessed as responders,” he said.
Citing other research findings, Lencioni said mRECIST is able to identify 2 to 3 times more responders and serve as a predictor for OS.
Since the mRECIST criteria were developed approximately 8 years ago, the changes have been incorporated into radiology charters at medical institutions even when standard RECIST 1.1 is used in studies. “At this time, we have a sort of unified understanding of how to interpret scans of [patients with] HCC.”
Lencioni said the findings of the REFLECT trial show the importance of having a diagnostic radiologist participate in tumor boards. “Specific expertise is a key factor,” he concluded.
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- 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.
- Independent imaging review (IRR) results in a phase 3 trial of lenvatinib (len) vs sorafenib (sor) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16, 2018; London, United Kingdom. Abstract P-028.