Ramucirumab Maintains Activity, Tolerability After Non-Sorafenib Frontline Therapy in HCC


The safety and efficacy of ramucirumab administered after a frontline, non–sorafenib-based systemic therapy in hepatocellular carcinoma was consistent with data from the sorafenib-receiving intention-to-treat population of the phase 3 REACH-2 study.

The safety and efficacy of ramucirumab (Cyramza) administered after a frontline, non–sorafenib (Nexavar)-based systemic therapy in hepatocellular carcinoma (HCC) was consistent with data from the sorafenib-receiving intention-to-treat (ITT) population of the phase 3 REACH-2 study, according to findings from an interim analysis of a REACH-2 expansion cohort presented at the International Liver Cancer Association 2020 Virtual Conference.1

Results from the interim subgroup analysis showed that at a median follow-up of 6.5 months, the median progression-free survival (PFS) was 5.5 months (95% CI, 1.3-7.5) with 18 events, which the authors deemed consistent with PFS data observed in patients receiving prior sorafenib in the REACH-2 trial (NCT02435433).1,2 In previously reported data, at median follow-up of 7.4 months the median PFS was 2.8 months in the ITT population treated with ramucirumab versus 2.8 months in those treated with placebo (HR, 0.45; 95% CI, 0.33-0.60; P < .0001).2

Overall survival (OS) data were immature, with only 10 events reported.1 At the time of the data cutoff on January 31, 2020, 22 of the 24 patients who received subsequent ramucirumab were off treatment and 2 had died.

“As of now, all second-line agents approved in HCC have come after prior sorafenib,” said Richard S. Finn, MD, said in an interview with OncologyLive®. “We have seen the approvals of lenvatinib [Lenvima] and atezolizumab [Tecentriq]/bevacizumab [Avastin] in the first-line. A question that remains to be answered is: How do we best sequence drugs given the changing landscape?” The emerging data from the open-label expansion (OLE) cohort “provide some reassurance that there are no new safety signals” while demonstrating progression-free survival (PFS) “comparable to the phase 3 cohort” in a population that did not receive frontline sorafenib, Finn explained.

The global OLE cohort of the REACH-2 trial, the results of which led to the May 10, 2019, approval of ramucirumab monotherapy3 for patients with HCC previously treated with sorafenib and an alpha-fetoprotein (AFP) of at least 400 ng/mL, was initiated to test ramucirumab in patients with advanced HCC and elevated baseline AFP (≥ 400 ng/mL) following treatment with a systemic therapy excluding sorafenib. “The open-label expansion is designed to gain some safety and efficacy data in a population of patients who had other first-line agents,” said Finn, a professor of medicine at the Geffen School of Medicine at the University of California Los Angeles in the Department of Medicine, Division of Hematology/Oncology. Longer-term insights from the OLE cohort are expected to shed light on best practices for therapeutic sequencing in HCC.

The primary end point of the OLE evaluation was safety, with secondary end points including PFS, OS, overall response rate (ORR), time to progression, protein kinase, patient-reported outcomes, and immunogenicity. Final analysis of all end points proceeded after all patients completed at least 3 cycles of ramucirumab or discontinued treatment with the VEGFR2 antagonist.1

Response assessments performed in accordance with RECIST 1.1 criteria indicated that the ORR in the OLE cohort was 16.7% (n = 24), comprised entirely of partial responses. There were no complete responses. The disease control rate was 54.2%, with stable disease observed in 37.5% of patients. Progressive disease (PD) and objective PD were seen in 41.7% of patients each; 4.2% of patients were not evaluable for response.

Data additionally demonstrated that, when compared with baseline values, patients’ albumin-bilirubin (ALBI) scores were preserved during ramucirumab therapy. Investigators measured albumin and bilirubin at baseline and prior to each cycle and calculated participants’ ALBI scores and grades to evaluate liver function throughout the treatment period. The median duration of therapy was 10.50 weeks (interquartile range, 6.00-31.86) and the median number of cycles received was 5.00 (interquartile range, 3.00-14.50). Reasons for treatment discontinuation were varied: 14 because of PD, 4 because of an adverse event (AE), 2 deaths, and 1 each because of physician decision and protocol violation, respectively.


Importantly, no deaths due to AEs occurred during ramucirumab therapy or within 30 days of treatment discontinuation. Most patients (91.7%) experienced 1 or more treatment-emergent AEs (TEAEs) of any grade, while slightly more than half (58.3%) experienced a minimum of 1 grade 3 or grade 4 TEAE. Hypertension, proteinuria, pneumonia, hyponatremia, and ascites represented the 5 most common grade 3 or 4 AEs, affecting 16.7%, 12.5%, 12.5%, 8.3%, and 4.2% of patients, respectively. There were no cases of grade 3 or 4 diarrhea, fatigue, nausea, abdominal distension, decreased appetite, edema, or vomiting.1 

Regarding TEAEs of special interest (TE AESI), Finn said no grade 4 or 5 events occurred while patients were receiving ramucirumab. Fifty percent of patients experienced at least 1 TE AESI; 33.3% reported a minimum of 1 grade 3 TE AESI. Liver injury/failure was the most prevalent category of grade 3 TE AESIs (20.8%), followed by bleeding/hemorrhagic events (12.5%). The 5 most prevalent grade 3 TE AESIs included hypertension (16.7%), proteinuria (12.5%), gastric varices hemorrhage (4.2%), gastrointestinal hemorrhage (4.2%), and ascites (4.2%).

OLE Eligibility Criteria

REACH-2, which was the first positive phase 3 trial conducted in a biomarker-selected patient population with HCC,2 enrolled patients with disease confirmed by histology or radiological imaging and met Barcelona clinic liver cancer staging criteria for stage B or C disease that is refractory or not amenable to locoregional therapy. Patients were also required to have at least 1 untreated target lesion, a Child-Pugh Class A score, an ECOG performance status score of 0 or 1, baseline alpha-fetoprotein of at least 400 ng/mL, and adequate hematologic and biochemical parameters.

OLE addenda to these original REACH-2 specifications included the following: receipt of 1 to 2 prior systemic therapy regimens, excluding sorafenib or chemotherapy, and permission for patients with liver transplants to participate in the OLE cohort. Regarding prior systemic therapies received, most of the patients in the OLE cohort received lenvatinib (Lenvima; 33%), nivolumab (Opdivo; 25%), or atezolizumab coadministered with bevacizumab (Avastin; 13%).1

In accordance with newly added exclusion criteria, patients treated with prior immunotherapy who experienced any clinically significant grade 3 or higher immune-related AE or any grade neurologic, ocular, pneumonitis, cardiomyopathy, or hepatitis immune-related AE, or who needed steroids or other immunosuppressive agents at the time of enrollment were not permitted to participate in this expansion cohort.1 Enrollment is ongoing and will continue in the REACH-2 OLE cohort until accrual completes (N =44), Finn concluded.


  1. Finn RS, De Toni EN, Yau T, et al. Ramucirumab for patients with advanced hepatocellular carcinoma and elevated alpha fetoprotein following a non-sorafenib based systemic therapy: interim results from an expansion cohort of the phase 3 Reach-2 study. Poster presented at: International Liver Cancer Association 2020 virtual conference; September 11-13, 2020; virtual. Accessed September 11, 2020. https://www.postersessiononline.eu/pr/aula_poster.asp
  2. Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. doi:10.1016/S1470-2045(18)30937-9
  3. FDA approves ramucirumab for hepatocellular carcinoma. News release. FDA. May 10, 2019. Accessed September 15, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ramucirumab-hepatocellular-carcinoma
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