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Randomized Controlled Trial
. 2020 Aug;5(4):e000797.
doi: 10.1136/esmoopen-2020-000797.

Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials

Andrew X Zhu #  1   2 , Ryan D Nipp #  3 , Richard S Finn  4 , Peter R Galle  5 , Josep M Llovet  6   7 , Jean-Frederic Blanc  8 , Takuji Okusaka  9 , Ian Chau  10 , David Cella  11 , Allicia Girvan  12 , Jonathon Gable  12 , Lee Bowman  12 , Chunxiao Wang  12 , Yanzhi Hsu  13 , Paolo B Abada  12 , Masatoshi Kudo  14
Affiliations
Randomized Controlled Trial

Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials

Andrew X Zhu et al. ESMO Open. 2020 Aug.

Abstract

Background: Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab.

Patients and methods: Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted.

Results: In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings.

Conclusions: Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient-clinician discussions about the benefit-risk profile of this therapy.

Trial registration number: NCT01140347; NCT02435433, NCT02435433.

Keywords: hepatocellular carcinoma; patient-reported outcomes; quality of life; ramucirumab.

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Conflict of interest statement

Competing interests: AXZ: Consulting or advisory role: Eisai, Bristol-Myers Squibb, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Exelixis, Eli Lilly and Company; Research funding: Eli Lilly and Company, Bayer, Bristol-Myers Squibb, Novartis, Merck. RN: None. PRG: Consulting/advisory boards and personal fees: AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Ipsen, Eli Lilly and Company MSD, Merck, Novartis, Roche, Sirtex Medical, Sillajen. RSF: Consulting: AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech. JML: Consulting: Eli Lilly and Company, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai, Celsion Corporation, Exelixis, Merck, Ipsen, Glycotest, Navigant, Leerink Swann, Midatech, Fortress Biotech, Sprink Pharmaceuticals, Nucleix, CanFite. Research funding; Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Ipsen. J-FB: Personal and consulting fees: Eli Lilly and Company, Bayer, BMS, Eisai, Ipsen, Onxeo, during the conduct of the study. TO: Advisory role: Eli Lilly and Company, Nippon Boehringer Ingelheim, Dainippon Simitomo Pharma, Ono Pharmaceutical, Nano Carrier, Zeria Pharmaceutical, Daiichi Sankyo. Research grant: Eli Lilly and Company, Novartis Pharma K.K., Kowa K.K., Takeda Bio Development Center Limited, Nippon Boehringer Ingelheim, Dainippon Simitomo Pharma, Pfizer Jana, Bayer Yakuhin, Chugai Pharmaceutical, Yakuruto Honsha, Ono Pharmaceutical, Eisaid, AstraZeneca K.K., Merck Serono, OncoTherapy Science, Kyowa Hakko Kirin, Shizuoka Industry, Baxter, Nano Carrier, Zeria Pharmaceutical, Glaxo Smith Kline K.K., Nobelpharma. Honoraria/personal fees: Eli Lilly and Company, Novartis Pharma K.K., Dainippon Simitomo Pharma, Pfizer Jana, Bayer Yakuhin, Chugai Pharmaceutical, Yakuruto Honsha., Ono Pharmaceutical, Eisai Co, AstraZeneca K.K., Merck Serono, Baxter, Nobelpharma, Bristol-Myers Squibb Company, Nipponchemofa, EA Pharma, FUJIFILM RI Pharma, Astellas Pharma, Nippon Kayaku, Daiichi Sankyo, Celgene, K.K., MSD, K.K., Teijin Pharma. IC: Advisory board: Sanofi Oncology, Eli Lilly and Company, Bristol-Myers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics; Astra-Zeneca, Oncologie International, Pierre Fabre; Research funding: Eli-Lilly and Company, Janssen-Cilag, Sanofi Oncology, Merck-Serono. Honorarium: Eli Lilly and Company. DC: Consultant for Eli Lilly and Company, during the conduct of the study; outside the submitted work. Consultant for Abbvie; BMS; Pfizer; Novartis; Bioverativ; Ipsen; FACIT.org, president. AG, JG, LB, PBA; CW: Employee and minor shareholder of Eli Lilly and Company. YH is a former employee of Eli Lilly and Company. MK: Consulting or advisory role: Bayer, Bristol-Myers Squibb, Eisai, MSD, Ono Pharmaceutical. Personal fees/Honoraria: Bayer, Eisai, MSD. Research funding: Abbvie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Medico’s Hirata, Otsuka, Takeda, Taiho Pharmaceutical.

Figures

Figure 1
Figure 1
Time to first deterioration in FHSI-8 total score. Data shown are from (A) pooled and (B) REACH-2 populations. The curves and medians were estimated using the Kaplan-Meier method, HR (95% CI) was estimated using a Cox regression model. In case of no FHSI-8 deterioration, the subject was censored at the time of the last FHSI-8 recording. FHSI-8, Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index.
Figure 2
Figure 2
Time to deterioration of FHSI-8 symptom items in patients in the (A) pooled; and (B) REACH-2 populations. Data in panel A are shown longitudinally in online supplementary figure S2. FHSI-8, Functional Assessment of Cancer Therapy hepatobiliary symptom index; N, number of patients in intent-to-treat population; N/A, not available (medians could not be calculated due to low number of events); RAM, ramucirumab.
Figure 3
Figure 3
Longitudinal depiction of time to deterioration of FHSI-8 symptom items in patients with advanced hepatocellular carcinoma and baseline AFP ≥400 ng/mL. Data represent pooled individual patient data from REACH-2 and REACH (AFP ≥400 ng/mL) populations. FHSI-8 symptom items included (A) lack of energy; (B) nausea; (C) pain; (D) weight loss; (E) back pain; (F) fatigue; (G) jaundice and (H) stomach pain or discomfort. The curves and medians were estimated using the Kaplan-Meier method, HR (95% CI) was estimated using a COX regression model. AFP, alpha-fetoprotein; FHSI-8, Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index; N/A, medians could not be calculated due to low number of events.
See this image and copyright information in PMC

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