Overall survival and objective response in advanced unresectable hepatocellular carcinoma : A subanalysis of the REFLECT study
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved..
BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy.
METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization.
RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC.
CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease.
CLINICALTRIALS:.
GOV NUMBER: NCT01761266.
IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
|---|---|
| Enthalten in: |
Journal of hepatology - 78(2023), 1 vom: 01. Jan., Seite 133-141 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kudo, Masatoshi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.12.2022 Date Revised 31.01.2023 published: Print-Electronic ClinicalTrials.gov: NCT01761266 CommentIn: J Hepatol. 2023 Jan;78(1):8-11. - PMID 36323356 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jhep.2022.09.006 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM348556241 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM348556241 | ||
| 003 | DE-627 | ||
| 005 | 20231226040527.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jhep.2022.09.006 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1161.xml |
| 035 | |a (DE-627)NLM348556241 | ||
| 035 | |a (NLM)36341767 | ||
| 035 | |a (PII)S0168-8278(22)03111-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kudo, Masatoshi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Overall survival and objective response in advanced unresectable hepatocellular carcinoma |b A subanalysis of the REFLECT study |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.12.2022 | ||
| 500 | |a Date Revised 31.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT01761266 | ||
| 500 | |a CommentIn: J Hepatol. 2023 Jan;78(1):8-11. - PMID 36323356 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND & AIMS: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy | ||
| 520 | |a METHODS: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization | ||
| 520 | |a RESULTS: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC | ||
| 520 | |a CONCLUSIONS: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease | ||
| 520 | |a CLINICALTRIALS: | ||
| 520 | |a GOV NUMBER: NCT01761266 | ||
| 520 | |a IMPACT AND IMPLICATIONS: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a landmark analysis | |
| 650 | 4 | |a lenvatinib | |
| 650 | 4 | |a mRECIST | |
| 650 | 4 | |a response status | |
| 650 | 4 | |a surrogate endpoint | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Sorafenib |2 NLM | |
| 650 | 7 | |a 9ZOQ3TZI87 |2 NLM | |
| 700 | 1 | |a Finn, Richard S |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Shukui |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Kwang-Hyub |e verfasserin |4 aut | |
| 700 | 1 | |a Ikeda, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Ann-Lii |e verfasserin |4 aut | |
| 700 | 1 | |a Vogel, Arndt |e verfasserin |4 aut | |
| 700 | 1 | |a Tovoli, Francesco |e verfasserin |4 aut | |
| 700 | 1 | |a Ueshima, Kazuomi |e verfasserin |4 aut | |
| 700 | 1 | |a Aikata, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a López, Carlos López |e verfasserin |4 aut | |
| 700 | 1 | |a Pracht, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Zhiqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Daniele, Bruno |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Joong-Won |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Tamai, Toshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Saito, Kenichi |e verfasserin |4 aut | |
| 700 | 1 | |a Dutcus, Corina E |e verfasserin |4 aut | |
| 700 | 1 | |a Lencioni, Riccardo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of hepatology |d 1993 |g 78(2023), 1 vom: 01. Jan., Seite 133-141 |w (DE-627)NLM012604372 |x 1600-0641 |7 nnns |
| 773 | 1 | 8 | |g volume:78 |g year:2023 |g number:1 |g day:01 |g month:01 |g pages:133-141 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jhep.2022.09.006 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 78 |j 2023 |e 1 |b 01 |c 01 |h 133-141 | ||