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ORIGINAL RESEARCH
Comparative Efficacy of Cabozantiniband Regorafenib for Advanced
HepatocellularCarcinoma
Robin K. Kelley . Patrick Mollon . Jean-Frédéric Blanc .
Bruno Daniele . Thomas Yau . Ann-Lii Cheng . Velichka Valcheva
.
Florence Marteau . Ines Guerra . Ghassan K. Abou-Alfa
Received: April 29, 2020 / Published online: May 18, 2020� The
Author(s) 2020
ABSTRACT
Background: No trials have comparedcabozantinib and regorafenib
for the second-line treatment of advanced hepatocellular car-cinoma
(HCC).Objectives: Conduct a matching-adjusted indi-rect comparison
(MAIC) of the efficacy andsafety of second-line cabozantinib and
rego-rafenib in patients with advanced HCC anddisease progression
after prior sorafenib.
Methods: The CELESTIAL and RESORCE trialswere used for indirect
comparison of second-line cabozantinib and regorafenib in
advancedHCC. Population-level data were available forRESORCE,
individual patient data (IPD) forCELESTIAL. To align with RESORCE,
theCELESTIAL population was limited to patientswho received
first-line sorafenib only. To mini-mize potential effect-modifying
populationdifferences, the CELESTIAL IPD were weightedto balance
the distribution of clinically relevantbaseline characteristics
with those of RESORCE.Overall survival (OS) and progression-free
sur-vival (PFS) were evaluated for the matching-adjusted
second-line CELESTIAL populationand compared with those for RESORCE
usingweighted Kaplan-Meier curves and parametricmodeling. Rates of
grade 3/4 treatment-
Digital Features To view digital features for this articlego to
https://doi.org/10.6084/m9.figshare.12213854.
Electronic Supplementary Material The onlineversion of this
article (https://doi.org/10.1007/s12325-020-01378-y) contains
supplementary material, which isavailable to authorized users.
R. K. Kelley (&)UCSF, Helen Diller Family Comprehensive
CancerCenter, San Francisco, CA, USAe-mail:
[email protected]
P. Mollon � V. Valcheva � F. MarteauIpsen Pharma,
Boulogne-Billancourt, France
J.-F. BlancHôpital Haut-Lévêque, CHU de Bordeaux,
Bordeaux,France
B. DanieleAzienda Ospedaliera G Rummo, Benevento,Italy
B. DanieleOspedale del Mare, Naples, Italy
T. YauUniversity of Hong Kong, Pokfulam, Hong Kong
A.-L. ChengNational Taiwan University Cancer Center,
NationalTaiwan University Hospital, Taipei, Taiwan,Republic of
China
I. GuerraIQVIA Ltd, London, UK
G. K. Abou-AlfaMemorial Sloan Kettering Cancer Center, New
York,NY, USA
G. K. Abou-AlfaWeill Medical College at Cornell University,
NewYork, NY, USA
Adv Ther (2020) 37:2678–2695
https://doi.org/10.1007/s12325-020-01378-y
https://orcid.org/0000-0002-1984-2430https://orcid.org/0000-0001-6172-9485https://orcid.org/0000-0002-5221-9755https://orcid.org/0000-0002-9152-6512https://orcid.org/0000-0002-3476-0046https://orcid.org/0000-0002-1522-8054https://doi.org/10.6084/m9.figshare.12213854https://doi.org/10.1007/s12325-020-01378-yhttps://doi.org/10.1007/s12325-020-01378-yhttps://doi.org/10.1007/s12325-020-01378-yhttps://doi.org/10.1007/s12325-020-01378-yhttp://crossmark.crossref.org/dialog/?doi=10.1007/s12325-020-01378-y&domain=pdfhttps://doi.org/10.1007/s12325-020-01378-y
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emergent adverse events (TEAEs) affecting[ 5%of patients in any
study arm were compared.Results: In the matching-adjusted
second-linepopulations (CELESTIAL, effective samplesize = 266;
RESORCE, n = 573), median (95%confidence interval) OS was similar
forcabozantinib and regorafenib (11.4 [8.9–17.0]versus 10.6
[9.1–12.1] months; p = 0.3474, log-rank test). Median PFS was
longer for cabozan-tinib than regorafenib (5.6 [4.9–7.3] versus
3.1[2.8–4.2] months; p = 0.0005, log-rank test).There was a trend
for lower rates of some grade3/4 TEAEs with regorafenib than
withcabozantinib, which may reflect the exclusionof
sorafenib-intolerant patients from RESORCEbut not from CELESTIAL, a
difference that theMAIC methods could not remove. Only diar-rhea
rates were statistically significantly lowerfor regorafenib (p B
0.001).Conclusions: Cabozantinib may achieve simi-lar OS and
prolonged PFS compared with rego-rafenib in patients with
progressive advancedHCC after prior sorafenib.
PLAIN LANGUAGE SUMMARY
Cabozantinib and regorafenib are treatmentsapproved for some
patients with advancedhepatocellular carcinoma (HCC), a type of
livercancer, after disease progression despite priorsorafenib
treatment. Cabozantinib, regorafeniband sorafenib are tyrosine
kinase inhibitors(TKIs), meaning that they slow cancer progres-sion
by targeting specific ways that tumorsgrow. Cabozantinib and
regorafenib offer ben-efits to patients compared with placebo
(i.e., notreatment) for those who have progressed
despite sorafenib treatment. No clinical studieshave compared
cabozantinib and regorafenibdirectly. This study compared the
efficacy andsafety of cabozantinib and regorafenib usingdata from
trials of each drug versus placebo:CELESTIAL for cabozantinib and
RESORCE forregorafenib. These two trials were similar—bothinvolved
patients with progressive advancedHCC who had received previous
cancer treat-ment. There were some important differences,but these
were minimized using statisticalmethods (matching and
adjustments/‘‘weight-ing’’) allowing outcomes to be
meaningfullycompared. One difference that could not beremoved by
the statistical methods was thatpatients who were intolerant to
prior sorafenibwere excluded from RESORCE but were eligiblefor the
CELESTIAL trial. In the otherwise mat-ched populations, treatment
with cabozantinibwas associated with similar overall survival
andsignificantly longer progression-free survivalthan regorafenib.
Rates of diarrhea were signif-icantly lower for regorafenib than
cabozantinib,suggesting that regorafenib may be better tol-erated,
but this may reflect the exclusion ofsorafenib-intolerant patients
from RESORCE.These findings cannot replace a head-to-headstudy, but
may help in guiding decision-makingbetween cabozantinib and
regorafenib inpatients with progressive advanced HCC
aftersoraftenib treatment.
Keywords: Cabozantinib; CELESTIAL; Hepato-cellular carcinoma
(HCC); Indirect treatmentcomparison; Matching-adjusted
indirectcomparison (MAIC); Regorafenib; RESORCE;Second-line;
Systemic therapy; Targeted therapy
Adv Ther (2020) 37:2678–2695 2679
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Key Summary Points
Why carry out this study?
The tyrosine kinase inhibitorscabozantinib and regorafenib
areapproved for the treatment of patientswith advanced
hepatocellular carcinoma(HCC) who have progressed despite
priortreatment with sorafenib.
No clinical trials have directly comparedcabozantinib and
regorafenib for thesecond-line treatment of advanced HCC.
This matching-adjusted indirectcomparison (MAIC) used data from
thephase 3 CELESTIAL (NCT01908426) andRESORCE (NCT01774344) trials
togenerate comparative efficacy and safetyestimates for
cabozantinib versusregorafenib in patients with progressiveadvanced
HCC after prior sorafenibtherapy.
What was learned from this study?
In patients with progressive advancedHCC who have received prior
sorafenibtreatment, cabozantinib may achievesimilar overall
survival and prolongprogression-free survival compared
withregorafenib; regorafenib may be associatedwith lower rates of
grade 3 or 4 diarrhea.
A MAIC cannot replace a head-to-headrandomized controlled trial,
but thesefindings may help in guiding clinicaldecision-making
between cabozantiniband regorafenib when treating patientswith
progressive advanced HCC in theabsence of direct trial
evidence.
INTRODUCTION
The era of targeted therapy for liver cancerbegan in 2007 with
the approval of sorafenib forthe first-line management of patients
with
advanced hepatocellular carcinoma (HCC)[1–4]. More than a decade
later, the range oftherapeutic options for HCC has broadened
toinclude a number of new targeted therapieswith proven survival
benefit in phase 3 trials. Inthe first-line setting, the tyrosine
kinase inhi-bitor (TKI) lenvatinib has now been approvedfor
patients with unresectable disease [5, 6].Approved second-line
treatment options (afterprior treatment with sorafenib) now include
theTKIs regorafenib [7, 8] and cabozantinib [9, 10]in patients with
advanced HCC, the anti-vascular endothelial growth factor receptor
2(VEGFR2) monoclonal antibody ramucirumabin patients with
alpha-fetoprotein levels[ 400 ng/ml [11, 12] and the checkpoint
inhi-bitors nivolumab and pembrolizumab (pro-grammed cell death
receptor-1 antibodies) asmonotherapy or, in the case of nivolumab,
incombination with ipilimumab (a cytotoxicT-lymphocyte-associated
protein 4 antibody)[13–16].
The arrival of second-line agents foradvanced HCC extends the
previous therapeu-tic offering for patients, many of whom
presentwith advanced disease at the time of diagnosisand have had
few therapeutic options availableto them [17]. Accordingly, 5-year
survival ratesfor localized, regional and distant HCC aretypically
poor (31%, 11% and 2%, respectively)[18], highlighting the
importance of newsecond-line therapies and the clinical
imperativeto optimize their use.
The TKIs regorafenib and cabozantinib areboth approved as
second-line agents forpatients with HCC after prior treatment
withsorafenib [7–10]. They share a drug class andoral mode of
administration, but they differ intheir molecular targeting
profiles. Regorafenibtargets multiple receptor tyrosine
kinases,including those involved in tumor angiogenesis(VEGFR-1, -2,
-3, TIE2), oncogenesis (KIT, RET,RAF-1, BRAF, BRAFV600E),
metastasis (VEGFR3,PDGFR, FGFR) and tumor immunity (CSF1R)[19].
Cabozantinib also has inhibitory activityagainst tumor angiogenesis
and oncogenesis,but it additionally targets the hepatocytegrowth
factor receptor protein (MET), involvedin tumor growth and
invasion, and othertyrosine kinases, including those involved
in
2680 Adv Ther (2020) 37:2678–2695
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modulation of tumor immunity (e.g., AXL,MER) [20, 21]. Current
HCC managementguidelines recommend either agent in advanceddisease
following progression after sorafenibon the basis of evidence from
the pivotalRESORCE (NCT01774344) and CELESTIAL(NCT01908426) phase 3
trials [1, 8, 10, 22, 23].
RESORCE compared once-daily regorafenib160 mg to placebo for
weeks 1–3 of every 4-weekcycle (in patients with HCC who were
tolerantto sorafenib, but who had progressed duringsorafenib
treatment; n = 573) [8]. CELESTIALcompared once-daily cabozantinib
60 mg toplacebo (continuous dosing) in patients withadvanced HCC
who had progressed after at leastone systemic treatment for HCC and
may havereceived up to two previous systemic regimensfor advanced
HCC (n = 707), one of which wasrequired to be sorafenib [10].
In the second-line (sorafenib-tolerant) pop-ulation included in
RESORCE, regorafenibimproved median overall survival (OS)
andprogression-free survival (PFS) compared withplacebo (hazard
ratio [HR] [95% confidenceinterval, CI], 0.63 [0.50–0.79] and
0.46[0.37–0.56], respectively; one-sided p\0.0001for both) [8]. The
most common clinicallyrelevant grade 3 or 4 treatment-emergent
adverseevents (TEAEs) were hypertension, hand-footskin reaction,
fatigue and diarrhea [8]. In themixed second- and third-line
populationincluded in CELESTIAL, cabozantinib alsosignificantly
improved OS and PFS comparedwith placebo (HR [95% CI], 0.76
[0.63–0.92],two-sided p = 0.005 and 0.44 [0.36–0.52], two-sided
p\0.001, respectively). Cabozantinibalso prolonged median OS and
PFS in thesubgroup of patients who had only receivedprevious
systemic treatment with sorafenib(stratified HR [95% CI], 0.70
[0.55–0.88] and0.40 [0.32–0.50], respectively). Similar toRESORCE,
hand-foot reaction (assessed aspalmar-plantar erythrodysesthesia),
fatigue anddiarrhea were among the most common grade 3or 4 events;
higher rates of hypertension andincreased aspartate
aminotransferase (AST) levelwere also recorded with cabozantinib
comparedwith placebo [10].
While the CELESTIAL and RESORCE trialsprovide robust evidence
for the second-line use
of either cabozantinib or regorafenib in pro-gressive advanced
HCC, at the time of writing,there have been no randomized
controlled trialsto compare the two agents directly. In theabsence
of head-to-head trial data, indirecttreatment comparisons offer a
means ofestimating probable treatment outcomes ifcomparator drugs
were used in the same way insimilar patients [24, 25]. Standard
indirecttreatment comparisons estimate the effect sizesof
individual treatments relative to a commonreference arm (e.g.,
placebo); these relativeestimates are then compared. This approach
isused in network meta-analyses, but it relies onthe studies
involved being sufficiently similar inall respects other than the
treatments beingcompared [26]. When this is not the case and
astandard indirect treatment comparison is notvalid,
population-adjustment methods are usedto minimize between-trial
population differ-ences. These approaches weight individualpatient
data (IPD) to reduce differences in thedistribution of clinically
relevant covariates,thereby reducing the potential for bias
incomparative outcome estimates. Propensityscore matching is one
method of populationmatching, but it requires IPD to be available
forall studies being compared [25]. When IPD areavailable for only
one of two studies beingcompared, a matching-adjusted
indirectcomparison (MAIC) method can be used. A MAICweights the IPD
for the available study so thatits baseline characteristics match
those of areference comparator study for which onlypublished
aggregate-level data are available [25].MAIC analyses are routinely
used for healthtechnology assessment [24, 25], and theirpotential
to inform clinical decision-making inthe absence of direct
comparative data has beenutilized across a range of cancer types
(e.g.,breast cancer, prostate cancer, basal cell carci-noma)
[27–29], including HCC [30–32].
We report here the first MAIC of second-lineTKI options for HCC,
providing an assessmentof the comparative efficacy and safety
ofcabozantinib and regorafenib for patients withadvanced HCC who
have received sorafenib asthe only prior systemic therapy (see Fig.
1 for agraphical summary of the study).
Adv Ther (2020) 37:2678–2695 2681
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METHODS
Data Source Identification And Eligibility
The CELESTIAL trial of cabozantinib (n = 707)[10] and RESORCE
trial of regorafenib (n = 573)[8] were identified in the published
literatureand assessed for their feasibility for a standardindirect
treatment comparison (ITC) of TKIsrecently approved for the
second-line manage-ment of advanced progressive HCC followingprior
sorafenib treatment.
RESORCE included a second-line populationof patients with
advanced HCC who toleratedsorafenib, but who had progressed
followingsorafenib treatment only [8, 12]. In contrast,CELESTIAL
included a mixed second- and third-line population [10]. While
CELESTIAL patientsmust have received previous treatment
withsorafenib (by default), they may also havereceived a second
systemic treatment foradvanced HCC prior to recruitment to the
trial.Furthermore, CELESTIAL did not excludepatients who were
intolerant to sorafenib.
Despite these notable population differences,the availability of
IPD for CELESTIAL (obtainedfrom Exelixis with a data cutoff date of
1 June2017) enabled isolation of a pure second-lineCELESTIAL
subpopulation for comparison withRESORCE. The similarity of the
efficacy andsafety outcomes reported for the two trialsconfirmed
their potential for use in an indirecttreatment comparison of
second-line cabozan-tinib versus regorafenib in patients with
pro-gressive advanced HCC.
To evaluate whether a standard ITC wasfeasible for RESORCE
(regorafenib) and thesecond-line CELESTIAL (cabozantinib)
subpop-ulation, a panel of expert oncologists convenedin June 2018
to review the design similaritiesand baseline population
characteristics of thetwo trials (Supplemental Tables S1 and S2).
Thepanel identified differences in several effect-modifying
covariates with the potential to biasa standard ITC. Therefore, a
MAIC analysisapproach was selected to compare the safetyand
efficacy of regorafenib, using the aggregatepopulation data
published for RESORCE and
Fig. 1 Overview of the study
2682 Adv Ther (2020) 37:2678–2695
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IPD for the second-line subpopulation fromCELESTIAL.
Matching-Adjusted Indirect Comparison:Cabozantinib and
Regorafenib
The MAIC analysis was conducted in accor-dance with the
established methodology out-lined in the guidance from the
NationalInstitute for Health and Care Excellence [25, 33]as
summarized in Supplemental Fig. S1 (see theelectronic supplementary
material).
Population MatchingThe IPD from CELESTIAL were used to identify
apure second-line population of patients whoreceived cabozantinib
after sorafenib only. TheIPD also allowed the clinically meaningful
differ-ences in potential effect-modifying covariates tobe
minimized by weighting the baseline charac-teristics of the
second-line CELESTIAL subpopu-lation so as to match them to those
of thepublished RESORCE population-level statistics(e.g., means,
medians, percentages). The baselinedifferences between the trials
that had beenidentified as being potential effect modifiers bythe
expert panel were assessed for colinearity, andthe following
covariates were selected as thematching criteria: age, race,
geographical region,Eastern Cooperative Oncology Group Perfor-mance
Status, Child-Pugh class, duration of priorsorafenib treatment,
extrahepatic disease,macrovascular invasion, etiology of HCC
(hep-atitis B, alcohol use and hepatitis C) and
serumalpha-fetoprotein level. Patients in CELESTIALwith missing IPD
for any of the selected matchingcriteria were excluded from the
analysis.
Outcome Evaluation: Survival AnalysisSurvival outcomes for the
matching-adjustedsecond-line CELESTIAL population were
thenevaluated and compared with those published forRESORCE. For
cabozantinib, median OS and PFSestimates were derived from weighted
Kaplan-Meier (KM) curves fitted to the survival data [34].For
cabozantinib, confidence intervals (CIs) forthe KM weighted curves
were generated fromsimulations [35] and for median survival
usingWoodruff’s method [36]. For regorafenib, KM
curves and median survival estimates weresourced from the
RESORCE publication [8].
MAIC analyses can be ‘anchored’ or‘unanchored,’ with
methodologic guidelinesgenerally favoring an anchored analysis
approach,when feasible [25]. An anchored MAIC gener-ates estimates
relative to a common comparatorarm, such as placebo. An unanchored
analysisinvolves no common comparator arm and basesestimates on
absolute outcomes. An unan-chored analysis involves more
assumptionsthan an anchored approach, but is necessarywhen there is
no common comparator arm(e.g., single-arm studies) or when
assumptionsunderpinning an anchored approach are notsatisfied. For
anchored hazard ratios to be valid,the proportional hazards
assumption must besatisfied (i.e., the treatment effect must be
pro-portional over time and the survival curves fit-ted to each
treatment group must have a similarshape) [25, 33].
In the present analysis, the feasibility ofconducting an
anchored analysis (with placeboas the common comparator arm) was
assessed.The proportional hazards assumption was tes-ted for OS and
PFS by visual inspection of thelog-cumulative hazard plots to
ensure that therewas no pattern of non-parallelism. The test
wasconducted for the matching-adjusted andunmatched second-line
cabozantinib popula-tions versus placebo from CELESTIAL, for
theregorafenib versus placebo populations fromRESORCE and for the
matching-adjustedand unmatched second-line cabozantinibCELESTIAL
population versus the regorafenibRESORCE population. The findings
of the visualinspection of the log-cumulative hazard plotswere then
validated by visual inspection of thescaled Schoenfeld residuals
and using theGrambsch-Therneau test (a statistical test basedon the
scaled Schoenfeld residuals) [33, 37].
Where the proportional hazards assumptionwas not satisfied and
an anchored analysis notsupported, an unanchored analysis was
con-ducted by fitting individual parametric survivalcurves to each
treatment arm, in line with bestpractice guidelines. Parametric
model selectionwas based on an analysis of Akaike’s informa-tion
criterion and Shwarz’s Bayesian
Adv Ther (2020) 37:2678–2695 2683
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information criterion (AIC/BIC), with superiormodel fit
indicated by lower AIC and BIC [33].
Outcome Evaluation: SafetyIncidence of grade 3 or 4 TEAEs
affecting[ 5%of patients in any of the second-line CELESTIALor
RESORCE treatment arms was compared forcabozantinib versus
regorafenib. In an anchoredanalysis, the estimated relative effects
(log oddsratios [ORs]) of cabozantinib versus placebo inthe
weighted population were generated andcompared with log-ORs for
regorafenib versusplacebo, computed from the published data.Safety
outcome estimates of cabozantinib versusregorafenib were
constructed in the log-ORscale.
If a TEAE of interest did not occur in either ofthe placebo arms
of the trials (preventing ananchored log-OR analysis), an
unanchoredanalysis of the active treatment arms was con-ducted. The
number of TEAEs occurring inCELESTIAL was used to compute a
weighted,unanchored estimate.
Analyses
The analyses were performed using R version3.5.2 (R Core Team,
2014). The package ‘survey’version 3.36 was used to fit weighted
survivalmodels with weights computed from the MAICused as sampling
weights.
Compliance with Ethics Guidelines
The results presented in this manuscript arebased on previously
published studies. All pro-cedures performed in those studies
involvinghuman participants were in accordance withthe ethical
standards of the local InstitutionalReview Boards for each site and
with the 1964Helsinki Declaration and its later amendmentsor
comparable ethical standards. Informedconsent was obtained from all
individual par-ticipants included in the CELESTIAL
(Clini-calTrials.gov identifier NCT01908426) andRESORCE
(ClinicalTrials.gov identifierNCT01774344) trials.
RESULTS
Patient Characteristics
RESORCE involved a total of 573 second-linepatients with
advanced HCC who were ran-domized to regorafenib (n = 379) or
placebo(n = 194) following progression on sorafenib. Intotal, 495
second-line patients were enrolled inCELESTIAL and randomized to
cabozantinib(n = 331) or placebo (n = 164). When limited tothe
CELESTIAL patients for whom data wereavailable for all
effect-modifying characteristics,the pre-matched population size
reduced fur-ther to 484 patients (cabozantinib, n = 326;placebo, n
= 158) and, following matching, toan effective sample size of 266
patients (non-additive with respect to each treatment
arm:cabozantinib, n = 187; placebo, n = 81)(Table 1).
Application of MAIC weighting to the base-line IPD from
CELESTIAL was effective in bal-ancing the effect-modifying
baselinecharacteristics of the second-line CELESTIALand RESORCE
populations, most notablypatient ethnicity and geographical region
oforigin, HCC etiology, proportion of patientswith Eastern
Cooperative Oncology Group(ECOG) performance status 0 and HCC
etiology(Table 2). As a result, there were no discernableclinically
relevant differences between thebaseline characteristics of the
matching-ad-justed second-line CELESTIAL population andthe RESORCE
populations (Table 2).
Survival Outcomes
KM-Derived EstimatesEstimated median (95% CI) OS derived fromthe
weighted KM curves were similar:11.4 (8.9–17.0) months for the
matching-adjustedcabozantinib population and 10.6 (9.1–12.1)months
for the regorafenib population(p = 0.3474, log-rank test). In
comparison,equivalent OS estimates for the placebo armswere 7.2
(6.1–10.8) for the matching-adjustedsecond-line CELESTIAL
population and7.8 (6.3–8.8) months for RESORCE (Fig. 2 andTable
3).
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Estimated median (95% CI) PFS was5.6 (4.9–7.3) months for the
matching-adjustedcabozantinib population compared with3.1 (2.8–4.2)
months for regorafenib, a statisticallysignificant difference (p =
0.0005, log-rank test).For the placebo arms, equivalent estimates
were1.9 (1.9–2.1) for the matching-adjusted second-line CELESTIAL
population and 1.5 (1.4–1.6)months for RESORCE (Fig. 3 and Table
3).
Parametric Modeling EstimatesVisual inspection of the log of
cumulative haz-ard versus time plots displayed a distinct patternof
non-parallelism for both OS and PFS, indi-cating that the
proportional hazards assump-tion was not valid, and an anchored
analysiswas not supported (Supplemental Fig. S2). Theplots of
scaled Schoenfeld residuals versus timeshowed a systematic
departure from the hori-zontal for both outcomes, confirming
theassessment that the proportional hazardsassumption was not
supported, as did the non-zero slopes (at the 5% significance
level) givenby the Grambsch-Therneau test (SupplementalFig. S3). In
line with recommended practice, anunanchored analysis was therefore
conducted
by fitting individual parametric survival curvesto each
treatment arm [33].
Analysis of AIC and BIC for differentcandidate models identified
the log-logisticdistribution as the best-fit model for OS and
thegeneralized gamma model as the best-fit modelfor PFS
(Supplemental Tables S3 and S4). Thedirection of the survival
trends generated by theparametric modeling mirrored those of
theweighted KM analyses for both the activetreatment and the
placebo arms (SupplementalTable S5). As for the KM-derived
estimates,median (95% CI) OS estimates were similar andthe 95% CIs
overlapped: 11.40 (10.01–12.96)months for the matching-adjusted
second-line cabozantinib population versus10.29 (9.15–11.56) months
for the regorafenibpopulation. For the placebo arms
equivalentestimates were 8.27 (7.00–9.76) months for
thematching-adjusted second-line CELESTIALpopulation and 7.30
(6.30–8.47) months forRESORCE (Table S5).
For PFS, the median (95% CI) estimate waslonger for the
matching-adjusted second-linecabozantinib population (5.49
[4.92–6.13]months) compared with the regorafenib popu-lation (3.39
[3.05–3.78] months). There was no
Table 1 MAIC population sizes
CELESTIAL population RESORCEpopulationUnmatched
Matching-adjusted
n(overall)
n(second line)
n(second line withnon-missing data)
Effective sample size n (published)
Active
treatment
470 331 326 187 379
Placebo 237 164 158 81 194
Total 707 495 484 266a 573
a Non-additive with respect to each treatment arm. The ESS is
computed separately for each patient group asðPi
ŵiÞ2Piðŵ2i Þ(the
squared sum of weights [numerator] and sum of squared weights
[denominator]). The ESS computed for the full populationwill not
equate to the sum of the ESS for each patient group individually,
unless all the weights are the same for eachtreatment armn number
of patients enrolled and randomized
Adv Ther (2020) 37:2678–2695 2685
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overlap in the CIs for the cabozantinib andregorafenib PFS
estimates, suggesting the dif-ference in favor of cabozantinib was
statisticallysignificant. For the placebo arms, equivalentestimates
were 2.35 (2.11–2.61) months for thematching-adjusted second-line
CELESTIALpopulation and 1.87 (1.68–2.09) months forRESORCE (Table
S3).
Safety Outcomes
TEAEs of interest (grade 3 or 4 occurring in morethan 5% of
patients in any trial arm) were ASTincrease (‘‘increased AST’’ in
RESORCE),diarrhea, elevated bilirubin, fatigue, hyperten-sion and
palmar-plantar erythrodysesthesiasyndrome (hand-foot skin reaction
in RESORCE).
An anchored log-OR analysis found nosignificant difference
between the matching-adjusted cabozantinib and
regorafenibpopulations in terms of frequency of grade 3 or4 TEAEs:
fatigue (p = 0.9313); elevated bilirubin(p = 0.8558) or increased
AST (p = 0.2201). Thisresult was consistent for both the
matching-adjusted and unmatched cabozantinib popula-tions
(Supplemental Table S6). Although therewas a possible trend toward
a higher rate ofgrade 3 or 4 hypertension in the matching-adjusted
cabozantinib population comparedwith the regorafenib population,
the confidenceintervals for the estimate crossed zero (indicat-ing
no difference), and a test of the nullhypothesis confirmed that the
difference wasnot statistically significant (p = 0.0611) (Fig. 4and
Supplemental Table S6).
Table 2 Baseline characteristics of the MAIC populations
CELESTIAL second-line population RESORCE population
Unmatched(n = 495)a
Matching-adjusted(n = 266)b
Published(n = 573)
Age\ 65 years, % 53.33 54.97 54.97
Female, % 17.58 18.63 12.04
Asian geographical region, % 22.83 37.70 37.70
White, % 58.18 35.95 35.95
ECOG performance status 0, % 56.97 65.79 65.79
Child–Pugh class A, % 98.79 97.91 97.91
Duration of prior sorafenib treatment,
mean (months)
7.65 11.63 11.63
Extrahepatic disease, % 76.16 71.90 71.90
Macrovascular invasion, % 29.41 28.62 28.62
Etiology, %
Hepatitis B 37.37 37.70 37.70
Alcohol use 21.52 25.31 25.31
Hepatitis C 25.10 20.77 20.77
Alpha-fetoprotein[ 400 ng/ml, % 40.81 43.46 43.46a Includes
patients with missing data for effect-modifying baseline
characteristicsb Effective sample size; excludes patients with
missing data for effect-modifying baseline characteristicsECOG
Eastern Cooperative Oncology Group
2686 Adv Ther (2020) 37:2678–2695
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Owing to the low frequency of grade 3 or 4palmar-plantar
erythrodysesthesia in theplacebo-treated patients (one case in
RESORCE;no cases in CELESTIAL) and no cases of grade 3or 4 diarrhea
in the RESORCE placebo arm, ameaningful anchored log-OR estimate
couldnot be constructed for these TEAEs.Unanchored estimates were
thereforecomputed. The unanchored analysis found nosignificant
difference in rates of palmar-plantar erythrodysesthesia between
the matching-adjusted cabozantinib and regorafenib popula-tions (p
= 0.848), but significantly lower rates ofdiarrhea in the
regorafenib population com-pared with both the unmatched and
matching-adjusted cabozantinib populations (p = 0.001and p\0.001
respectively) (Fig. 4 and Supple-mental Table S6).
DISCUSSION
Outcome Interpretation
From the present analysis, we report compara-tive efficacy and
safety estimates for cabozan-tinib and regorafenib for the
second-linetreatment of patients with advanced HCC after
prior sorafenib, using data from the phase 3CELESTIAL and
RESORCE trials. The treatmentlandscape for HCC is expanding
rapidly, andthere is a resultant need for head-to-head clini-cal
trial data to guide second-line HCC treat-ment decisions. In this
setting, indirecttreatment comparisons offer standardizedmethods
for generating comparative estimatesthat are widely accepted for
health technologyassessment [24, 25] and are increasingly
recog-nized in the clinical sphere for their potential toguide
clinicians in their decision-making[27–32].
A standard indirect treatment comparison ofcabozantinib and
regorafenib is not feasibleowing to clinically relevant differences
in thebaseline characteristics of the RESORCE popu-lation and the
second-line subpopulation fromCELESTIAL. Therefore, a MAIC was
selected as amore robust method of comparison, with anunanchored
approach selected for the survivalanalysis on the basis of the
results of three testsof the proportional hazards (PH)
assumption,which indicated that the PH assumption wasnot satisfied.
For OS, this conclusion was furthervalidated by the identification
of the log-logisticmodel as the best-fit parametric model;
log-logistic models are accelerated failure time models
0 5 10 15 20 25 30 35
64
326 221 140 87 51 27 16158 87 45 24 16 11 7
Months
0.00
0.25
0.50
0.75
1.00(a)
Prob
abilit
y of
sur
viva
l
Number of patients at risk
CabozantinibPlacebo95% CI
0 5 10 15 20 25 30 35
379 247 153 78 41 13194 111 49 26 11 5
Months
0.00
0.25
0.50
0.75
1.00(b)
Prob
abilit
y of
sur
viva
l
Number of patients at risk
RegorafenibPlacebo
CabozantinibPlacebo
RegorafenibPlacebo
95% CI
Fig. 2 Kaplan-Meier curves for overall survival in the
matching-adjusted second-line CELESTIAL population (a) and
theRESORCE population (b). CI confidence interval
Adv Ther (2020) 37:2678–2695 2687
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and do not produce a single hazard ratio, mak-ing them
incompatible with the PHassumption.
The matching and statistical adjustmentsteps of a MAIC analysis
help to reduce thepotential for bias by minimizing
populationdifferences that might modify or obscure theability to
discern true treatment effects. In thepresent analysis, weighting
the baseline IPD forsecond-line CELESTIAL patients to align
themwith the baseline RESORCE characteristics waseffective in
reducing discernible populationdifferences. In the unanchored
survival analy-sis, cabozantinib was associated with similar OSand
prolonged PFS compared with regorafenib.These findings were
consistent across analysesfor both the KM-derived and parametric
mod-eling survival estimates. There is, however, aneed for caution
when interpreting the PFSresult owing to differences in the tumor
assess-ment schedules used in the CELESTIAL andRESORCE trials.
RESORCE assessed tumorgrowth every 6 weeks for the first eight
cyclesand every 12 weeks thereafter during treatment.
In CELESTIAL, tumors were assessed every8 weeks after
randomization and performeduntil 8 weeks after radiographic
progression ortreatment/placebo discontinuation, whicheveroccurred
later. Assessment of PFS was, therefore,initially more frequent for
patients in RESORCEthan in CELESTIAL and, thereafter, more
fre-quent in CELESTIAL than in RESORCE. Thisdifference may have
introduced bias into thePFS result in the current analysis. At the
indi-vidual patient level, the direction of any suchbias would
depend on the timing of tumorgrowth. It would, for example, favor
cabozan-tinib if tumor growth occurred at week 10(assessed at week
12 in RESORCE, but not untilweek 16 in CELESTIAL), yet favor
regorafenib iftumor growth occurred at week 13 (assessed atweek 16
in CELESTIAL, but not until week 18 inRESORCE). Thus, the overall
direction of bias, ifany, remains unclear.
The grade 3 or 4 TEAE profiles for regorafeniband cabozantinib
were generally similar forboth matching-adjusted and
unmatchedcabozantinib populations (Fig. 4). The
Table 3 Median survival estimates for the matching-adjusted
second-line CELESTIAL population and the RESORCEpopulation:
weighted Kaplan-Meier estimates
KM-derived estimate, months(median [95% CI])
p value
Overall survival
Active treatment Cabozantinib (ESS = 187) 11.4 (8.9–17.0)
0.3474a
Regorafenib (n = 379) 10.6 (9.1–12.1)
Placebo CELESTIAL (ESS = 81) 7.2 (6.1–10.8) NE
RESORCE (n = 194) 7.8 (6.3–8.8)
Progression-free survival
Active treatment Cabozantinib (ESS = 187) 5.6 (4.9–7.3)
0.0005a
Regorafenib (n = 379) 3.1 (2.8–4.2)
Placebo CELESTIAL (ESS = 81) 1.9 (1.9–2.1) NE
RESORCE (n = 194) 1.5 (1.4–1.6)
CI confidence interval, ESS effective sample size, KM
Kaplan-Meier, NE not evaluateda Log-rank test
2688 Adv Ther (2020) 37:2678–2695
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exception was rates of grade 3 or 4 diarrhea,which were
statistically significantly lower inthe regorafenib population than
in either theunmatched or matching-adjusted
cabozantinibpopulations. There was also a trend towardhigher rates
of hypertension in the cabozan-tinib compared with regorafenib
populations;however, the difference was not
statisticallysignificant. When interpreting the safetyresults, it
is also noteworthy that sorafenib-intolerant patients were excluded
from RESORCE,but not from CELESTIAL. The MAIC procedureswere not
able to adjust for this between-trialdifference, resulting in the
possibility of a biastoward higher rates of TKI treatment
intoler-ance (and possibly later-stage disease) in theCELESTIAL
population. Overall, the wide con-fidence intervals depicted in the
forest plot oflog-OR estimates for TEAEs with cabozantinib(versus
regorafenib) indicate a high degree ofimprecision in the estimates,
likely arising fromthe very low frequency of grade 3 or 4 events
inthe placebo arms, particularly in CELESTIAL.
Limitations
Specific limitations associated with the PFS andTEAE estimates
have been discussed. While
MAIC procedures can reduce the impact ofpotentially
effect-modifying baseline character-istics for reported covariates,
they were not ableto adjust for between-trial differences in
assess-ment schedules or for the presence of sorafenib-intolerant
patients in the CELESTIAL popula-tion (versus their exclusion from
RESORCE).Such differences are unavoidable features ofsome indirect
treatment comparisons [27, 28]and network meta-analyses [38, 39],
but arerelevant factors to consider when interpretingtheir
results.
There are additional limitations to MAICanalyses that are also
worth of consideration.Matching cannot account for all
differencesbetween trial populations, and it is possible thatthe
results of this MAIC are affected by someresidual between-trial
differences, as evidencedby the difference in survival outcomes for
theplacebo arms despite matching and adjustment(Tables 3 and S5).
Additional effect modifierscan exist between comparator trials,
despitebaseline weighting and matching. For example,treatment
adherence following randomizationcan differ in comparator trials,
affecting resul-tant drug exposure and influencing
treatment-related outcomes. There may also be differencesin unknown
prognostic variables (i.e., covari-ates that affect outcome but do
not alter
0 5 10 15 20 25 30 35
326 133 48 13 4 2 2158 23 8 2 2 1 0
Months
0.00
0.25
0.50
0.75
1.00(a)Pr
obab
ility
of s
urvi
val
0 5 10 15 20 25 30 35
379 110 34 14 8 4194 20 5 1 0 0
Months
0.00
0.25
0.50
0.75
1.00(b)
Prob
abilit
y of
sur
viva
l
Number of patients at risk
CabozantinibPlacebo95% CI
Number of patients at risk
RegorafenibPlacebo
CabozantinibPlacebo
RegorafenibPlacebo
95% CI
Fig. 3 Kaplan-Meier curves for progression-free survival in the
matching-adjusted second-line CELESTIAL population(a) and the
RESORCE population (b). CI confidence interval
Adv Ther (2020) 37:2678–2695 2689
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treatment effect). In an anchored analysis,purely prognostic
variables do not affect inter-pretation of the results because they
do notaffect the relative treatment effects for eachdrug versus
placebo because of within-studyrandomization. However, in the
present unan-chored analysis, where the comparison ofcabozantinib
and regorafenib is based on abso-lute rather than relative
treatment outcomes,the results may be influenced by
potentialimbalances in unknown prognostic variables atstudy entry
or (particularly relevant to OS) byheterogeneity in
post-progression treatments.Heterogeneity in use of downstream
therapies isanother possible cofounding variable. InCELESTIAL, more
than one-quarter of patients(26% cabozantinib; 33% placebo)
received sub-sequent systemic or local liver-directed anti-cancer
therapy [10]. The equivalent proportion
is not reported for RESORCE and is not knownfor the
matching-adjusted second-line CELES-TIAL population, but some
degree of between-trial heterogeneity in use of
post-progressiontreatments is likely.
Finally, the reduced effective sample sizeresulting from MAIC
matching and adjustmentsdecreases the statistical power of
subsequentanalyses. A lack of power in this analysis wasreflected
in the low rates of TEAE, and theresultant imprecision was evident
in the highanchored log-ORs and large CIs for some
TEAEs.Furthermore, the necessary use of an unan-chored survival
analysis and related discardingof placebo data can result in
artificially narrowinterval estimates, with arbitrary
implicationson statistical significance. For these reasons,
theresults of a MAIC cannot replace evidence froma randomized
controlled trial.
Increased aspartate aminotransferaseUnmatched cabozantinib
populationMatching-adjusted cabozantinib population
Diarrheaa
Unmatched cabozantinib populationMatching-adjusted cabozantinib
population
Elevated bilirubineUnmatched cabozantinib
populationMatching-adjusted cabozantinib population
FatigueUnmatched cabozantinib populationMatching-adjusted
cabozantinib population
Palmar-plantar erythrodysesthesiaa Unmatched cabozantinib
populationMatching-adjusted cabozantinib population
HypertensionUnmatched cabozantinib populationMatching-adjusted
cabozantinib population
Favors cabozantinib Favors regorafenib
Log OR estimates422– 0–3 1–4– 1 3 5
Fig. 4 Forest plot of grade 3 or 4 TEAE log-OR (95% CI)estimates
for the unmatched and matching-adjustedsecond-line CELESTIAL
populations compared with the
RESORCE population. aUnanchored analysis. CI confi-dence
interval, OR odds ratio, TEAE treatment-emergentadverse event
2690 Adv Ther (2020) 37:2678–2695
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Clinical Interpretation
Despite these limitations, when evidence fromhead-to-head trials
is not available, a MAICoffers insight into the plausible
comparativeresults for different therapies in a commonclinical
context, which can be valuable forhealthcare professionals and
health technologydecision-makers. Such insights are
particularlyimportant when selecting the optimum treat-ment
approach for patients with advanced HCCfor whom the prognosis has
traditionally beenpoor, with few therapeutic options
available.First-line treatment in advanced HCC fre-quently fails
after a period of time owing toadaptive or intrinsic resistance,
diseaseprogression or significant toxicity [17]: thus,there is a
growing need for second- and later-line treatment options and for
insights that willhelp to guide clinicians when selecting
theoptimum treatment sequence for their patients.
From a clinical perspective, the results of thisanalysis
reinforce and further those of a recentnetwork meta-analysis of
randomizedcontrolled trials of second-line agents for use inHCC
after prior sorafenib [38]. The networkmeta-analysis included 13
trials and 11 differentsecond-line therapies for advanced HCC
andgenerated anchored efficacy and safetyestimates using everolimus
as the commoncomparator with OS as the primary endpoint.Of the 11
treatments included in the analysis,only cabozantinib and
regorafenib significantlyprolonged OS [38]. Overall, the authors
con-cluded that second-line cabozantinib and rego-rafenib offered
the best combination of efficacyand safety for patients with
advanced HCC fol-lowing prior sorafenib therapy. They furthernoted
that the role of cabozantinib may be ofparticular importance in
patients who wereintolerant to sorafenib, because
sorafenib-in-tolerant patients were excluded from theRESORCE trial
of regorafenib [38]. In clinicalpractice, a range of factors must
inform deci-sion-making in optimum treatment sequenc-ing. As well
as the anticipated effectiveness andtolerability, treatment
selection is influenced bypatient characteristics (e.g.,
comorbidities) andtheir preferences, route of administration,
dos-ing regimen and implications for patient
quality of life. Also worthy of consideration area patient’s
response to and tolerance of priortreatment as well as the
molecular targets ofavailable therapeutic options and whether
theycomplement those of prior treatment andaddress possible
mechanisms of resistance (e.g.,AXL, MER) [20, 21].
CONCLUSION
MAIC analyses permit indirect comparisonsbetween clinical trials
with heterogeneouspopulations but with common treatment out-comes.
In this MAIC analysis, which used datafrom the CELESTIAL and
RESORCE trials,unanchored survival estimates suggestcabozantinib
may be associated with similar OSand prolonged PFS compared with
regorafenibin patients with advanced progressive HCC whowere
receiving second-line treatment followingprogression after prior
sorafenib; regorafenibwas associated with lower rates of
diarrhea.Although this MAIC provides a useful indica-tion of the
comparative efficacy and safety ofthese two second-line agents, it
is not areplacement for a head-to-head comparativetrial.
ACKNOWLEDGEMENTS
The authors thank all patients involved in thesestudies as well
as their caregivers, care team,investigators and research staff in
participatinginstitutions.
Funding. This study, manuscript develop-ment and the journal’s
Rapid Service andOpen Access fees were funded by Ipsen.
TheCELESTIAL study was sponsored by Exelixis.The sponsor was
involved in the design of thestudy, analysis and interpretation as
well asreview of the manuscript.
Medical Writing, Editorial and OtherAssistance. The authors
thank Antonio RemiroAzocar (PhD) and Professor Gianluca Baio
ofUniversity College London, London, UK, fortheir contribution to
the study analysis and
Adv Ther (2020) 37:2678–2695 2691
-
Alison Chisholm (MPH) and Tamzin Gristwood(PhD) of Oxford
PharmaGenesis, Oxford, UK,who provided medical writing and
editorialsupport, which was sponsored by Ipsen inaccordance with
Good Publication Practiceguidelines.
Authorship. All named authors meet theInternational Committee of
Medical JournalEditors (ICMJE) criteria for authorship for
thisarticle, take responsibility for the integrity ofthe work as a
whole and have given theirapproval for this version to be
published.
Disclosures. GK Abou-Alfa: Research grantsfrom ActaBiologica,
Agios, Array, AstraZeneca,Bayer, Beigene, Bristol-Myers Squibb,
CasiPharmaceuticals, Celgene, Exelixis, Genentech,Halozyme, Incyte,
Mabvax, Polaris Puma, QEDTherapeutics and Roche; consultancy fees
fromAgios, AstraZeneca, Autem, Bayer, Beigene,Berry Genomics,
Bioline, Bristol-Myers Squibb,Celgene, CytomX, Debio, Eisai,
Exelixis, Fla-tiron, Genoscience, Incyte, Ipsen, Jansen, LAM,Lilly,
Loxo Oncology, Merck, MinapharmPharmaceuticals, Pfizer, QED
Therapeutics,RedHill Biopharma, Silenseed, Sillajen, Sobi,Targovax,
Therabionics, Twoxar and Yiviva. J-FBlanc: Consultancy fees from:
Bayer, Bristol-Myers Squibb, Esai Co. Ltd, Lilly, Ipsen andOnxeo.
A-L Cheng: Consultancy fees fromAstraZeneca, Bayer Schering Pharma,
BayerYakuhin, Bristol-Myers Squibb, CSR PharmaGroup Inc., Eisai,
Eli Lilly, Genentech/Roche,Merck Sharp & Dohme, Novartis and
OnoPharmaceutical; travel grants from Bayer Yaku-hin, Eisai,
Genentech/Roche and Roche (Tai-wan). B Daniele: Personal fees and
non-financialsupport from Bayer, Ipsen and Sanofi; personalfees
from AstraZeneca, Eli Lilly, Esai Co. Ltd,Incyte, Merck Sharp &
Dohme and Roche.I Guerra: employee of IQVIA, which was con-tracted
by Ipsen to conduct the analysis. RKKelley: Research grants (to
institution) for clin-ical trials from Adaptimmune, Agios,
AstraZe-neca, Bayer, Bristol-Myers Squibb, Eli Lilly, EMDSerono,
Exelixis, Merck, Novartis, PartnerTherapeutics, QED Therapeutics,
and TaihoPharmaceutical Group; consultancy fees (toinstitution)
from Agios, AstraZeneca, and
Bristol-Myers Squibb; consultancy fees (to self)from
Genentech/Roche and Gilead; travel sup-port (to self) from Ipsen.
Thomas Yau: Consul-tancy fees from Bayer, Bristol-Myers
Squibb,Eisai and Merck Sharp & Dohme. F Marteau, PMollon and V
Valcheva: employees of Ipsen.
Compliance with Ethics Guidelines. Theresults presented in this
manuscript are basedon previously published studies. All
proceduresperformed in those studies involving humanparticipants
were in accordance with the ethicalstandards of the local
Institutional ReviewBoards for each site and with the 1964
HelsinkiDeclaration and its later amendments or com-parable ethical
standards. Informed consent wasobtained from all individual
participants inclu-ded in the CELESTIAL (ClinicalTrials.gov
iden-tifier NCT01908426) and RESORCE(ClinicalTrials.gov identifier
NCT01774344)trials.
Data Availability. Where patient data canbe anonymized, Ipsen
will share all individualparticipant data that underlie the results
repor-ted in this article with qualified researchers whoprovide a
valid research question. Study docu-ments, such as the study
protocol and clinicalstudy report, are not always available.
Proposalsshould be submitted to [email protected] will be
assessed by a scientific review board.Data are available beginning
6 months andending 5 years after publication; after this time,only
raw data may be available.
Open Access. This article is licensed undera Creative Commons
Attribution-NonCommer-cial 4.0 International License, which
permitsany non-commercial use, sharing, adaptation,distribution and
reproduction in any mediumor format, as long as you give
appropriate creditto the original author(s) and the source,
providea link to the Creative Commons licence, andindicate if
changes were made. The images orother third party material in this
article areincluded in the article’s Creative Commonslicence,
unless indicated otherwise in a creditline to the material. If
material is not includedin the article’s Creative Commons licence
andyour intended use is not permitted by statutory
2692 Adv Ther (2020) 37:2678–2695
-
regulation or exceeds the permitted use, youwill need to obtain
permission directly from thecopyright holder. To view a copy of
this licence,visit
http://creativecommons.org/licenses/by-nc/4.0/.
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Comparative Efficacy of Cabozantinib and Regorafenib for
Advanced Hepatocellular
CarcinomaAbstractBackgroundObjectivesMethodsResultsConclusions
Plain Language SummaryIntroductionMethodsData Source
Identification And EligibilityMatching-Adjusted Indirect
Comparison: Cabozantinib and RegorafenibPopulation MatchingOutcome
Evaluation: Survival AnalysisOutcome Evaluation: Safety
AnalysesCompliance with Ethics Guidelines
ResultsPatient CharacteristicsSurvival OutcomesKM-Derived
EstimatesParametric Modeling Estimates
Safety Outcomes
DiscussionOutcome InterpretationLimitationsClinical
Interpretation
ConclusionAcknowledgementsReferences