Page 24 - Read Online

Page 12 of 14 Daniele et al. Hepatoma Res 2021;7:61 https://dx.doi.org/10.20517/2394-5079.2021.58

Notwithstanding the very low statistical power of BOOST that does not allow drawing any firm conclusions,
the lack of any positive efficacy signal and the very poor compliance to sorafenib, together with all the
available evidence mentioned above, led us to believe that there is no more room for programming further
similar trials. Unfortunately, the lack of generalizability of study results to Child-Pugh B patients will also
affect new drugs in HCC. Patients with CP-B were either completely excluded from registered trials of
[29]
[30]
regorafenib and lenvatinib or allowed only if the Child score was 7 in the nivolumab CheckMate 040
study (with only 49 patients actually enrolled in the expansion cohort) . The analysis of this latter group of
[31]
patients indicated that, similar to sorafenib, nivolumab can be administered to some patients with Child-
Pugh B liver function. However, the efficacy of nivolumab in this setting remains to be demonstrated. A
retrospective analysis of a subgroup of 73 patients randomized in the CELESTIAL trial (51 to cabozantinib
and 22 to placebo) who progressed to Child-Pugh B class at Week 8 of treatment showed that, while the OS
benefit of cabozantinib over placebo was maintained, some Grade 3/4 adverse events (fatigue, ascites, AST
elevation, and thrombocytopenia) were more common in the cabozantinib arm, while others (palmar-
plantar erythrodysesthesia and hypertension) were more frequent in the placebo arm .
[32]
Thus, systemic treatment of advanced HCC patients with Child-Pugh B liver cirrhosis will remain an unmet
need in the next years as well.

In conclusion, the BOOST trial failed and suggests that, when a wide registration of drugs (i.e., not fully
supported by scientific evidence) has occurred, it may preclude advancing the knowledge of the actual
efficacy of these drugs in selected populations. In fact, due to the availability of a drug in the general practice
setting, neither will the investigators propose nor will the patients accept to be randomized to BSC. This
scenario, as well as the BOOST results, should inspire researchers and the industry to plan clinical trials in
definitive populations early in the development plan and the regulators to ask for more definitive evidence
before clearing drugs for the general use in practice .
[33]

DECLARATIONS
Acknowledgments
We thank Giuliana Canzanella, Marilena Martino, Maria Teresa Ribecco, Fiorella Romano, Giovanni de
Matteis, Alfonso Savio, Lucia Sparavigna, Antonia Del Giudice, Simona Bevilacqua, Manuela Florio,
Valentina Barbato, Anna Gimigliano for trial management at the Clinical Trial Unit of the Istituto
Nazionale Tumori, IRCCS, Fondazione G.Pascale, Napoli.

Authors’ contributions
Contributed conception, design and implementation of the research, to the analysis and interpretation of
the data and to the writing of the manuscript: Daniele G, Schettino C, Piccirillo MC, Gargiulo P, Perrone F,
Gallo C, Arenare L, Daniele B
Contributed to acquisition and interpretation of data: Farinati F, Federico P, Tamberi S, Crivellari G,
Barni S, Tortora R, Izzo F, Frassoldati A, Cavanna L, Mucciarini C, Bolondi L, Dinota A, Pelizzaro F,
Di Maio M, Bilancia D
All the Authors give final approval of the manuscript to be submitted.

Availability of data and materials
Data of this study will be shared with publication upon reasonable and motivated request to the Principal
Investigator of the study (bruno.daniele@aslnapoli1centro.it). The following IPD will be available for
sharing: baseline characteristics of patients, treatment data, safety data, follow-up data. There will be no
time limit for data sharing.