Thread by @LizzieAbyMD

For #GIJournalClub – we will discussing the @NEJM article:
Atezolizumab + Bevacizumab in Unresectable HCC (IMbrave150 trial) by Dr. Richard Finn et al.
Expert opinion: @SeragHashem
Moderators: @AtoosaRabiee @jturnesv

nejm.org/doi/full/10.10…

#livertwitter #GIJC #hpbcsm

Background:
- Sorafenib in 2008: improved OS + longer time to radiologic progression vs placebo
nejm.org/doi/full/10.10…

Single agent PD-L1 inhibitor w/o improved OS
- Nivoumab vs sorafenib: No statistically significant improvement in OS w/nivolumab
sciencedirect.com/science/articl…

Background – drug mechanisms:
- Atezolizumab: a programmed death ligand 1 (PD-L1) inhibitor
- Bevacizumab: a monoclonal antibody targeting the VEGF
- Sorafenib: multikinase inhibitor

Picture credit: nature.com/articles/s4157…

Clinical Question
In this phase III trial, for patients with advanced HCC does Atezolizumab + Bevacizumab (combo tx) lead to improved overall & progression free survival in those w/o previous systemic treatment?

Design:
-Open-label, global, phase 3 trial
-Patients: adults, locally advanced or unresectable (or both) HCC, no previous systemic treatment, not amenable to curative or locoregional therapies or had progressed
-501 randomly assigned, 2:1 Atezolizumab + bevacizumab vs sorafenib

Excluded 🛑
- ECOG score 2-5
- Child Pugh Class B or C
- History of autoimmune disease
- Co-infection w/HBV or HCV
- Untreated esophageal or gastric varices [all patients enrolled had an EGD w/in 6 months of enrollment, given association b/w VEGF therapy & bleeding risk]

Primary endpoints
- Overall survival (OS)
- Progression free survival (PFS)

Secondary endpoints:
- Objective response rate
- Duration of response
- Time to deterioration of quality of life, physical functioning, and role functioning

📈Analysis: Intention to treat

Results:
- Reduced death w/combo tx vs sorafenib (28.6% vs 39.4%; HR for death: 0.58, P<0.001)
- OS was longer w/combo tx at both 6 & 12 months vs sorafenib
* 6 months: 84.7% (combo tx) vs 72.2% (sorafenib)
* 12 months: 67.2% (combo tx) vs 54.6% (sorafenib)

Results:
- 58.6% & 66.1% of patients receiving combo tx vs sorafenib had disease progression or died
- PFS was significantly longer w/combo tx vs sorafenib (6.8 vs. 4.3 months; HR 0.59; P<0.001)
- Objective response rates were 27.3% vs 11.9% w/combo tx vs sorafenib (P<0.001)

Treatment w/combo tx delayed median time to deterioration:
1⃣Patient-reported quality of life (11.2 vs 3.6 months w/combo tx vs. sorafenib; HR 0.63)
2⃣Physical functioning (13.1 vs. 4.9 months; HR, 0.53)
3⃣Role functioning (9.1 vs. 3.6 months; HR, 0.62)

Safety:
- The incidence of adverse events (AEs) of any grade was similar between groups: 98.2% vs 98.7%.
- Serious AEs: more frequent w/combination tx (38.0% vs 30.8%)
- AEs leading to dose modification or interruption occurred in 49.5% vs 60.9% of pts on combo tx vs sorafenib

Limitations
- Open label, but a blinded independent review of imaging was done to reduce bias
- CTP B & C were excluded & all patients had an EGD w/in 6 months. The safety of combo tx in more decompensated patients needs further study
- Supported by F. Hoffmann–La Roche/Genentech

⭐️Conclusions⭐️
Atezolizumab plus bevacizumab (vs sorafenib) resulted in significantly better overall survival and progression free survival in patients with unresectable HCC without prior systemic treatment

nejm.org/doi/full/10.10…
#livertwitter #GIJC