Outcomes of durvalumab (D) with or without tremelimumab (T) in routine clinical practice according to HIMALAYA trial eligibility: Preliminary results of the international DT-real study.
Authors: Celsa Ciro , Nishida Naoshi , Chamseddine Shadi , Arvind Ashwini , Li Michael , Toyoda Hidenori , Ulahannan Susanna Varkey , Fulgenzi Claudia A.M. , Manfredi Giulia F , D'Alessio Antonio , Stefanini Bernardo , Cabibbo Giuseppe , Cammà Calogero , Scheiner Bernhard , Rimassa Lorenza , Kelley Robin Kate , Singal Amit , Kaseb Ahmed Omar , Kudo Masatoshi , Pinato David James 
Published: January 2025

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Background:
HIMALAYA showed that D+T and D are effective options for unresectable hepatocellular carcinoma (uHCC). However, data on outcomes according to the adherence to HIMALAYA inclusion criteria in routine clinical practice are lacking.
Methods:
In the context of a prospectively maintained database including 1293 patients (pts) with uHCC treated with immunotherapy, we analysed pts treated with D+T or D across 8 centres in USA, Asia and Europe. Pts who met >1 key exclusion criterion of HIMALAYA (prior systemic therapy, Child-Pugh class B-C, Vp4 thrombosis) were defined HIMALAYA-OUT and compared with HIMALAYA-IN pts for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0.
Results:
Up to February 2024, 108 pts (mean age 66 years, male sex 81%) started D+T (n=69, 64%) or D (n=39, 36%). 62 pts (57%) were treated in 1° line and 46 (43%) in >2° line. Child-Pugh class was A in 67 pts (62%). Vp4 was present in 17 pts (16%). 31 pts (29%) were HIMALAYA-IN and 19/31 (61%) received D+T. After a median follow-up of 4.3 months (m, 95%CI 3.3-4.9), median OS (mOS) was 11.5 m and 12-m OS rate was 42%. mOS was not reached in HIMALAYA-IN pts (12-m OS rate 62%) and 8.9 m (95%CI 6.0-12.1) in HIMALAYA-OUT pts. Survival hazard ratio (HR) for HIMALAYA IN vs OUT was 0.28 (95%CI 0.09-0.93, p=0.037). Median PFS was 2.6 m (95% CI 2.2-5.2) overall, 4.6 m (95%CI 2.1-8.5) in HIMALAYA-IN and 2.6 m (95%CI 1.9-5.2) in HIMALAYA-OUT pts (HR 0.70, 95%CI 0.38-1.30, p=0.266). ORR and DCR (evaluable in 53 pts, 49%) were 15.1% (95%CI 6.5-29.7%) and 43.4% (95%CI 27.5-65.1) (Table). Any grade TRAEs occurred in 31.5% (95% 21.8-44.0%), grade 3-4 TRAEs in 8.3% (95%CI 3.8-15.8%), TRAEs requiring systemic corticosteroids in 8.3% (95%CI 3.8-15.8%) and discontinuation due to toxicity in 3.7% (95%CI 1.0-9.5%).
Conclusions:
Preliminary observational data from DT-Real study suggest a reproducible efficacy and safety of D+T and D in pts with uHCC fitting the inclusion criteria of HIMALAYA in routine clinical practice.

HIMALAYA IN (n=31)
HIMALAYA IN
HIMALAYA OUT (n=77)
HIMALAYA OUT

D+T (n=19)

D (n=12)

D+T (n=50)

D
(n=27)

mOS (m, 95%CI)
NR
NR
NR
8.9 (6.0-12.2)
11.2 (6.6-13.2)
4.9 (2.6-12.2)

12-m OS (%)
61.8
63
88.9
37.2
37.4
44.4

mPFS (m, 95%CI)
4.6 (2.1-8.4)
8.5 (2.1-8.5)
2.4 (1.6-2.5)
2.6 (1.9-5.2)
2.4 (1.8-6.7)
2.6 (1.8-5.2)

ORR (%,95%CI) (N=53)
23.1 (4.8-67.4)
25.0 (5.1-73.1)
0
12.5 (4.1-29.2)
13.8 (3.8-35.3)
9.1 (0.2-50.6)

DCR (%, 95%CI)
46.2 (16.9-100)
50.0 (18.3-100)
0
42.5 (24.8-68.1)
41.4 (21.4-72.2)
45.4 (14.8-100)

Any grade TRAEs (%,95%CI)
32.3 (15.5-59.3)
31.6 (11.6-68.7)
33.3 (9.1-85.4)
31.2 (20.0-46.4)
28.0 (15.3-47.0)
37.1 (17.8-68.1)

Grade 3-4 TRAEs (%, 95%CI)
9.7 (2.0-28.3)
15.8 (3.3-46.1)
0
7.8 (2.9-17.0)
4.0 (0.5-14.4)
14.8 (4.0-38.0)