Durvalumab plus gemcitabine-cisplatin improves survival in advanced BTC across genomic variants

First-line treatment with durvalumab plus gemcitabine and cisplatin (GC) leads to improved overall (OS) and progression-free survival (PFS) in advanced biliary tract cancer (BTC) across genomic variants, according to the results of the phase III study TOPAZ-1, presented at the ESMO Asia 2022.

“Benefit was consistently observed with durvalumab plus GC for OS, objective response rate, and PFS, including in participants with clinically actionable alterations, though the prevalence of some alterations was low,” said Do-Youn Oh, co-author of the study, from the Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

In the TOPAZ-1 study, durvalumab plus GC significantly improved OS relative to placebo plus GC in patients with previously untreated advanced BTC. [N Engl J Med 2022;doi:10.1056/EVIDoa2200015]

To assess the efficacy outcomes by tumour mutations, Oh and colleagues randomized eligible patients to receive durvalumab plus GC or placebo plus GC. They performed genomic profiling of formalin-fixed paraffin-embedded tumour tissues from biomarker-evaluable patients (BEPs) using the FoundationOne panel (Foundation Medicine, Cambridge, MA).

Finally, the researchers descriptively assessed mutation prevalence and outcomes across subtype and geographical region subgroups based on the 25 February 2022 data cutoff.

A total of 685 patients were included, of whom 441 were BEPs (64 percent of full analysis set). The most frequently altered genes were TP53, CDKN2A/CDKN2B/MTAP on chromosome 9p21, KRAS, and ARID1A. Mutation prevalence varied by subtype, which was consistent with earlier studies.

Durvalumab plus GC was effective in patients with clinically actionable and high-prevalence genomic alterations. Durvalumab, compared with placebo, demonstrated similar OS benefit for patients with either wild-type or altered genotypes. [ESMO Asia 2022, abstract 680]

The hazard ratios (HRs) for OS with durvalumab plus GC for patients with mutant or wild-type genes were as follows: IDH1 (wild-type: HR, 0.77, 95 percent confidence interval [CI], 0.61‒0.96; mutant: HR, 0.76, 95 percent CI, 0.31‒1.84), ERBB2 amplification (wild-type: HR, 0.72, 95 percent CI, 0.57‒0.90; mutant: HR, 1.71, 95 percent CI, 0.82‒3.56), BRCA1/ BRCA2 (wild-type: HR, 0.76, 95 percent CI, 0.61‒0.95; mutant: HR, 0.43, 95 percent CI, 0.12‒1.53), BRAF (wild-type: HR, 0.76, 95 percent CI, 0.61‒0.95; mutant: HR, 0.62, 95 percent CI, 0.21‒1.79), and FGFR2 rearrangement (wild-type: HR, 0.76, 95 percent CI, 0.61‒0.95; mutant: HR, 0.55, 95 percent CI, 0.12‒2.60).

Of note, 95 percent CIs for some genomic alterations were wide due to their low prevalence. Although patient numbers were low for many of these alterations, HRs <1 were observed for all clinically actionable mutant subtypes, except ERBB2 alterations, indicating the OS benefit with durvalumab.

“However, response rates were nominally higher in the majority of durvalumab plus GC vs placebo plus GC groups, including ERBB2 alterations, suggesting activity in these subgroups,” the researchers said.

Likewise, PFS benefit with durvalumab plus GC was similar in patients with either wild-type or altered genotype, according to Oh.

“BTC is a heterogeneous group of diseases, both anatomically and molecularly,” Oh said.