68O - Impact of mutation status on efficacy outcomes in TOPAZ-1: A phase III study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+GC) in advanced biliary tract cancer (BTC)

Background

In the double-blind, Phase 3 TOPAZ-1 study (NCT03875235), overall survival (OS) with D+GC versus PBO+GC was significantly improved in patients (pts) with previously untreated advanced BTC (Oh et al. NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2200015). An exploratory objective of the TOPAZ-1 study was to assess efficacy outcomes by tumour mutations.

Methods

Eligible pts were randomised 1:1 to receive D+GC or PBO+GC. Genomic profiling of formalin-fixed paraffin-embedded tumour tissues from biomarker-evaluable pts (BEPs) was performed using the FoundationOne® panel (Foundation Medicine, Cambridge, MA). Mutation prevalence and outcomes based on the 25 February 2022 data cut-off were descriptively assessed across subtype and geographical region subgroups.

Results

BEPs comprised 441/685 pts (64% of full analysis set). TP53, CDKN2A/CDKN2B/MTAP on chromosome 9p21, KRAS and ARID1A were the most frequently altered genes. Mutation prevalence varied by subtype, consistent with previous reports. OS hazard ratios (HR) with D+GC versus PBO+GC for pts with mutant or wild-type genes that are clinically actionable with prevalence greater than 3% are shown (Table). While prevalence is low for many of the alterations, HRs<1 are noted for all clinically actionable mutant subtypes except ERBB2 alterations. However, response rates were nominally higher in the majority of D+GC vs PBO+GC groups, including ERBB2 alterations, suggesting activity in these subgroups Table: 68O

Prevalence of clinically actionable alterations in TOPAZ-1 by primary tumour location and geographical region

RoW, rest of the world

Conclusions

BTC mutation prevalence in TOPAZ-1 by primary tumour location and geographical region was consistent with other studies. Although pt numbers were low and the confidence intervals were broad, pts with clinically actionable alterations (IDH1, BRAF and BRCA1/2 mutations and FGFR2 rearrangements) appeared to benefit from D+GC.

Clinical trial identification

NCT03875235.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Elaine Groat, PhD, of CMC Connect, McCann Health Medical Communications, with funding from AstraZeneca, in accordance with Good Publication Practice (GPP3) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.W. Valle: Financial Interests, Personal, Advisory Board: Astra-Zeneca, Agios, QED, NuCana BioMed, Servier, Image Equipment Ltd. (AAA), Hutchinson Medipharma, Zymeworks, Sirtex, Baxter, Autem, Hutchinson Medipharma; Financial Interests, Personal, Invited Speaker: Ipsen, Mylan, Incyte; Financial Interests, Institutional, Research Grant, Grant funding for ABC-12 study: AstraZeneca; Financial Interests, Institutional, Research Grant, University of Manchester: RedX. L. Antonuzzo: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Amgen, MSD, BMS; Financial Interests, Institutional, Other, research founding: novartis. D. Tougeron: Financial Interests, Personal, Advisory Board: AstraZeneca, Sanofi, AMGEN, MSD, Roche, Servier, Servier, Pierre Fabre. B.J. Tan: Financial Interests, Institutional, Other, Grant and research support: Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelixis, and Zymeworks. M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Ono, Takeda, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, NIHON Servier, Takeda; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, NIHON SERVIER, Delta-Fly Pharma, Syneos Health, Merus.N.V. V. Guthrie, P. McCoon, Y.S. Lee, N. Rokutanda: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Watras: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of AstraZeneca Poland: AstraZeneca. G. Cohen: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of AstraZeneca. Position is Global Clinical Lead in Immuno-oncology: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Own stock in the company as an employee: AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. All other authors have declared no conflicts of interest.