4397 - An adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies

Background

Durvalumab (D), a PD-L1 inhibitor with efficacy in platinum refractory advanced urothelial cancer (UC), was investigated by combining with targeted therapy inhibitors (FGFR1,2,3, PARP, TORC 1 + 2) with a PD-L1 monotherapy arm (D alone) as a non-randomized control. An FGFRi monotherapy arm was also included.

Methods

Platinum refractory, immuno-therapy naïve UC patients were allocated, depending on tumour DNA alterations determined by next generation sequencing (NGS), to: arm A (randomisation of D + FGFRi AZD4547 vs AZD4547 monotherapy: for FGFR mutations/fusions), arm B (D + PARPi olaparib: for BRCA1/2, ATM and HRR gene alterations (GA) and unselected patients), arm E (D + mTORi vistusertib: enriched for TSC1/2 and RICTOR GA). Arm D (D only) followed by Arm F (D + STAT3 mRNA ASO danvatirsen) for patients without “actionable” GA. Primary objectives included safety and tolerability. Key secondary objectives included assessment of ORR and OS rate. Efficacy analysis was explored based on PD-L1 expression and tumour mutational burden (TMB).

Results

As of March 2019, of 393 patients’ whose tumours were screened with NGS, 154 started study drug and had a baseline tumor assessment. Confirmed responses were assessed according to RECIST 1.1 and ranged from 20% to 29% (Table). TMB and PD-L1 were inconsistent across arms (e.g. 38% TMB high for Arm E vs 5% in Arm A combination and 17% in Arm D). D monotherapy (n = 29) had an ORR of 28% [80% CI 17% - 41%] with 12% [80% CI 3.2% - 28%] and 45% [80% CI 24% - 63%] of patients alive and progression free and alive at 12 months, respectively. Complete responses were not prominent in any study arm. Arms A, D and E completed earlier than arms B and F. Data will be updated based on additional follow-up.Table:

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Conclusions

Combination treatments with durvalumab are tolerated. Clinical activity was seen in all arms of the study including both biomarker-selected and unselected individuals.

Clinical trial identification

NCT02546661; 11-Sep-2015.

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca AB, 151 85 Södertälje, Sweden.

Funding

AstraZeneca.

Disclosure

T. Powles: Honoraria (self): AstraZeneca, Roche, MSD, Pfizer, Novartis, Seattle Genetics, Ipsen; Research grant / Funding (institution): AstraZeneca, Roche, MSD. A. Balar: Honoraria (self): AstraZeneca; Roche-Genentech; Merck; Advisory / Consultancy: AstraZeneca, Genentech/Roche, Merck, Incyte, Seattle Genetics, DragonFly, Nektar; Research grant / Funding (institution): Merck, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb, AstraZeneca, Nektar; Shareholder / Stockholder / Stock options: EpiVax Oncology. G. Gravis: Travel / Accommodation / Expenses: BMS; Pfizer; Janssen; Ipsen. R. Jones: Honoraria (self): AstraZeneca; MSD; Merck Serono; Roche; BMS; Janssen; Astellas; Honoraria (institution): AstraZeneca, Janssen, Astellas; Advisory / Consultancy: AstraZeneca; MSD; Roche; BMS; Pfizer; Janssen; Astellas; Research grant / Funding (institution): Roche; Pfizer; AstraZeneca; Travel / Accommodation / Expenses: BMS; MSD; Astellas. A. Ravaud: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; BMS; AstraZeneca; Roche; MSD; Ipsen; Research grant / Funding (institution): Pfizer. J. Florence: Advisory / Consultancy: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS; Pfizer; Novartis; Sanofi; Astellas; Research grant / Funding (institution): Astellas; Travel / Accommodation / Expenses: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS. P. Grivas: Advisory / Consultancy: Merck & Co; Genentech; Dendreon; Bayer; Pfizer; Bristol-Myers Squibb; Exelixis; AstraZeneca; Biocept; Clovis Oncology; EMD Serono; Seattle Genetics; Foundation Medicine; Driver Inc.; QED Therapeutics; Heron Therapeutics; Janssen; Speaker Bureau / Expert testimony: Genentech; Bristol-Myers Squibb;; Travel / Accommodation / Expenses: AstraZeneca; Clovis Oncology; Research grant / Funding (institution): Merck & Co.; Genentech; Bayer; Mirati; Oncogenex; AstraZeneca; Pfizer; Clovis Oncology; Bavarian Nordic; Immunomedics. D.P. Petrylak: Advisory / Consultancy: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen; Research grant / Funding (institution): Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; Shareholder / Stockholder / Stock options: Bellicum, Tyme. M. Galsky: Advisory / Consultancy: AstraZeneca, BMS, Genentech, Merck, Pfizer, Dracen, Dragonfly Therapeutics, Astellas, Seattle Genetics, Janssen; Research grant / Funding (institution): AstraZeneca, BMS, Merck, Dendreon, Roche-Genentech. J. Carles: Advisory / Consultancy: Bayer; Johnson & Johnson; Bristol-Myers Squibb; Astellas Pharma; Pfizer; Sanofi; MSD Oncology; Roche; AstraZeneca; Speaker Bureau / Expert testimony: Bayer; Johnson & Johnson; Asofarma; Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma, AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb Intern. S. Sridhar: Advisory / Consultancy: AstraZeneca, Roche, Merck, BMS, Bayer, Janssen, Astellas. H. Arkenau: Leadership role: Sarah Cannon Research Institute; Research grant / Funding (self): AstraZeneca; Roche; BMS; Novartis; GSK; Servier; Astellas; Array; Iovance; Cytomx; Research grant / Funding (institution): Sarah Cannon Research Institute; Travel / Accommodation / Expenses: Iovance. D. Carroll: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Spouse / Financial dependant: Azeria Therapeutics. J. DeCesare: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. F. Mercier: Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Stat Process sarl (Paris, France) - CRO; Health Data Process (Alicante, Spain) - CRO. D. Hodgson: Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: AstraZeneca. J. Stone: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: GSK. J. Cosaert: Full / Part-time employment: AstraZeneca. D. Landers: Research grant / Funding (institution): Clinical Experimental Pharmacology Group, CRUK Manchester Institute, Manchester, UK; AstraZeneca; Full / Part-time employment: AstraZeneca.