Abstract 57P
Background
In TOPAZ-1 (NCT03875235), D + GC significantly improved overall survival (OS) vs PBO + GC for patients (pts) with advanced BTC (Oh et al. J Clin Oncol 2022;40(suppl. 4): Abs 378). D (immune checkpoint inhibitor) may cause imAEs; imAEs have been associated with improved OS (Zhou et al. BMC Med 2020;18:87).
Methods
Safety was assessed in pts who received ≥1 dose of study treatment: D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on days 1 and 8 Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. imAE (AEs of special/possible interest, linked to drug exposure, likely immune-mediated mechanism, no clear alternate aetiology) incidences were calculated by programmatic adjudication. OS hazard ratio (HR) and median OS (mOS) were calculated using the Kaplan-Meier method. Confidence interval (CI) for mOS was derived based on Brookmeyer-Crowley method.
Results
imAEs occurred in more pts in D + GC vs PBO + GC (Table; 1 pt may have >1 imAE). Incidence of Grade 3/4 or serious imAEs was low; median time to onset (mTTO) varied. The most common imAEs (>1% of pts in either arm) were hypothyroid events, dermatitis/rash, hepatic events and adrenal insufficiency (Table). imAEs in D + GC required concomitant treatment more frequently than PBO + GC (Table). imAEs were generally manageable and consistent with the known safety profile. In D + GC, mOS was numerically greater in pts with an imAE of any grade (17.3 months; 95% CI, 12.4–non-calculable]) vs those without (12.6 months; 95% CI, 10.5–13.6; OS HR 0.62; 95% CI, 0.38–0.97). Table: 57P
| D + GC (N=338) | PBO + GC (N=342) | |
| Any imAE, n (%) | 43 (12.7) | 16 (4.7) |
| Grade 3 or 4 | 8 (2.4) | 5 (1.5) |
| Serious | 6 (1.8) | 5 (1.5) |
| With outcome of death | 0 | 1 (0.4) |
| Leading to treatment discontinuation | 3 (0.9) | 4 (1.2) |
| mTTOa | 108.0 (1–511) | 86.5 (4–533) |
| Hypothyroid events, n (%) | 20 (5.9) | 5 (1.5) |
| mTTOa | 111.0 (1–394) | 98.0 (43–292) |
| Dermatitis/rash, n (%) | 12 (3.6) | 1 (0.3) |
| mTTOa | 71.5 (1–344) | 134.0 (134–134) |
| Hepatic events, n (%) | 4 (1.2) | 2 (0.6) |
| mTTOa | 90.0 (7–221) | 268.5 (4–533) |
| Adrenal insufficiency, n (%) | 4 (1.2) | 1 (0.3) |
| mTTOa | 206.0 (86–511) | 143.0 (143–143) |
| Concomitant treatment (%) | ||
| Systemic corticosteroids | 8.0 | 3.5 |
| High dose steroids | 3.8 | 2.9 |
| Endocrine therapy | 6.5 | 1.5 |
| Other immunosuppressant | 0.3 | 0.3 |
aDays (range; in pts with an imAE)
Conclusions
Most imAEs were Grade 1/2 and manageable; imAEs did not increase discontinuation. imAEs occurred at any time during/after treatment; mTTO varied depending on type. Although pt numbers are low, imAEs may be associated with greater OS benefit; further investigation is warranted.
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 Publications Practice (GPP3) guidelines.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
L. Antonuzzo: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Amgen, MSD, BMS; Financial Interests, Institutional, Other, research founding: Novartis. H. Takahashi: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Mylan, Yakult, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Funding: Taiho Pharmaceutical. J.O. Park: Other, Personal, Advisory Board: Roche, AstraZeneca, Bayer; Other, Personal and Institutional, Other, Clinical study: BMS, Ono, Roche, AstraZeneca, MSD, Exelisix; Other, Personal, Other, Co-author: BMS; Other, Personal, Other, Writing engagement: Bayer, Ipsen, Roche, Guerbet. A. Sookprasert: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol, Eisai, Merck, Roche, Janssen, Pfizer, Novartis. S. Yang: Financial Interests, Personal, Other, Speaker’s Bureau & Advisory Board: AbbVie, Ipsen; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Roche. J.E. Cundom: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, AstraZeneca, Takeda, Roche. M. Petrova: Financial Interests, Personal, Invited Speaker: AstraZeneca, EwoPharm, Takeda; Financial Interests, Personal, Advisory Board: Servier, Roche; Non-Financial Interests, Principal Investigator: AstraZeneca, Sanofi. G.M. Vaccaro: Financial Interests, Personal, Invited Speaker: Incyte; Financial Interests, Personal, Advisory Board: Helsinn Therapeutics, Array Biopharma, Taiho Oncology, Merck Sharp & Dohme Corporation, Exelixis; Financial Interests, Personal, Other, Food and beverage: Eisai. M. Holmblad: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Xiong: Financial Interests, Personal, Stocks/Shares: AstraZeneca. K. Heider: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Rokutanda: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: 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.