September 12, 2022: “Updated results from the TOPAZ-1 Phase III trial showed AstraZeneca’s Imfinzi (durvalumab), in combination with standard-of-care chemotherapy demonstrated a clinically meaningful and durable overall survival (OS) benefit as a treatment for patients with advanced biliary tract cancer (BTC).
These results from TOPAZ-1, the first Phase III trial to show improved OS with an immunotherapy combination in this setting, will be presented today at the European Society for Medical Oncology (ESMO) Congress 2022 in Paris (abstract #56P).
The updated results for Imfinzi plus chemotherapy (gemcitabine plus cisplatin) showed enhanced clinical efficacy after an additional 6.5 months of follow-up, demonstrating a 24% reduction in the risk of death versus chemotherapy alone (based on a hazard ratio [HR] of 0.76; 95% confidence interval [CI], 0.64–0.91).
Updated median OS was 12.9 months versus 11.3 with chemotherapy. More than two times as many patients were estimated to be alive at two years versus chemotherapy alone (23.6% versus 11.5%). Results were seen across all prespecified subgroups, regardless of disease status, tumour location or PD-L1 expression.
In addition, OS benefit was observed in patients whose tumours stayed the same size (stable disease) as well as in patients whose tumours got smaller or disappeared (responders).
The safety profile of Imfinzi plus chemotherapy continued to be well-tolerated, with no new safety signals observed with longer follow-up.
Grade 3 or 4 treatment-related AEs were experienced by 60.9% of patients treated with Imfinzi and chemotherapy, and by 63.5% of patients receiving chemotherapy alone.
Imfinzi plus chemotherapy did not increase the discontinuation rate due to adverse events (AEs) compared to chemotherapy alone (8.9% for the Imfinzi combination versus 11.4% for chemotherapy).
Do-Youn Oh, MD, PhD, Professor, Division of Medical Oncology, Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine, and principal investigator in the TOPAZ-1 Phase III trial, said: “It’s exciting to see the improved overall survival delivered by durvalumab plus chemotherapy over the current standard of care for patients with advanced biliary tract cancer after a median follow-up of nearly two years.
With limited treatment advances over the past decade, these patients have long faced a dismal prognosis. For the first time, an immunotherapy-based combination has shown the ability to alter the course of treatment for this disease and should become the new standard of care.”
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “These longer-term data reinforce the survival benefit and well-tolerated safety profile of Imfinzi added to standard-of-care chemotherapy for patients with advanced biliary tract cancer.
With these results, the exploratory data from the HIMALAYA trial and the recent FDA approval based on the TOPAZ-1 trial, we are continuing to advance our commitment to extend survival for patients with gastrointestinal tumours who desperately need new treatment options.”
Summary of updated results: TOPAZ-1
| Imfinzi + chemotherapy (N=341) | Chemotherapy (n=344) | |
|---|---|---|
| OSi,ii | ||
| Median OS (95% CI) (in months) | 12.9 | 11.3 |
| HR (95% CI)iii | 0.76 (0.64, 0.91) | |
| OS rate at 12 months (95% CI) (%)iv | 54.3 | 47.1 |
| OS rate at 24 months (95% CI) (%) | 23.6 | 11.5 |
| OS by BoRv,vi | ||
| Median OS (95% CI), responders, months | 19.5 | 15.7 |
| HR (95% CI) respondersiii | 0.69 (0.46, 1.04) | |
| Median OS (95% CI), stable disease (SD), months | 13.6 | 11.5 |
| HR (95% CI) SDiii | 0.77 (0.62, 0.96) | |
| 12-month OS rate in responders (95% CI) (%)iv | 75.8 | 75.0 |
| 12-month OS rate in SD (95% CI) (%)iv | 57.5 | 48.0 |
| 24-month OS rate in responders (95% CI) (%)iv | 40.6 | 20.5 |
| 24-month OS rate in SD (95% CI) (%)iv | 20.7 | 10.6 |
OS, overall survival; HR, hazard ratio; CI, confidence interval; BoR, best overall response; SD, stable disease
i. 6.5 months of additional follow-up (data cut-off: 25 February 2022) after the primary analysis, with 76.9% overall OS event maturity
ii. At data cut-off for this analysis, median (95% CI) follow-up time (calculated using the inverse Kaplan-Meier techniques with the censoring indicator of OS reversed) was 23.4 (20.6–25.2) months for Imfinzi plus chemotherapy and 22.4 (21.4–23.8) months for chemotherapy
iii. HRs were calculated using a Cox proportional hazards model
iv. OS rates calculated using Kaplan-Meier techniques
v. To avoid immortal time bias, only participants surviving ≥ 3 months were included in this OS by best objective response analysis
vi. BoR was assessed by the investigator per Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 in all randomised participants with measurable disease at baseline and defined as response (complete response or partial response), SD or progressive disease (PD); BoR was determined based on the IA data cut-off (11 August 2021)
Earlier this month, Imfinzi in combination with chemotherapy was granted approval in the US as a treatment for adults with locally advanced or metastatic BTC based on results from TOPAZ-1. Regulatory applications are also currently under review in Europe, Japan and several other countries based on the TOPAZ-1 results.
In October 2021, the TOPAZ-1 trial met the OS primary endpoint at a predefined interim analysis, reducing the risk of death by 20% versus chemotherapy (based on a HR of 0.80; 95% CI, 0.66-0.97; 2-sided p=0.021).
HIMALAYA Phase III trial exploratory analysis by aetiology in unresectable hepatocellular carcinoma at ESMO
Also at ESMO, an exploratory analysis from the HIMALAYA Phase III trial evaluated the impact of disease causes on outcomes for patients with unresectable hepatocellular carcinoma (abstract #714P).
Data from HIMALAYA suggest a trend for OS benefit over sorafenib with the STRIDE regimen regardless of the underlying disease cause (hepatitis B virus [HBV], hepatitis C virus [HCV] or nonviral). Similar trends were observed with Imfinzi versus sorafenib across subsets.
In 2021, positive results from the HIMALAYA Phase III trial showed a single priming dose of tremelimumab, an anti-CTLA4 antibody, added to Imfinzi (STRIDE regimen) demonstrated a statistically significant and clinically meaningful improvement in OS versus sorafenib as a 1st-line treatment for patients with unresectable hepatocellular carcinoma (HCC) who had not received prior systemic therapy and were not eligible for localised treatment.
Patients treated with the STRIDE regimen experienced a 22% reduction in the risk of death versus sorafenib (based on a HR of 0.78, 96.02% CI 0.65-0.93; p=0.0035). Nearly one in three (31%) patients were still alive at three years versus one in five (20%) for sorafenib.
When subsets were adjusted for prognostic factor imbalances, patients with HBV treated with the STRIDE regimen experienced a 36% reduction in the risk of death versus sorafenib (based on a HR of 0.64, 95% CI 0.47-0.86).
Median duration of response was 25.69 months versus 17.00 months for sorafenib. Patients with HCV treated with the STRIDE regimen experienced an 11% reduction in the risk of death versus sorafenib (based on a HR of 0.89; 95% CI 0.63-1.25). Median duration of response was 13.5 months versus 15.7 months for sorafenib.
Nonviral patients treated with the STRIDE regimen experienced a 23% reduction in the risk of death versus sorafenib (based on a HR of 0.77; 95% CI 0.59-1.00). Median duration of response was 13.21 months versus 6.01 months for sorafenib.
The safety profiles of STRIDE and durvalumab were consistent across aetiology subgroups.
In the past, viral HCC (disease associated with cirrhosis related to chronic hepatitis B or hepatitis C) has been the primary aetiology of the disease.
Over the last two decades, the prevalence of non-viral HCC (disease associated with non-viral factors including liver disease, obesity and diabetes) has significantly increased.
HIMALAYA is the only Phase III trial to demonstrate a survival benefit for immunotherapy in participants with non-viral HCC.
The STRIDE regimen is under review by global regulatory authorities in unresectable HCC based on the results of the HIMALAYA trial.”
