Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Plain language summary of the TOPAZ-1 study: durvalumab and chemotherapy for advanced biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Incidence and factors associated with cutaneous immune-related adverse events to immune check point inhibitors: An ambispective cohort study.

Background: Although immune checkpoint inhibitors (ICIs) have become the frontline treatment option for patients with various advanced cancers due to improved survival, they can be associated with a spectrum of cutaneous immune-related adverse events (cirAEs). However, little is known regarding the occurrence and patterns of cirAE-related ICI therapy in patients of different races other than white populations. Therefore, we investigated the incidence and associated factors of cirAEs among cancer patients in northern Thailand. Methods: A referral-center-based ambispective cohort study was conducted from January 1, 2017, to March 31, 2021. Based on a linked database and merged patient-level data, adult patients with pathologically confirmed cancer who were diagnosed and received ICI therapy regardless of cancer type and followed up through August 31, 2021, were included. All cirAE-related ICI therapy was based on clinical evaluation and ascertainment by a board-certified dermatologist. The incidence of cirAE-related ICI therapy with confidence intervals (CIs) across cancer- and ICI therapy-specific groups was estimated. Factors associated with cirAEs were evaluated using multivariable modified Poisson regression to estimate risk ratios (RRs) and 95% CIs. Results: The study included 112 patients (67 men [59.8%]; mean age, 65.0 [range, 31.0-88.0] years), who were mainly diagnosed with lung cancer (56.3%), followed by liver cancer (19.6%). The overall incidence of cirAE-related ICI therapy was 32.1% (95% CI, 24.1-41.4); however, there was no substantial difference in sex, cancer type, or individual ICI therapy. The two identified prognostic risk factors of cirAE-related ICI therapy were age >75 years (adjusted RR, 2.13; 95% CI, 1.09-4.15; P=0.027) and pre-existing chronic kidney disease stages 3-4 (adjusted RR, 3.52; 95% CI, 2.33-5.31; P<0.001). Conclusions: The incidence of cirAE-related ICI therapy among Thai cancer patients was comparable to that in white populations. Early identification, particularly in elderly patients and those with CKD, should be implemented in clinical practice to help optimize therapeutic decision-making and patient health outcomes.

Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer.

BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)

Effect of Insurance Type on Stage at Presentation, Surgical Approach, Tumor Recurrence and Cancer-Specific Survival in Resectable Non-Small Lung Cancer Patients.

PURPOSE: The aim of this study was to identify the association between Thailand's insurance types and stage at presentation, surgical approach, tumor recurrence and cancer-specific survival in resectable non-small cell lung cancer (NSCLC) patients in northern Thailand. PATIENTS AND METHODS: Medical records of patients with NSCLC who underwent pulmonary resection at Chiang Mai University Hospital from January 2007 through December 2015 were retrospectively reviewed. Patients were divided into two groups: patients with the Universal Coverage Scheme (UCS) or Social Security Scheme (SSS) and patients with the Civil Servant Medical Benefit Scheme (CSMBS) or private insurance (PI). Patient characteristics were assessed. The primary outcome was cancer-specific survival while the secondary outcome was tumor recurrence. Cox's regression and matching propensity score analysis was used to analyze data. RESULTS: This study included 583 patients: 344 with UCS or SSS and 239 with CSMBS or PI. Patients with UCS or SSS were more likely to be active smokers, have a lower percent predicted FEV1, present with higher-stage tumors and worse differentiated tumors, present with tumor necrosis, and undergo an open surgical approach than those with CSMBS or PI. At multivariable analysis of all patients cohort, there were no significant differences in terms of early stage at presentation (adjusted odds ratio (ORadj) = 0.94, 95% confidence interval (CI) = 0.65-1.37), undergoing lobectomy (ORadj = 0.59, 95% CI = 0.24-1.46), and recurrent-free survival (adjusted hazard ratio (HRadj) =1.20, 95% CI = 0.88-1.65) between groups (UCS/SSS versus CSMBS/PI). However, patients with UCS or SSS had shorter cancer-specific survival (HRadj = 1.61, 95% CI = 1.22-2.15). The results from the propensity score matched patient cohort were not different from those analyses on the full patient cohort. CONCLUSION: Thai insurance types have an effect on cancer-specific survival. The Thai government should recognize the importance of these differences, and further multi-center studies with a larger sample size are warranted to confirm this result.

Outcomes of pulmonary resection in non-small cell lung cancer patients older than 70 years old.

BACKGROUND: An appropriate treatment of older lung cancer patients has become an important issue. The aim of this study is to evaluate the short and long-term surgical outcomes in lung cancer patients using 70 years as a cut-point, and to identify prognostic factors of cancer-specific mortality in patients older than 70 years. METHODS: Medical records of non-small cell lung cancer (NSCLC) patients who underwent pulmonary resection at Chiang Mai University Hospital from January 2002 through December 2016 were retrospectively reviewed. Patients were divided into age less than 70 years (control group) and 70 years or more (study group). Primary outcomes were major post-operative complications and in-hospital death (POM); secondary outcome was long-term survival. Multivariable regression analysis was used. RESULTS: This study included 583 patients, 167 for study group, and 416 for control group. There were no differences in POM, both at univariable and multivariable analyses, however, for long-term cancer-specific mortality, the study group was more likely to die (HRadj = 1.40, 95%CI = 1.03-1.89). Adverse prognostic factors for long-term mortality in study group were having universal coverage scheme (HRadj = 1.70, 95%CI = 1.03-2.79), the presence of intratumoral lymphatic invasion (HRadj = 2.83, 95%CI = 1.28-6.29), perineural invasion (HRadj = 2.80, 95%CI = 1.13-6.94), underwent lymph node sampling (HRadj = 2.23, 95%CI = 1.16-4.30) and higher stage of disease (HRadj = 2.02, 95%CI = 1.06-3.85 for stage III, HRadj = 3.40, 95%CI = 1.29-8.94 for stage IV). CONCLUSIONS: In-hospital mortality and composite post-operative complications are acceptable in pulmonary resection for NSCLC patients older than 70 years. However, these patients had shorter long-term survival, especially who have some adverse prognostic factors. Further studies with larger sample size are warranted.