PracticeUpdate Oncology May 2019

EDITOR’S PICKS 9

Capecitabine ComparedWith Observation in Resected Biliary Tract Cancer

The Lancet Oncology Take-home message

• This phase III study investigated if adjuvant capecitabine is beneficial for patients with resected biliary tract cancer. In the intention-to-treat analysis, the median recurrence-free survival was 24.4 months in the capecitabine group and 17.5 months in the observation group. According to per-protocol analysis, the median recurrence-free survival was 25.9 months in the capecitabine group and 17.4 months in the observation group. • Although the study did not meet its primary endpoint, the data strongly suggest a survival benefit in the range of 14.7 months with adjuvant capecitabine. Neil Majithia MD Abstract

Abstract PURPOSE Evidence-based treatments for meta- static, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activ- ity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS ANDMETHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radio- therapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m 2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduc- tion of 50% or more in the sum of target CNS lesion volumes without progression of nontar- get lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median sur- vival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B). CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted. TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epider- mal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases. J Clin Oncol 2019 Mar 12;[EPub Ahead of Print], RA Freed- man, RS Gelman, CK Anders, et al. www.practiceupdate.com/c/81137

BACKGROUND Despite improvements in multi- disciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adju- vant therapy. We aimed to determine whether adjuvant capecitabine improved overall sur- vival compared with observation following surgery for biliary tract cancer. METHODS This randomised, controlled, multicen- tre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eli- gible patients were aged 18 years or older and had histologically confirmed cholangiocarci- noma or muscle-invasive gallbladder cancer who had undergone a macroscopically com- plete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooper- ative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for bil- iary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m 2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or obser- vation commencing within 16 weeks of surgery. Treatment was not masked, and allocation con- cealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. FINDINGS Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecit- abine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. Themedian follow-up for all patientswas 60 months (IQR 37-60). In the intention-to-treat analy- sis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation

group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sen- sitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HRwas 0·71 (95%CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecit- abine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analy- sis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the obser- vation group. Adverse events were measured in the capecitabine group only, and of the 213 patientswho received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most fre- quent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol anal- yses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemother- apy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. Capecitabine Compared With Observation in Resected Biliary Tract Cancer (BILCAP): A Ran- domised, Controlled, Multicentre, Phase 3 Study. Lancet Oncol 2019Mar 25;[EPub Ahead of Print], JN Primrose, RP Fox, DH Palmer, et al. www.practiceupdate.com/c/81577

VOL. 3 • NO. 2 • 2019