CNS Relapse Highlighted Among HERACLES-A Patients

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Long-term follow-up of a group of HERACLES-A trial participants with HER2-positive chemorefractory metastatic colorectal cancer (CRC) has detected an “unexpectedly high” rate of central nervous system (CNS) metastases, report Italian researchers.  

Over a median of 6.7 years of follow-up, 19% of a cohort of 32 patients developed CNS metastases, as either isolated disease (n=3) or alongside metastases in lymph nodes, liver, bone and the lung. 

Overall, 28% of these patients had previously achieved an objective response to treatment with trastuzumab and lapatinib, while 28% had achieved stable disease for at least 4 months, giving a disease control rate of 56%. 

The median time to CNS metastases was 7.9 months and median overall survival (OS) was 11.4 months in this group, following on from previously reported median progression-free survival (PFS) and OS durations in the overall trial cohort of 4.7 and 10.0 months, respectively,  

In a letter to JAMA Oncology, Salvatore Siena, from Grande Ospedale in Milan, and co-authors say that two patients received stereotactic brain radiation and one patient underwent neurosurgical excision of a cerebellum metastasis, and that these treatments were “overall favorably associated with OS”, with the patient who received surgery achieving PFS for 11.5 months. 

Two patients with a poor performance status received best supportive care and a third was lost to follow-up, they add. 

The investigators hypothesize that the “unexpectedly high occurrence of CNS metastases” in this patient population may be “a biological tropism towards CNS of [HER2]-amplified cells”, “a limitation of these drugs targeting [HER2] to cross the blood-brain barrier”, or perhaps an increased risk of less common metastases with the longer survival duration.  

Believing that “CNS may represent a sanctuary of CRC relapse in this setting, mirroring what occurs with [HER2]-targeted therapies in breast and gastric cancers”, the team concludes that further research might “investigate the potential of next-generation [tyrosine kinase inhibitors] with improved CNS activity, such as neratinib and tucatinib.” 

Reference  

Sartore-Bianchi A, Lonardi S, Aglietta M, et al. Central nervous system as possible site of relapse in ERBB2-positive metastatic colorectal cancer: Long-term results of treatment with trastuzumab and lapatinib. JAMA Oncol; Advance online publication 23 April 2020. doi:10.1001/jamaoncol.2020.0571