The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has promising activity in HER2 amplified salivary gland tumors, according to data published in the Annals of Oncology.
The publication is for 'Arm Q,' which is one of nearly 40 single-arm phase two treatments in the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH or EAY131) trial. NCI-MATCH is being co-led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and the National Cancer Institute (NCI), part of the National Institutes of Health.
We saw that two of the three NCI-MATCH patients with salivary gland tumors had significant tumor shrinkage by at least 30% with T-DM1 treatment, and this benefit lasted. The benefit lasted two years in the patient with squamous cell cancer of the parotid gland, and nine months in the case of mucoepidermoid carcinoma of the parotid gland."- Komal Jhaveri, MD, FACP, lead researcher
Jhaveri is a medical oncologist and early-phase clinical trials specialist at Memorial Sloan Kettering Cancer Center in New York.
"This is a hint of activity that needs to become the focus of a larger trial," said Dr. Jhaveri.
Another recent T-DM1 trial (not part of the NCI-MATCH trial) reported interim results at the 2019 annual meeting of the American Society of Clinical Oncology.
In that trial (NCT02675829), nine of the 10 patients with salivary gland cancers treated with T-DM1 responded either with tumor shrinkage by computed tomography (CT) scan or as assessed by positron emission tomography (PET). As a result, that trial has since been expanded to enroll additional patients.
T-DM1 is a targeted therapy that contains the monoclonal antibody trastuzumab, which binds to the HER2 protein found on some cancer cells. It also contains the cytotoxic drug DM1, which inhibits tumor cell division.
Unlike chemotherapy, antibody-drug conjugates like T-DM1 are intended to target and kill tumor cells while sparing healthy cells. T-DM1 has improved overall survival and led to a new standard of care in HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane.
The primary objective of each arm in NCI-MATCH is to estimate the proportion of patients who had an objective response (OR). Under predefined criteria, an OR rate greater than 16% in a given NCI-MATCH arm would warrant further study of the agent(s).
Although the results from Arm Q did not meet these criteria, the signal in salivary gland tumors is important.
We are excited about the prospect of this and other upcoming MATCH arms to shed new light on responsive tumor types, as there is far less data available in rare and uncommon disease types from previously conducted trials," said Keith T. Flaherty, MD, a medical oncologist at Massachusetts General Hospital Cancer Center in Boston and ECOG-ACRIN study chair for the overall NCI-MATCH trial.
"Salivary cancer is a particularly understudied area and seeing evidence of benefit for a molecularly targeted approach strongly supports further focus on this cancer type."
Patients received T-DM1 at 3.6 mg/kg intravenously every three weeks until toxicity or disease progression.
Of the 38 patients enrolled in Arm Q, 36 were included in the efficacy analysis. Overall, this was a heavily pretreated group of patients with multiple unique histologies (excluding breast and gastric). Seventeen patients (47%) had stable disease with median duration of 4.6 months, including eight of 10 patients with ovarian and uterine carcinomas.
The six-month progression-free survival rate was 23.6%. Common toxicities were fatigue, anemia, fever and thrombocytopenia. However, this arm did not find any new toxicities for T-DM1.
There was a trend for tumor shrinkage with higher levels of gene copy number as determined by the tumor sequencing assay. The median HER2 copy number was 17 (range: seven-139). Notably, the patient with squamous cell cancer of the parotid gland had a HER2 gene copy number of 129 and the patient with mucoepidermoid carcinoma of the parotid gland had a copy number of 21.
"NCI-MATCH seeks to determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of their cancer type," said Lyndsay Harris, MD, Associate Director, Cancer Diagnosis Program, NCI, and co-PI of the NCI-MATCH trial.
"In certain studies, such as this, we also saw benefit in rare tumor types. Such discoveries could be eligible to move on to larger, more definitive trials."
The publication (Annals of Oncology, Volume 30, Issue 11, November 2019) marks a milestone for the NCI-MATCH trial, being the first results manuscript to appear in print.
Genentech Inc. provided ado-trastuzumab emtansine for Arm Q under a Clinical Trial Participation Agreement between NCI and Genentech.
Of the newly-discovered genetic variants, a third predispose women towards developing hormone-responsive breast cancer, the type of disease found in four out of five breast cancer patients, which respond to hormonal treatments such as tamoxifen. 15% of the genetic variants predispose women to the rarer type, estrogen-receptor-negative breast cancer. The remaining genetic variants play a role in both types of breast cancer.
In the majority of cases, the genetic change affected gene expression - in other words, how active a particular gene was and how much of a particular protein it created - rather than altering the type of protein itself. For instance, nine different variants regulate the same gene, the Estrogen Receptor (ESR1) gene. Many other variants affect places in the DNA where the Estrogen Receptor protein binds, and, in turn regulates other genes. This highlights the importance of the ESR1 gene and its protein product, the Estrogen Receptor, in breast cancer development.
While each genetic variant only increases the risk of developing breast cancer by a very small amount, the researchers say that added together, these will allow them to 'fine tune' genetic testing and give women a much clearer picture of their genetic risk. This will then allow doctors and clinicians to provide advice on the best strategy for reducing their risk and preventing onset of the disease.
Professor Doug Easton, also from the University of Cambridge, said: Our work would not have been possible without the help of the 200,000 volunteers who allowed us to study their DNA. It is also testament to the work of hundreds of researchers from all over the world who collaborated on this study."
