I presented the phase II basket trial of ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers. In this study we looked at this very rare disease. Salivary gland cancers account for about 0.8% of all cancers and within this group the salivary duct cancers are an aggressive subtype that is associated with metastatic disease and poor prognosis. There’s no established standard of care and no FDA approved therapy for these patients.
So we looked at from a molecular angle HER2 amplification turns out to be quite common in this rare tumour and it’s 8% of salivary gland cancers and up to 30% of salivary duct carcinomas. We looked at an FDA approved HER2 antibody drug conjugate called ado-trastuzumab emtansine to look at its activity in patients with metastatic salivary gland cancers that are HER2 amplified. Of the ten patients we accrued we saw 90% were male and with a median age of 65, so it is a disease of predominantly older men although I did have a young woman on this study so it’s by no means entirely exclusive. Those patients were heavily pre-treated with a median of two lines of prior therapy, including HER2 targeted therapy with trastuzumab and pertuzumab as well as antiandrogen therapy.
Out of those ten patients we saw a 90% response rate. Overall response was our primary endpoint and this was measured by RECIST version 1.1 or PERCIST, based on metabolic response on PET scans. We allowed that because many of those tumours metastasised to bone and lymph nodes only and therefore if they have to go through RECIST we would have to exclude many patients. So rather to include them we allowed PERCIST which is also a widely used response assessment tool. So by RECIST or PERCIST we saw a 90% response rate and we looked at the two ways of measuring separately and in cases where we had both RECIST and PERCIST they corresponded very well and the responses were also very deep.
So overall this was a good response. We then looked at the secondary endpoints of progression free survival, duration of response and toxicity. We saw a very nice duration – after a median of follow-up of twelve months the median duration of response or progression free survival were not reached and some patients were still responding to therapy after two years of treatment. So very durable efficacy. In terms of toxicity this drug was well tolerated, we only saw predominantly grade 1 and 2 elevated liver enzymes and thrombocytopenia which is consistent with what’s known in breast cancer.
We also looked at the biomarker HER2 amplification. We identified them through next generation sequencing but they correlated very well with FISH in terms of looking at the HER2/CEP17 ratio on the FISH. With next generation sequencing we used a fold change of 2 or greater, that’s a copy number fold change, being the cut-off and that correlated very well with FISH and also correlated very well with immunohistochemistry 3 .
So overall we saw outstanding responses. We’re still doing further work to look at the biomarkers, the translational work on cell-free DNA looking at acquired resistance mechanisms. We’re looking at also dimerization assays to determine the degree of dimerization and HER2 receptor internalisation that will suck the antibody drug into the cancer cell to render the cell kill. While we’re looking at it, to me, as an oncologist, what’s most important is that with these outstanding results we’d like this drug to be made available to more patients. To get there we need to finish the trial. This trial is ongoing, we’ve only accrued ten patients, it’s such a rare disease. I hope to get the message out there that salivary gland cancers, although there’s no approved treatment, we need to test for HER2 and if it’s positive for amplification then these patients should ideally go on a clinical trial. This trial is currently open at Memorial Sloan Kettering, we hope to accrue a total of 24 patients. We needed to reject an old hypothesis by having six confirmed responses. We’ve already achieved that so that’s why we’re reporting the trial early but we still need to do the work to generate more data and hopefully get this drug FDA approved. That would be a win for patients.
Currently there is no established standard of care. In early disease surgery is still the mainstay of treatment along with chemoradiation as adjuvant therapy or neoadjuvant therapy. But once they become metastatic the current standards, there’s no established standard but the chemotherapy and antiandrogen therapies are considered as options based on some retrospective case series and also some limited phase II trials. In HER2 amplified salivary gland cancers there is a trial that was just published last year looking at trastuzumab plus chemotherapy and that showed an encouraging response rate, also validating that HER2 is an important target in salivary gland cancers.