Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers

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Published: 5 Jun 2017
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Dr Bob Li - Memorial Sloan Kettering Cancer Center, New York, USA

Dr Li talks to ecancer at ASCO 2017 about results from a phase II basket trial looking at Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers.

Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 2% of lung cancers, resulting in receptor dimerisation and kinase activation with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine. 

Ado-trastuzumab emtansine is active and well tolerated in pts with HER2 mutant lung cancers.

 

Firstly I presented a phase II trial of ado-trastuzumab emtansine in patients with HER2 mutant lung cancers. This is a result from a phase II basket trial, so this is the first cohort of that basket trial. We demonstrated that in this subset of patients with HER2 activating mutations that ado-trastuzumab emtansine produced an overall response rate of 44% with a median duration of response of 5 months and a progression free survival of 4 months. However, when you say duration of response those responses tend to happen late and therefore the actual benefit for patients on treatment tends to be much longer so the progression free survival time on treatment for those responders ranged from 4 to 11 months.

This treatment was well tolerated with mainly grade 1 or 2 adverse events which were consistent with the breast cancer experience with thrombocytopenia and elevated liver enzymes. We did see some infusion reactions that were easily managed with antihistamines and acetaminophen. There were no treatment related dose reductions or treatment related deaths so all the patients didn’t suffer severe toxicity.

We also looked at the molecular subtypes and the characteristics of HER2 in these patients we found that amongst those patients with HER2 activating mutations only one patient had concurrent amplification by FISH and next generation sequencing. In terms of protein expression by immunohistochemistry they ranged between 0, 1 and 2 , there were no IHC or immunohistochemistry 3 in this group of 18 patients. When we looked further with mass spectrometry after laser microdissection to look at the quantitative protein levels we did not find high levels of protein in patients with activating mutations, except for the one with amplification. So this is contrary to popular belief that you need high quantities of protein for ado-trastuzumab emtansine, or TDM1, to work. In those activated HER2 mutations when the proteins are activated, even when the actual quantity is low, those patients still respond which means the HER2 receptor was able to pull the antibody drug conjugate inside the cell and for the drug to work.

Overall this is the first positive clinical trial for patients with HER2 mutant lung cancers and the results, I personally believe, are promising and warrant a multicentre confirmatory trial to get this drug approved for patients.

When it comes to the overall response rate you mentioned there could anything be done to get it above this one-third that it’s got so far?

At the moment the single agent activity is 44%. This is already way above the standard of care in this patient population who were actually heavily pre-treated, up to four lines of prior therapy with 50% of them had prior HER2 targeted therapy as well. In this pre-treated population the overall response rate with standard chemotherapy is 10% according to Dr Mazières’ work from the EUHER2 cohort published in Annals of Oncology last year. So 44% compared to the standard of 10% is way better and for a well-tolerated drug I believe this is already a big step forward for these patients with an oncogenic driver who do not have an approved targeted therapy for use.

To answer your question, how do we get that above 44%? More translational work needs to be done. We are actively pursuing translational imaging using HER2 targeted imaging, zirconium trastuzumab PET scans to predict, to refine, the patient selection, to look at heterogeneity, to look at the drug uptake in order to really refine our precision medicine and select the best patients who would respond. So really matching the right drug to the right patient. By using that refinement we may be able to get the response rate to much higher.
So that’s one aspect, another aspect is combination therapies, perhaps, down the track. We are doing preclinical modelling using patient derived xenografts. These are biopsies from the very patients who were treated. We implanted these tumours that were biopsied into mice and when they start to grow we implant it into a batch of mice. We then test various different drugs on the mice to look at xenograft preclinical drug sensitivity and test multiple hypotheses in terms of single agents, different agents and combinations. So this is active work being done at Memorial Sloan Kettering right now and we hope through the lab, the new science coming out from the lab, may inform us what is the best combination strategy in the future for this agent.

However, right now we already have a drug that is much better than the standard of care and these patients are alive, thousands of them in the United States alone, many more around the world, readily identified by routine multiplex testing of lung cancers and next generation sequencing. These patients need an active treatment today so I open my arms to all collaborators and partners to conduct the trial to hopefully seek regulatory approval.