AACR 2014
Phase II trial shows dacomitinib benefits a subgroup of patients with head and neck cancer
Dr Byoung Chul Cho - Yonsei University College of Medicine, Seoul, Republic of Korea
Can you tell us more about your work with this new agent, dacomitinib?
Dacomitinib has been tested in non-small cell lung cancer, especially EGFR mutated non-small cell lung cancer. It’s in phase III trials now and in most of the phase II trials, especially in EGFR mutated non-small cell lung cancer, it has been showing a lot of promising activity in this disease.
You’ve found a biomarker that could help identify good candidates – how many lung cancer patients could this benefit?
In the Asian population the EGFR mutation occurs in around 30% of patients but in Western populations it’s only 10%.
Why did you choose to look at people with recurrent or metastatic cancer?
Although so far the EGFR tyrosine kinase inhibitors, including dacomitinib, have shown activity in EGFR mutated non-small cell lung cancer, given the variety of data showing EGFR is overexpressed in head and neck cancer we do believe that this drug has activity in this disease too. So that’s why we are doing this kind of study.
Why a pan inhibitor rather than a more specific one?
Cancer activates EGFR family signalling by upregulating or overexpressing EGFR. But it also activates other family members of EGFR such as HER2, HER3 and HER4. So so far other first generation EGFR tyrosine kinase inhibitors only target EGFR itself. But second generation EGFR tyrosine kinase inhibitors such as dacomitinib have activity in all EGFR family members.
Why is this preferential?
Besides EGFR other members of the EGFR family also contribute to cancer progression and invasion and metastasis. It is well known that HER2 and HER3, other members of EGFR, have robust action in cancer metastasis and progression so that’s why we are targeting other members of EGFR.
What happened in your trial of 48 patients?
In our study about 20% of patients did respond to dacomitinib and progression free survival is around 3 months and overall survival is 6 months. The interesting point and important point of our study is that we found a predictive signature by using next generation sequencing and other high throughput screening methods. This approach has not been done in head and neck cancer so far so this is the first time to date to perform a comprehensive biomarker study in head and neck, recurrent metastatic head and neck cancer, in a clinical trial setting.
And you’ve found both positive and negative predictive markers?
Yes, both. But we found that the PI3 kinase, lack of PI3 kinase mutation and lack of cytokine gene overexpression predicts better progression free survival, better objective response rate and better overall survival in our patient subset.
How do you think this could be applied clinically, and is toxicity an issue?
First of all the toxicity profile is well manageable and easily predictable. So a lot of doctors, especially oncology doctors, have a lot of experience in EGFR tyrosine kinase inhibitors, including dacomitinib, in a clinical trial setting. We also have a lot of experience in first generation EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. So we all know the toxicity profile of EGFR TKIs so toxicity doesn’t matter in this setting. The second question is the future prospective of our study results. I think that our predictive signature to dacomitinib in this disease setting is really robust and progression free survival and objective response rate and overall survival is almost double in predictive biomarker signature positive patients compared with negative patients. So I think that this should be incorporated in the future phase III trial comparing dacomitinib versus other standard of care chemotherapy in recurrent metastatic head and neck squamous cell carcinoma.
Is there any evidence to suggest that these very ill patients benefitted in any way?
Usually historical data showed that these patients usually die within six months. In our data patients without PI3 kinase pathway mutations and/or without cytokine gene overexpression, they live longer, almost one year. So it means that although this is a single arm phase II study patients without any alteration in our biomarker signature do live longer than our expectation.
What would your take-home message be for doctors?
PI3 kinase pathway mutation and cytokine gene expression level is a really important biomarker when we treat the head and neck cancer patients with dacomitinib. This of course should be tested and validated in future phase III randomised trials but we do believe that this is a really promising biomarker signature that we should have notion.
