AACR 2014

Subset of breast cancer patients found to benefit from neratinib in latest trial

Dr John W. Park - University of California San Francisco, San Francisco, USA

What’s the significance of the compound neratinib in high-risk breast cancer in the I-SPY study?

Neratinib is an irreversible small molecule tyrosine kinase inhibitor of the entire ErbB-HER family so it is different from existing anti-HER agents that are available for breast cancer. It has shown promising preclinical and clinical activity in breast and other cancers therefore it was of interest to us to evaluate in this neoadjuvant phase II trial called I-SPY2.

And you were looking for complete pathological remission?

Pathologic complete response, path CR, pCR, that was the endpoint of this study.

What did you find?

We first of all found that the adaptive randomisation worked very well. It’s quite an innovative design that has not really been widely available or tested previously so it’s a new type of evaluation mechanism for novel agents. Then within the trial framework we discovered that or observed that neratinib did show particular benefit in a signature, that specific signature was the HER2 positive hormone receptor negative signature of breast cancer, and neratinib there was significantly superior to the control treatment which was trastuzumab based chemotherapy combination.

What are the benefits of adaptive randomisation?

Unlike a traditional trial that if it’s a randomised trial would continue to randomise on a completely arbitrary basis with no biasing or no directionality as the trial proceeded, this trial begins that way but as response data is collected during the trial the trial is designed to learn from the responses in a subtype and signature specific way so subtypes and signatures that appear to be benefitting then are assigned the study treatment which is benefitting them more frequently as the randomisation proceeds. Conversely subtypes and signatures that appear not to be benefitting show declining assignment until it actually can reach zero and no further patients, since none benefitted previously or not a sufficient number benefitted previously, they will not continue to be evaluated in the trial. So therefore the trial directs assignment to the subtypes of patients who are likely to show the most benefit and away from those that are not likely to show benefit.

So you’re getting a more refined study?

We’re enriching in the patients who are most likely to benefit so that benefits the patient population in the trial, it gets to the endpoint of the trial faster because we are loading up or enriching in the patients most likely to generate the final endpoint so we can reach the endpoint more rapidly and at the end of the trial we will have a biomarker defined population, a subtype defined population, where there is the most benefit.

Is the most powerful biomarker HER2 positivity?

For neratinib it actually was, and these signatures were all pre-specified, it actually was HER2 positive plus hormone receptor negative. That predefined signature was the signature in which neratinib showed the greatest benefit. There was also benefit in the HER2 positive patients overall but the most benefit in that was what we called the graduation signature, the signature in which neratinib showed the most benefit and reached the threshold value that was predetermined to be the positive threshold, that signature was the HER2 positive hormone receptor negative signature.

If this is a precursor to entering phase III of the study, what’s the next step?

A lot of stakeholders are involved in planning a phase III process, including the I-SPY investigators, the drug sponsor and others. So we’re continuing to look at possible phase III designs. But the fact that neratinib showed a positive result and benefit in neoadjuvant breast cancer with standard chemotherapy is the motivation for us to do that. One potential phase III design would be to include neratinib with existing standard of care which actually changed during I-SPY2, so I-SPY2 when it began for HER2 positive patients standard of care was essentially a trastuzumab based chemotherapy, now pertuzumab also has gained approval for HER2 positive neoadjuvant breast cancer. So trastuzumab Herceptin with chemotherapy is a very real standard of care so potentially neratinib could be evaluated on top of that standard of care as an addition which might provide further benefit. So that’s one phase III design that is being actively considered, there are other potential phase III concepts too and we’ll see what the consensus builds towards.

What are the implications for neoadjuvant therapy?

What we’re reporting today at the AACR Annual Meeting is our results with I-SPY2 which is a neoadjuvant trial. That has spurred the active discussion about looking at neratinib in a phase III trial for neoadjuvant patients and that’s the report we’re here for today. But separately neratinib is being evaluated for the treatment of HER2 positive metastatic breast cancer, stage 4, and it’s also being evaluated for adjuvant treatment, in fact extended adjuvant treatment after initial adjuvant treatment. So there are other settings in which neratinib is being evaluated but those are not part of our presentation today.

How do you think this could be clinically applied?

Sticking to the neoadjuvant data that we’re presenting today, again the activity that we’ve observed with neratinib justifies its consideration in a phase III trial, or larger phase III trial, for neoadjuvant patients. So I think that’s a very exciting prospect and efforts are well underway to further refine the concept that would actually emerge from this. But I am hopeful that neratinib moves into phase III and even more hopeful that someday it becomes available for patients with locally advanced breast cancer to help the outcomes get even better for that entity.

What would be your take-home message?

I think at least two messages. One is that adaptive trial designs are potentially powerful at getting at proof of concept questions and clinically relevant questions in an accelerated manner, specifically in this era of precision medicine where we are looking for as much information as we can find about who is likely to benefit and who is not. So this kind of approach is a potent way in which that can be attempted. Then the second is that specifically using that approach we have observed that neratinib has a lot of activity in the neoadjuvant setting in a particular signature, the HER2 positive hormone receptor negative signature and merits consideration for phase III testing based on this result.