The NeoALTTO trial was specifically designed to answer if the combination of lapatinib and trastuzumab that are two anti-HER2 drugs can improve the rate of pathologic complete response, that is the disappearance of the tumour from the breast, as compared to single blockade using either trastuzumab or lapatinib.
How were the end-points evaluated in this trial?
Essentially this trial had a primary endpoint that was the rate of pathological complete response in the combination arm as compared to the trastuzumab arm and the comparison between the two single agent arms, trastuzumab and lapatinib. The study also had secondary endpoints that the final analyses were presented at the European Breast Cancer Conference and were related to the event free survival and overall survival analysis in the intention to treat population and the association between pathologic complete response and survival assessed by landmark analysis.
What key outcomes were observed with regards to survival in using lapatinib with trastuzumab for HER2 positive breast cancer?
The results in the study in terms of secondary endpoints were negative in the sense that we didn’t see a statistically significant difference between the three different arms. So the combination did not significantly increase the overall survival and disease free survival rates. What we saw was that independently of the treatment arm in women achieving a pathological complete response the disease free survival rate at nine years, this is very important because the NeoALTTO is probably the largest study with the longest follow-up of almost ten years, so what we saw is at nine years the event free survival rates were 77% in those women achieving pathological complete response as compared to 61% in those women not achieving pathological complete response. When we looked at overall survival we also saw a strong significant association with an improved survival for women achieving a pathological complete response with a hazard ratio of 0.37 and a highly significant p-value.
Can the results from this trial change HER2 positive breast cancer treatment and how?
Unfortunately lapatinib didn’t make it to the clinic so we know the result of the ALTTO study that was not statistically significant. We also know that a dual HER2 blockage is currently used in clinical practice, especially in the neoadjuvant setting similar to the NeoALTTO study. So the new advanced setting is a very useful way to test if a combination or a new drug work because achieving a pCR with the results of the NeoALTTO will strongly support its long-term efficacy endpoint.
Is there anything you would like to add?
I would like to stress that the NeoALTTO is probably the neoadjuvant study with HER2 dual blockade in early breast cancer with the longest clinical follow-up. So we have ten years and this really helped us to believe even more in the setting of neoadjuvant studies for developing future trial concepts. So the pCR is really a long-term efficacy readout biomarker that we can evaluate very early in the treatment.
What we need to improve now is to better identify those patients that are more likely to achieve a pCR and for this we probably need to search for, look for, a biomarker-driven approach where we can select based on the biology of the tumour and enrich our clinical studies using a biomarker approach.