PHERGain trial ID's early breast cancer cases that benefit from dual HER2 blockade without chemo

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Published: 5 Jun 2023
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Dr Javier Cortes - Vall d’Hebron University Hospital, Barcelona, Spain

Dr Javier Cortes discusses results from the randomised, open-label, phase 2 PHERGain trial at ASCO 2023.

Improvements in 3-year survival were seen in early-stage HER2-positive breast cancer patients when treated with HER2 blockade and a novel chemotherapy de-escalation strategy.

The trial used a response-adapted design looking at PET scans and post-surgery pCR to ID the subset of patients who were able to benefit.

Basically, as we all know, we have tried to de-escalate chemotherapy in many tumour types and this is something we have achieved nicely in the oestrogen receptor positive, HER2 negative breast cancer patients. But the dream of doing the same in aggressive tumour types. in my opinion, was not achieved. So this is why we designed the PHERGain study that basically tried to de-escalate treatment in a very innovative way. Can we design and adapt it, the trial, to de-escalate treatment for a group of patients and only give chemotherapy in the patient population that might need it? 

So our study was an adaptive design trial and and basically we started all patients with trastuzumab and pertuzumab, anti-HER2 therapy, and endocrine therapy if appropriate, so trastuzumab/pertuzumab. After two cycles we did a PET scan to see if the patients achieved a response or not. If they achieved a response they continued with trastuzumab and pertuzumab with no chemo and if they did not achieve a response, 20% of the patients, we added chemotherapy on top of the antibodies against HER2. So for those patients who did continue with trastuzumab and pertuzumab and achieved pathological complete remission afterwards, they continued with no chemo, and if no pCR was observed, was reported, then we added chemotherapy. 

So basically this is an active trial so I don't care, for the purpose of the study, if the patient received or not chemotherapy. We analyse the total population, it doesn't matter how they behaved, how were the long-term outcomes regardless of whether they received, or not, chemotherapy. 

So this trial did have two primary endpoints. The first one was just maybe exploratory but it was a primary endpoint, it was pathological complete remission in those patients who achieved a response by PET. So those are the patients who continued with trastuzumab/pertuzumab. So, again, 20% of patients did not achieve a response by PET, 80% achieved a response by PET. Among these 80% of patients 37.9% achieved a pathological complete remission.

But what is much more interesting, and this is what we presented at at ASCO 2023m, is the invasive disease free survival for the total group of patients – it doesn't matter if they receive chemo or not, again, it doesn't matter – how did they behave? The invasive disease free survival at three years was just amazing – 95.4%. It was identical to what we might expect if all these patients would have been treated with chemotherapy and double blockade from the very beginning, which was even more amazing for those patients who did achieve response by PET, pathological complete remission. These are the patients who did never receive chemotherapy, only trastuzumab/pertuzumab. 30% of the total patient population, 30%. We did not have any metastasis at three years and invasive disease free survival was 98.8%, only one local relapse. 

What are the next steps for this study?

Well, first of all, I would like to to highlight that we are running PHERGain-2, which is a similar concept in tiny tumours and we'll start to design another trial. But, not for all patients, but maybe if we have patients with tumours higher than 15-20mm with node negative, I think that changes the strategy that could be implemented in the clinical practice. So let's start with trastuzumab/pertuzumab and let’s add chemotherapy only if needed. This is something I will start doing it in my practice.

I would like to add only that it's impossible to randomise patients to do randomised phase III trials to de-escalate chemotherapy – we need so many thousands of patients that it’s not… It’s something that also the companies, I don’t know if they will be very, very interested. So smarter designs, PHERGain is just one example, it could be other ones, in my opinion, is the way to move forward.