Comment: Pembro plus chemo in neoadjuvant and adjuvant treatment for early triple-negative breast cancer

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Published: 29 Sep 2019
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Prof Sherene Loi - Peter MacCallum Cancer Centre, Melbourne, Australia

Prof Sherene Loi speaks to ecancer at ESMO 2019 in Barcelona commenting on the KEYNOTE-522 Phase III results.

The trial added immune therapy to chemotherapy in treating patients with early triple-negative breast cancer.

Prof Loi discusses the interesting distinctions in the results of PDL1-positive and PDL1-negative patients and stresses the importance of waiting for long-term data.

 

This is the first neoadjuvant study to be reported in early stage triple negative breast cancer which looks at the value of adding pembrolizumab to CarboTaxol followed by AC neoadjuvant chemotherapy and then patients had surgery. The primary endpoint was pCR then pembrolizumab was continued for a year or patients were on placebo. There are two primary endpoints of pCR and event free survival. This presented the pCR endpoint.

The thing to note in the patients that were in this trial is that half the patients were node negative and three-quarters of the patients had stage T1/T2 tumours. So it’s not the highest risk population. The most interesting thing is that compared to the advanced setting where we had the recent approval of atezolizumab, that most patients, or 80% of patients, were PD-L1 positive by the Merck assay. So that’s very different to the IMpassion 130 data where only 40% of patients were PD-L1 positive.

The primary endpoint for pCR was significant. There was a statistically significant increase in the rate of pCR with the addition of pembrolizumab. The control arm pCR rate was about right at 50%, the delta was around 13.6% so that was strongly significant.

The interesting thing is if you look down at PD-L1 positive versus negative you can see that PD-L1 patients who are positive do better compared with PD-L1 negative patients. However, it does seem that the delta, so the change in pCR with the addition of pembrolizumab, did look to be relatively better, surprisingly, in the PD-L1 negative patients compared with the PD-L1 positive patients. That doesn’t mean they did as well as the PD-L1 positive patients but the relative increase surprisingly looked a little bit better. So that was very surprising to me and, for me, it really is very different from the advanced data where we saw effects only in PD-L1 positive patients. Here we’re seeing it across the board.

It really does make me wonder about the effects of myelosuppressive chemotherapy on patients who have a pre-existing immune response. In reality we don’t know what chemotherapy is doing to a pre-existing immune response. It’s highly plausible that giving such myelosuppressive chemotherapy is detrimental to the immune response which is pre-existing such as those in PD-L1 positive patients as well as that that we’re trying to facilitate. So that’s one interesting take on that and I think we need to investigate that further.

So it’s a landmark study; it’s important to have a proper control arm so we know that pembrolizumab adds. They did show early event free survival data but I think that’s way too early. It’s encouraging but we really need to wait. The adverse event rate with regards to immune related adverse events was consistent with other studies but we need to remember that 10-15% of these will be life long. So patients will require permanent replacement of endocrine function life long. For example, type 1 diabetes is extremely rare but giving a patient type 1 diabetes can be devastating if they’re going to be alive for a long time.

So we need to wait for long-term data outcomes, we need to understand the benefits, we need to see other trials and we also need to understand the safety of these agents. To me, it really suggests we really need to work out what chemotherapy is doing to patients with a pre-existing immune response. We know that patients who do have a pre-existing immune response are doing really well without pembrolizumab. So what’s chemo doing? How can we optimise the chemo-pembrolizumab combination? Is one year too much, is it too little? How can we understand that, maybe with biomarkers. We need to understand who needs the pembrolizumab. There’s no doubt in my mind that it will help patients be cured of their triple negative breast cancer but it’s a fine line who we give it to.