Rates of pathologic complete response after neoadjuvant datopotamab deruxtecan in neoadjuvant breast cancer

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Published: 2 Jun 2024
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Dr Jane Lowe Meisel - Winship Canter Institute, Atlanta, USA

Dr Jane Lowe Meisel speaks to ecancer about the results from the I-SPY2.2 trial which looked at rates of pathologic complete response after neoadjuvant datopotamab deruxtecan in neoadjuvant breast cancer.

The novel therapy was given as first in a sequence (Block A), followed by standard chemo/targeted therapies (Block B/C) if indicated.

Dr Meisel reports that datopotamab deruxtecan monotherapy was active, particularly in the HR-HER2- signature, but did not meet the pre-specified threshold for graduation.

Rates of pathologic complete response after neoadjuvant datopotamab deruxtecan in neoadjuvant breast cancer

Dr Jane Lowe Meisel - Winship Canter Institute, Atlanta, USA

The abstract I presented was the datopotamab deruxtecan arm of I-SPY2.2 which is a complex neoadjuvant chemotherapy trial for patients with high risk stage 2-3 breast cancer. It’s looking at neoadjuvant therapies and trying to figure out what are the novel things we can do in the neoadjuvant setting to help patients hopefully have a higher likelihood of cure, potentially with less toxicity. 

The way the study works is that there is an investigational block of treatment that patients go on first, so that can be one drug or a drug combination. In the case of the data I presented yesterday, or Friday, it was datopotamab deruxtecan given once IV every three weeks for four treatments. The patients do very well on that, we monitor them with blood tests, serial MRIs throughout that 12-week treatment block, and then a biopsy at the end of the treatment block. If they do well enough with regards to all those tests, helping us think they might have gotten a complete response from just the investigational drugs, then they can actually bypass more traditional chemotherapy and go to surgery after just those four treatments. If enough patients do that in a particular arm then that investigational treatment can, what we call, graduate, meaning go on to further phase III study. For example pembrolizumab actually did that as part of the I-SPY trial years ago and then went on to be studied in KEYNOTE-355 and also in KEYNOTE-522 to become part of the standard of care.

But if patients don’t get to complete response or don’t get to a predicted complete response with those first treatments then they go on to more traditional therapy. There’s a second block that’s a taxane-based chemotherapy for 12 weeks and then the third block is traditional AC. Similarly to what happens in block A there with the investigational treatment, if a patient has a good response after block B they’re able to go to surgery after that and bypass block C which is the Adriamycin-based therapy. 

So it’s kind of complicated, it’s a little easier to explain with slides, but basically the idea is that you’re personalising treatment a little bit more, getting responses in real time and therefore getting patients the drugs that they need but hopefully not overtreating them. So that was the basis of this trial. There are many different drugs being studied as part of I-SPY2.2 but this was one of the first arms of the study to fully enrol and is the first one to report out. 

So we reported out on 103 patients that were enrolled over the course of 10 months on this study. These patients all received datopotamab once every three weeks for four cycles. We reported out just on the results of the block A so we don’t yet have the data on everyone who went through block B and C but we know that of the 103 patients that started 32%, 33 of the 103 patients, were able to go straight to surgery after that first 12 weeks of treatment. So four cycles of datopotamab, they went straight to surgery, which is really pretty exciting. But the way the statistics work out, because you have to meet a certain threshold that’s actually fairly high in certain subgroups to graduate onto further study, statistically the drug did not meet criteria to go on to be studied further in a phase III trial on its own.

What I would say is that it’s still very exciting, it was extremely well tolerated and there is a lot of excitement about the potential for combining datopotamab with other drugs, potentially, in the neoadjuvant space. So datopotamab plus durvalumab is another arm of I-SPY2.2 that my colleague Dr Shatsky will be reporting on tomorrow. I would definitely encourage people to look at and watch that presentation. And there are some studies ongoing, such as TROPION-Breast04, which will look at a longer duration of datopotamab deruxtecan plus durvalumab in the neoadjuvant space. So there’s definitely more to come from this drug but those were the results of the dato arm of the I-SPY2.2.

The impact of the trial in clinic, we’ve somewhat already seen. I-SPY2.2 is the newest iteration of the trial but the trial began with I-SPY2 which started in 2010. Actually there have been almost two dozen agents studied now, a number of which have graduated to further study and some, like pembrolizumab, have actually changed the standard of care in some spaces, like the triple negative breast cancer. So my hope is that the trial will continue to have impact in that way. There are already new agents being studied in block A and new arms of that study being enrolled. So the trial continues to have a lot of uptake and there will be future potential arms of the study as well that will potentially change the standard of care.