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ASCO 2022 | DESTINY-Breast04: T-DXd provides significant improvement in OS + PFS in HER2-low mBC

Hope Rugo, MD, FASCO, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, talks on the results of the Phase III Destiney-breast04 (NCT03734029) trial investigating trastuzumab deruxtecan versus physicians choice of chemotherapy in HER2-low breast cancer. A total of 557 were included in the trial, including a small subset of 58 patients with triple-negative breast cancer (TNBC). HER2-low was defined as an immunohistochemistry (IHC) 1+ or 2+ without evidence of HER2 gene amplification and was centrally confirmed due to variation in what is considered 1+, 2+ or 0. The majority of patients were also HR-positive. Trastuzumab deruxtecan demonstrated a 49% reduction in risk of death or disease progression compared to chemotherapy in patients with HR-positive disease and 36% reduction in HR-negative. A significant improvement was observed in progression-free survival (PFS) and overall-survival (OS) in the entire population. Grade 1 or 2 nausea was the most common toxicity. There was an overall 10% rate of interstitial lung disease (ILD) or pneumonitis, resulting in 3 deaths (0.8%), highlighting the importance of the early identification of ILD. This interview took place at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting in Chicago, IL.

Transcript (edited for clarity)

Yeah, DESTINY-Breast04 Trial, which we participated in and I’m honored to be an author of, focused on patients who had centrally confirmed HER2 Low breast cancer of which a small subset were allowed to have triple negative disease as well. In total, in the trial population, only 58 patients had triple negative disease. HER2 Low is defined and for the purposes of that study as immunohistochemical staining of the cancer at one plus or two plus without evidence of HER2 gene amplification...

Yeah, DESTINY-Breast04 Trial, which we participated in and I’m honored to be an author of, focused on patients who had centrally confirmed HER2 Low breast cancer of which a small subset were allowed to have triple negative disease as well. In total, in the trial population, only 58 patients had triple negative disease. HER2 Low is defined and for the purposes of that study as immunohistochemical staining of the cancer at one plus or two plus without evidence of HER2 gene amplification. And as I mentioned, this was centrally confirmed because there’s a lot of variation at people’s sites in terms of what is called one plus two plus or zero.

So they didn’t include the zero. Although I have to say, the discussion of DESTINY-Breast04 made the point, which we’ve seen in another trial called DAISY, that even the tumors that are IHC0 actually have a little bit of HER2. And so what that means for response, we’re seeing responses in the IHC0, in some settings, we don’t know, but regardless DESTINY-Breast04 looked only at patients who had HER2 Low disease. They did not have to receive prior CDK 4/6 inhibitors, a subset did, and they could only have received one or two prior chemotherapy lines for metastatic disease.

The majority of patients had hormone receptor positive cancer, that was the primary endpoint. In that patient group, there was a statistically significant and clinically very important doubling in progression-free survival and a dramatic improvement in overall survival. Because they were able to see that in the hormone receptor positive group, they then went on and looked at the entire group, adding the 58 patients who had triple negative disease in that group. Also, there was a significant improvement in PFS and OS. They looked at the 58 patients with triple negative disease.

It’s very hard because it’s a tiny number, but it did look as though they still saw an improvement in PFS and OS, although outcome was worse as you would expect. It’s just so hard in a tiny group of patients, but it’s very encouraging. In terms of toxicity, we had seen a very nice assessment of toxicity over time from DESTINY-Breast-03 presented by Erica Hamilton yesterday at or the Saturday, first day of breast presentations at ASCO 2022. And this data fit well into that setting. So it doesn’t appear that the toxicity is any different if you have HER2 Low disease or HER2 positive disease.

Nausea was the most common toxicity, although grade one and two and diarrhea at a lesser level. The risk of left ventricular ejection, fraction, dysfunction, and ejection fraction dysfunction is concerning, but it really wasn’t an issue in this trial. We worry about it because the antibody is trastuzumab, but these patients did quite well. So was very encouraging. And having treated a lot of patients, I’ve never seen a decline in left ventricular ejection fraction or a cardiac function, but the other adverse event of special interest is interstitial lung disease or pneumonitis.

That is a known toxicity of this drug and some other antibody drug conjugates, notably, not for sacituzumab, and not for all deruxtecan ADCs, but for trastuzumab deruxtecan and some others. And what they saw was about a 10% rate of overall ILD but there were three deaths, it’s 0.8%, but I think it highlights the real importance of first identifying pneumonitis very early before it’s symptomatic and treating early, as well as stopping when patients become symptomatic. Because it’s fascinating. You never see grade four ILD. You only see grade three and five, you die. So if you really have that progression, it’s bad.

So I think that as we move forward and start using this drug in a huge number of hormone receptor positive patients who are HER2 low, we need to set up guidelines for how often to do scans because in the sort of era of cost control and not radiating our patients, sometimes I see patients who have scans very infrequently and that really won’t work with this drug. The incidence is greatest in the first year. So the idea would be that you really do need to do something to image the lungs, a CT scan without contrast at least every nine weeks for the first year.

Then you could be less frequent. I have seen a little ILD in the second year, didn’t progress to anything, but we did hold drugs. So it’s just a very important caveat, but breast cancer is the most common cancer diagnosis in the world. It’s the second most common cause of cancer death in the world. Hormone receptor positive, HER2 negative breast cancer represents 70% of all breast cancer. And we have a new drug that can change progression free survival and overall survival. This is why there was a standing ovation in the plenary session at ASCO.

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