Interpreting Clinical Trial Data in the Setting of HER2-Low Breast Cancer


Panelists focus on clinical trial data driving use of novel agents in the setting of HER2-low breast cancer and consider how they might select specific therapies.


Andrew Seidman, MD: We saw some very compelling data at the plenary session from DESTINY-Breast04. Tiffany, maybe you can take us through the key findings from that data and why you think it was selected for plenary presentation.

Tiffany Traina, MD: These are some of the most outstanding data that we saw coming out of this meeting, with great improvement for women with breast cancer. This was a randomized trial in a population of patients that were largely hormone receptor positive and considered HER2 [human epidermal growth factor receptor 2]-low, which was defined as HER2-1+ or 2+ and FISH [fluorescence in situ hybridization] not amplified by central review. A small subset of patients on trial were hormone receptor negative and made up about 11% of the overall study population. Patients were randomized to receive treatment of physician’s choice chemotherapy or the antibody-drug conjugate [ADC] trastuzumab deruxtecan. Standard treatment of physician’s choice chemotherapy was very reasonable. These were usual drugs that we would recommend in our practice, so it’s very applicable to the patient population.

Andrew Seidman, MD: Including paclitaxel.

Tiffany Traina, MD: Yes, exactly. What was incredibly impressive was the primary end point of progression-free survival was significantly prolonged with trastuzumab deruxtecan as compared with standard of care chemotherapy. Numerically the medians were more than double: 5.8 months for standard of care chemotherapy and more than 10 months with trastuzumab deruxtecan. Not only was the progression-free survival was impressive, but the overall survival benefit was remarkable with trastuzumab deruxtecan associated with a 2-year length of median overall survival. That was dramatic and practice changing. As you looked at forest plots and subsets, every group appeared to benefit from the antibody-drug conjugate over our conventional chemotherapy.

Andrew Seidman, MD: In terms of toxicity profile, when you look at overall adverse events, there were actually fewer with T-DXd [trastuzumab deruxtecan].

Tiffany Traina, MD: This population, when you looked at median prior lines of therapy, the median prior lines was 1 chemotherapy. Those with hormone receptor–positive disease generally had a couple of lines of endocrine therapy beforehand. About 60% or 70% of the hormone receptor–positive patients saw a prior CDK4/6 inhibitor, just to put into context what this population looked like. To your point about toxicity, the most common toxicities were related to nausea and cytopenias. One that has been of concern with this agent in the HER2+ literature that we have seen was interstitial lung disease. Thankfully, this was observed in lower incidence and also of lower grade. That’s somewhat promising as the DESTINY-Breast portfolio advances. We’re seeing a bit less of the interstitial lung disease risk.

Andrew Seidman, MD: It’s undoubted that others are going to try to target this population of HER2-low patients. No. 1, it’s demographically a big subset of breast cancer. There was another abstract, 1102, that came out of ASCO [American Society of Clinical Oncology Annual Meeting]. That abstract looked at another ADC out of China, MRG002. What can you tell us about that early experience?

Tiffany Traina, MD: As you mentioned, it’s an antibody-drug conjugate targeting HER2-low expression with a different payload, an MMAE [monomethyl auristatin E] payload. It’s an agent that we’re seeing very early signals of response with. There was about 35% overall response rate with this compound. It will be interesting to see benefit in this space. Prior agents that were considered HER2-directed therapies were not of benefit in this HER2-low subset. There’s a lot to understand about linkers, payload, strength of being able to identify the target, and whether that target is oncologic and if that matters.

Andrew Seidman, MD: Most of these patients in DESTINY-Breast04 were hormone receptor positive, as you pointed out. There are a lot of patients who will enjoy some durable remission on endocrine therapy on CDK4/6 inhibitor therapy. I suspect there’s going to be a lot of interest in testing patients for HER2-low before they’ve crossed into the world of chemotherapy. There was abstract 1056 from [Dr Laura Sabina] Lapuchesky [in Argentina], which examined HER2-low prognostic implication for patients on endocrine therapy plus CDK4/6 therapy. Is there anything we should take away from that retrospective look?

Tiffany Traina, MD: The big takeaway is that for patients who have hormone receptor–positive disease, this isn’t changing the paradigm of leading with endocrine therapy, CDK4/6 inhibitors, appropriate maximizing your benefit from endocrine approach before moving on to the need for chemotherapy, where this ADC would be placed. In the report you’re describing regardless of HER2-low expression level, CDK4/6 inhibitors continue to have benefit.

Andrew Seidman, MD: Stephanie, when your patient relapses after having had hormone receptor–positive HER2 breast cancer, and she has exhausted endocrine therapy and been through 1 line of chemotherapy, how important is it to biopsy her now? Does the detection of HER2 low make it more important, or was it already important for you?

Stephanie Graff, MD: I’ve always documented and tracked somebody’s HER2 status in a granular way because I’m obsessive compulsive and I like the nitty-gritty details in caring for somebody’s breast cancer. My practice will probably include looking back to see what their HER2 status was at the diagnosis of metastatic disease, which I would have documented as HER2 0, 1, 2, plus or minus.

Andrew Seidman, MD: Assuming it was 0 at first relapse, and it’s been 3 years.

Stephanie Graff, MD: I’ll probably rebiopsy given the remarkable outcome of DESTINY-Breast04. We do know that upregulation of HER2 is a mechanism of resistance to endocrine therapy, and there’s lot of heterogeneity in breast cancer. But it’s unclear what that looks like.

Andrew Seidman, MD: VK, can we rely on liquid biopsy for assessing HER2-low status? Some people are going to wonder whether they can do that.

Vijayakrishna Gadi, MD, PhD: That’s a fascinating question. I spoke with not a ctDNA group but a CTC [circulating tumor cells] group about this ability, because some of those technologies have additional channels to look for HER2 expression on the cells. You can use the CTC floating around in the bloodstream to say there’s low or high. It’s early, but maybe there’s a chance that we can understand how much HER2 expression is on the surface.

William Gradishar, MD: One of the other questions that hasn’t been answered from the data set that exist is whether there’s a differential expression of HER2-low depending on where the disease was biopsied. That’s there. We don’t know it yet, so that’s going to be important to understand as well.

Andrew Seidman, MD: We’ve seen that with PD-L status as well based on the organ. Absolutely.

Transcript edited for clarity.

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