Tiwari Highlights Updates in HER2+ and HER2-Low Breast Cancer

Shruti Tiwari, MD

During a recent OncLive State of the Science Summit™ on breast and lung cancer, Shruti Tiwari, MD, gave a presentation titled “Management of HER2-Positive and HER2-Low Breast Cancer,” in which she outlined key recent developments, including the effects of newer therapeutics such as fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa).

“We have a lot of newer treatments in this space and the challenge for the medical oncologists in the community is to decide how you’re going to sequence these new treatments,” Tiwari said. “That is a big challenge and none of us know the answer to that. All these studies were performed with the current standard of care in mind, and the standard of care changes after a new drug gets approved. So, the challenge is how you sequence these medications. It is becoming more and more challenging [to sequence drug therapies] in all aspects, not just HER2-positive breast cancer, but triple-negative breast cancer and hormone receptor–positive breast cancer.”

In an interview with OncLive, Tiwari, a medical oncologist at Virginia Cancer Specialists in Leesburg, discussed how the introduction of HER2-directed therapies in recent years has led to improved outcomes for patients, factors she considers when choosing a regimen for a patient in a given disease setting, and expectations for the future treatment of HER2-positive/HER2-low breast cancer.

OncLive: In the second line, how do you determine whether to use a tucatinib-based regimen vs trastuzumab deruxtecan in patients with HER2-positive breast cancer with central nervous system disease?

Tiwari: We have good data based off the results of the phase 2 HER2CLIMB study [NCT02614794] that trastuzumab [Herceptin], capecitabine [Xeloda], and tucatinibhave very good CNS efficacy. Twenty-four percent of patients did not require any treatment at one year and that is remarkable.

This is a very challenging disease space. It’s often very hard to control CNS metastases with systemic therapy alone [because] patients need regular surgery and different interventions to keep their disease under control. So, 24% to 25% patients not needing any intervention is remarkable. [The HER2CLIMB regimen] is usually my go to regimen as of now. We have some data with trastuzumab deruxtecan, but the big trials such as the [phase 1b/2] DESTINY-Breast07 trial [NCT04538742], are ongoing, so we don’t have that [complete] data set yet.

In the third line following treatment with trastuzumab deruxtecan for patients without CNS disease or with stable CNS metastases, how do you decide between ado-trastuzumab emtansine (Kadcyla) vs tucatinib?

We have a lot of data that were recently presented at the 2023 San Antonio Breast Cancer Symposium on the sequencing of antibody-drug conjugates [ADCs]. The data that were presented had to do with the sequencing of sacituzumab govitecan-hziy [Trodelvy] after trastuzumab deruxtecan or trastuzumab deruxtecanafter sacituzumab. There is some cross resistance; the progression-free survival [data ranged from] 2 to 3 months for the second-line ADC. I do have some concerns with trastuzumab emtansine, it may not have the same efficacy as it did in the second-line setting. I have been moving on to a tucatinib-based regimen for my third-line patients and after that, I will try trastuzumab emtansine, if needed.

How has the treatment paradigm of HER2-low breast cancer evolved in recent years?

This is a very exciting area of oncology. We finally have a drug that has been shown to have efficacy in HER2-low cancers and it’s quite impressive. If you look at the data, trastuzumab deruxtecan has very good efficacy in estrogen receptor (ER)–positive/HER2-low cancers and ER-negative/HER2-low cancers.

It’s good to have a non-chemotherapy option for our triple-negative patients after they have received their initial chemotherapy and to have a targeted drug in that space. It’s also a very well-tolerated regimen. Even for our ER-positive patients moving from one line of chemotherapy to another line can be very challenging. It is very exciting that we have a [new] drug in this space in addition to sacituzumab govitecan, which is also approved for HER2-low cancers. Again, the question is sequencing these [agents].

What unmet needs or unanswered questions remain in HER2-positive/HER2-low breast cancer?

There’s always a need for new drugs and more effective treatments. This is an evolving space. There are a lot of new trials and new ADCs that are being tested in this space.

We have 2 trials open at our practice [involving] HER2-low cancers and ADCs, one of which is testing DB-1303, which is a novel HER2-directed ADC that has a TROP1/2 payload. It is similar to prior ADCs, but it is also very well tolerated and there is much less alopecia with this drug. The other [trial is evaluating] a novel immune-stimulating ADC. We don’t have a lot of data on what to do after patients progress on an ADC and especially a very efficacious ADC like trastuzumab deruxtecan, so this trial [is open] in the space after progression.

[Although the] treatments [we have] work, they don’t work forever.We do need more efficacious treatments and more well-tolerated drugs to fill current treatment gaps, and patients travel from all over to Virginia Cancer Specialists to get on these studies because they are not open widely and only available at certain centers.