New Indications in HER2+ Breast Cancer Spark Discussions on Selection, Safety, and Sequencing

Tom Smith

The KATHERINE, FeDeriCa, DESTINY-Breast01, and HER2CLIMB trials have changed practice for patients with HER2-positive breast cancer for the better, explained Mei Wei, MD, who added that ongoing research evaluating whether HER2 expression could inform patient selection for ado-trastuzumab emtansine (T-DM1; Kadcyla), follow-up data regarding the pharmacokinetic equivalence of subcutaneous trastuzumab […]

The KATHERINE, FeDeriCa, DESTINY-Breast01, and HER2CLIMB trials have changed practice for patients with HER2-positive breast cancer for the better, explained Mei Wei, MD, who added that ongoing research evaluating whether HER2 expression could inform patient selection for ado-trastuzumab emtansine (T-DM1; Kadcyla), follow-up data regarding the pharmacokinetic equivalence of subcutaneous trastuzumab (Herceptin) and pertuzumab (Perjeta; HP) and intravenous (IV) HP, and the additive benefit of tucatinib (Tukysa) to T-DM1 in the second-line metastatic setting could push the needle even further.

“I’m excited about adjuvant and metastatic treatments for patients with HER2-positive disease. With so many new HER2-directed agents, patients with metastatic disease are able to achieve longer remission durations, which is very exciting,” said Wei. “Cure is now something we can potentially aim for in select patients with metastatic disease.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on breast cancer, Wei, a breast medical oncologist at the University of Utah, provided perspective on pivotal trial data in HER2-positive breast cancer.

OncLive®: Has T-DM1 become a standard approach for all-comers with residual disease after neoadjuvant therapy, based on findings from the KATHERINE trial?

Wei: The KATHERINE trial significantly changed the clinical practice pattern. If a patient has residual disease in the adjuvant setting after neoadjuvant chemotherapy, we can use T-DM1, which provides a 3-year DFS [disease-free survival] benefit compared with trastuzumab alone. In clinical practice, I think the majority of medical oncologists have been using that data to guide their clinical decisions.

The challenging part is that the clinical trial didn’t specifically mention [the bulk of] residual disease [that qualifies a patient for T-DM1]. Therefore, should we just apply the results to everyone no matter how big the residual disease is? That question was answered by biomarker data from the KATHERINE trial that were presented at the 2020 ASCO Virtual Scientific Symposium. The results showed that patients with high HER2 expression and residual disease benefit the most from T-DM1 in the adjuvant setting compared with patients who have low HER2 expression, who had similar outcomes with T-DM1 and trastuzumab. Unfortunately, HER2 expression testing is not routinely done in the clinical setting, so I don’t think those results are ready to be used to guide physicians at this moment. [The investigators] probably need longer follow-up to confirm that data as well.

Do you anticipate that HER2 RNA testing will be routinely done in practice?

By default, we do HER2 testing by [immunohistochemistry (IHC)] regionally, and then depending on the IHC results, we’d do [a fluorescence in situ hybridization (FISH)] test. The biomarker test [that was done in the KATHERINE trial] evaluates HER2 RNA, which is not done universally right now. Whether it’s worthwhile to do routinely depends on how good the data turn out to be. If longer follow-up data show that this test is critical to guide clinicians and really [shows that high HER2 expression is associated with] a significant benefit, then that can potentially become a routine test. But if [the difference in benefit is] not that significant, or if we have new drugs, or new data, then we probably will not make that a routine test.

How likely are you to offer the subcutaneous formulation of HP to patients, based on findings from the FeDeriCa trial?

I like the idea of changing the infusion of trastuzumab and pertuzumab to [a] subcutaneous [formulation]. Our patients will love it as well because infusions [generally take] an entire day, and patients [leave] exhausted, having spent most of their time in the hospital. The subcutaneous [formulation] is good for the patient and good for the hospital. The infusion also [causes] infusion-related reactions, which is another stress for the patient, physician, and nursing staff as well. The subcutaneous [formulation] saves time and does not cause [infusion-related] reactions, which [is great].

The tricky part with that data set is that the primary end point was the cycle 7 pertuzumab trough level concentration in a serum compared with IV treatment with trastuzumab and pertuzumab. We need to figure out whether the cycle 7 pertuzumab trough level alone is good enough to switch to this treatment. Will the anti-cancer efficacy be the same in patients who receive the subcutaneous formulation compared with those who receive the IV formulation? We didn’t test the trastuzumab trough level either, and the subcutaneous dose is different than the IV dose.

As a clinician, I’m kind of hesitant to use the subcutaneous formulation mainly because we don’t have follow-up data. Perhaps from a pharmacokinetic perspective, the data are good enough. Our institute is also looking at the price of the subcutaneous formulation since it has been approved by the FDA. My understanding is that the price is pretty high and also depends on the patient’s insurance coverage. There are some barriers [that need to be overcome] before we can really use this subcutaneous formulation in clinical practice.

Shifting to the metastatic setting, what did you find exciting about DESTINY-Breast01?

This is very promising trial. I was very excited when I saw these data. It’s just a single-arm, phase 2 trial, but the data are very exciting. All patients very heavily treated; the medium number of prior therapies was 6, and pretty much everybody received prior trastuzumab and T-DM1. Before the DESTINY-Breast01 and HER2CLIMB trial, if a patient had progressive disease on T-DM1, clinicians didn’t know what to do because we didn’t have good treatment.

DESTINY-Breast01 showed significant progression-free survival data in these heavily pretreated patients and also good data for patients with brain metastases, which is really exciting.

The only concern is ILD [interstitial lung disease]; 2.5% of patients experienced fatal ILD in the trial. The incidence rate is low enough, but the consequence can be fatal. We don’t want to treat the patient [if the treatment can be fatal]. Fam-trastuzumab deruxtecan-nxki [Enhertu] is a promising drug, but the ILD really makes everyone nervous.

Another thing is we don’t have a clear strategy to handle [ILD]. Should we obtain a baseline pulmonary function test? Should we routinely repeat a pulmonary function test? Should we just to monitor the patient to observe their clinical symptoms? We are getting CT scans to evaluate the patient’s treatment response already. Should we do extra scans to evaluate whether the patient has developed ILD? [For that, we’d use a] high-resolution CT scan, whereas cancer CT scans are usually not high resolution. Should we burden the patient by doing extra pulmonary function tests and extra scans, or should we just observe them? There are still lots of questions there. The DESTINY-Breast01 data did lead to an FDA approval for trastuzumab deruxtecan. Clinically, we are eager to use this drug if the patient needs it. We just need to be very cautious and closely monitor patients.

Will the risk of ILD limit where the drug can be used?

I suppose. If this problem remains, I can see that becoming a barrier. I did have a patient who had ILD from T-DM1, which [rendered her] ineligible for trastuzumab deruxtecan. A small patient population probably will not be able to use this drug, especially since we don’t have clear guidelines on how to manage [ILD]. Most of the time, if the patient develops [treatment-related] ILD, the drug should be permanently discontinued.

If the company plans to target the neoadjuvant or adjuvant setting, [ILD could be] a problem. For localized breast cancer, the goal is to cure the disease. However, if the treatment can increase the risk of ILD and potentially kill the patient, that will significantly limit the use of this drug, especially for localized breast cancer [where there are] other treatment options that work just as well and are better tolerated.

How have the data from the HER2CLIMB trial informed the use of tucatinib in practice?

This is a very exciting trial. DESTINY-Breast01 and HER2CLIMB opened a lot of clinicians’ eyes. We [now] feel we have more to offer our patients. HER2CLIMB proved that patients with and without brain metastases [can] benefit [from tucatinib]. The HER2CLIMB [regimen] has become a top option for a patient that has disease progression on T-DM1 and brain metastases.

For me, the tricky part is choosing between trastuzumab deruxtecan and tucatinib if I have patient who has disease progression on T-DM1. If the patient has untreated brain metastasis, I would probably use tucatinib. In HER2CLIMB, the investigators enrolled patients with untreated brain metastases, but in DESTINY-Breast01, all patients with brain metastases had been treated for their brain disease.

I had a patient who had disease progression in the brain and body on T-DM1, and when I switched to tucatinib, she had an excellent response, which was really exciting.

In the clinical trial, adverse effects included diarrhea and hand-foot syndrome, and everybody was nervous about the diarrhea. However, based on my experience, my patients tolerate [the triplet] pretty well. My sample size is not that huge, but [my patients who have received the triplet] feel great. The diarrhea [has not had a tremendous effect] on their quality of life, and the hand-foot syndrome doesn’t bother them that much either. Plus, 2 of the agents are pills, so patients can just take them at home; it’s just the trastuzumab that requires an infusion every 3 weeks, so it’s very convenient for patients as well.

Does margetuximab-cmkb (Margenza), which was recently FDA approved, have a clear role in the metastatic setting?

I haven’t used margetuximab [yet]. We already have trastuzumab deruxtecan and tucatinib, so I don’t know how that drug is going to fit into the landscape right now. I’m less excited about the results from [the SOPHIA trial]. We have this well-tolerated triplet with excellent treatment effect in patients with or without brain metastasis that is easy to administer. Trastuzumab deruxtecan, despite the ILD, is a 1-time infusion every 3 weeks that is also convenient and pretty well-tolerated, with excellent responses, even in heavily pretreated patients with brain metastases. Any other drugs have to prove [to be] better than [trastuzumab deruxtecan and tucatinib], either in terms of efficacy, tolerability, or convenience. Otherwise, I don’t see [a role for margetuximab prior to] trastuzumab deruxtecan or tucatinib. Margetuximab could be used following both drugs.

At this time, the first-line standard for metastatic HER2-positive disease should be THP [docetaxel, trastuzumab, and pertuzumab], and then the second-line standard should be T-DM1. In the third and fourth line, we can use tucatinib or trastuzumab deruxtecan. The fifth- and later-line choice will be up to the physician to select something from the manual that works for the patient’s individual needs.

Are there any ongoing clinical trials that could potentially challenge standard options that you’re excited about?

A trial is evaluating T-DM1 plus tucatinib after patient has progression of disease on THP. That’s a very exciting trial that will probably change the landscape a little bit. However, if the patient still has an opportunity to use [tucatinib] in the third-line setting, why do we have to use 2 drugs in the second-line setting, which can cause more toxicities? If we want to make tucatinib and T-DM1 a standard second-line treatment, that regimen has to perform significantly better than T-DM1 alone.

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