Less Toxic, More Personalized Treatments on the Horizon in HER2+ Breast Cancer

Naomi Dempsey, MD

Advancements in the HER2-positive breast cancer space are emphasizing the trend toward personalized treatment and less toxic regimens that offer better outcomes and quality of life to patients.

In early-stage HER2-positive breast cancer, the APT trial (NCT00542451)1 and later the ATEMPT (NCT01853748)2 trial have shown promising results with de-escalated treatments using paclitaxel and trastuzumab (Herceptin) or trastuzumab emtansine (Kadcyla; T-DM1), respectively. These trials indicate high rates of invasive disease-free survival, suggesting that patients can achieve optimal outcomes with reduced toxicity.

For patients with stage II and III disease, the TRAIN-2 trial (NCT01996267) demonstrated that omitting anthracycline from treatment does not compromise efficacy but reduces cardiotoxicity, a significant advancement in patient care.

Ongoing efforts aim to continue to tailor treatments based on individual patient factors, such as age, overall health, and tumor biology. According to Naomi Dempsey, MD, trials like ATEMPT 2.0 (NCT04893109)3 and CompassHER2 RD (NCT04457596)4 are exploring ways to personalize treatment and address specific challenges, such as central nervous system (CNS) recurrences. Not only do these trials aim to find new and effective targeted treatments, but ones that cause fewer adverse effects.

Looking forward, Dempsey sees a future of personalized medicine in HER2-positive breast cancer, with a focus on preventing CNS recurrences and developing more active agents.

“The future of HER2-positive breast cancer is one of personalized medicine and of understanding the biology and mechanisms of resistance to HER2-targeting agents,” shared Dempsey, breast medical oncologist at Baptist Health Miami Cancer Institute, in an interview with Targeted Oncology^TM.

In the interview, Dempsey, MD, discussed developments in the HER2-positive breast cancer space, including personalized approaches, less toxic treatments, promising trial results, and more.

3D rendered medically accurate illustration of breast cancer: © SciePro - stock.adobe.com

Targeted Oncology: What are some of the most recent advancements in the treatment of HER2-positive breast cancer? How have they changed patient outcomes?

Dempsey: The treatment of HER2-positive breast cancer has been evolving in recent years with advancements that have allowed us to better personalize treatment. Particularly in the early-stage setting, clinical trial results have provided a basis for de-escalation to less toxic treatments without sacrificing efficacy in selected patients.Such results have also demonstrated that pathologic complete response [pCR] is an important biomarker to tailor adjuvant therapy and that escalated therapy is needed for those who do not achieve pCR.

How do you approach personalized treatment plans for these patients? What data can you discuss?

For patients with stage I, HER2-positive breast cancer, we are in an era of de-escalation. The APT trial was a single-arm, phase 2 trial evaluating patients with node-negative, HER2-positive breast cancer measuring 3 cm or less who received paclitaxel weekly for 12 weeks in combination with trastuzumab for 1 year.1 The final planned analysis of the APT trial showed a 10-year invasive disease-free survival of 91.3% with trastuzumab.

I think what is interesting about these numbers is that most of those invasive disease-free survival [IDFS] events were local recurrences and new contralateral breast cancers that we would not really expect this regimen to be preventing. The rationale for the regimen is to prevent metastatic disease, and the 10-year recurrence-free interval was 96.3%. This means that we are doing a great job with trastuzumab reducing distant recurrences, and that maybe even still, this regimen is more toxic than what we need to achieve optimal outcomes.

With that in mind, the ATEMPT trial was designed.² The ATEMPT trial was a randomized phase 2 trial comparing the APT regimen of trastuzumab vs T-DM1, and patients were randomized 3:1 to the T-DM1 arm. It is important to note that this trial was not designed to compare efficacy of the 2 regimens; it was designed to compare toxicity. The primary end point was clinically relevant toxicity [CRT], and the trial found really no difference with CRT 46% with T-DM1 vs 47% with the APT regimen.

But I think many of us who use both regimens can tell you anecdotally that patients tolerate the T-DM1 much better with less neuropathy, less fatigue, less missed days of work, less alopecia. And although the ATEMPT trial was not designed to compare efficacy, the 5-year IDFS was 97% with T-DM1 and 91.1%, with trastuzumab. I would again urge caution with a head-to-head efficacy comparison, but I think we can use these numbers to get a sense of the activity of T-DM1 in this setting. The recurrence-free interval of 98.3% at 5-years with T-DM1 is excellent.

Because T-DM1 appeared to have excellent efficacy in ATEMPT, but this trial did not meet its primary end point of lower CRT, the ATEMPT 2.0 trial³ was designed. ATEMPT 2.0 is a randomized phase 2 trial that randomizes patients with stage I, HER2-positive breast cancer 3:1 to 6 cycles of T-DM1 followed by subcutaneous trastuzumab to complete 1 year vs trastuzumab. This is a trial we do currently have open at the Miami Cancer Institute. Patients are excited about the idea of potentially being able to omit cytotoxic chemotherapy. We will be looking out for the results from ATEMPT 2.0 in the near future.

What about stage II and III HER2-positive breast cancer?

We have also had some success with de-escalation in stage II and III HER2-positive breast cancer. Previously, these patients were all receiving anthracycline in addition to HER2-directed antibodies. The TRAIN-2 trial was a randomized phase 3 trial of patients with stage II to III HER2-positive breast cancer who received neoadjuvant chemotherapy either with or without anthracycline.⁵ The primary end point of pathologic complete response was similar in both arms: 67% with the anthracycline arm and 68% with a non-anthracycline arm. Three-year overall survival was 97.7% in the anthracycline group and 98.2% in the non-anthracycline group. This was regardless of hormone receptor status or nodal status. I think this is important, showing that we do not achieve additional benefit with the inclusion of anthracycline. Based on those results, most breast oncologists began to omit anthracycline in the US.

Omission of anthracycline for the majority of patients with stage II and III HER2-positive breast cancer has been an important de-escalation that has improved tolerability with similar outcomes. It is equally important to identify those patients who are at high risk of recurrence and require escalation of therapy.

The first step towards escalation was made with the KATHERINE trial [NCT01772472],⁶ which was a randomized phase 3 trial of patients with HER2-positive breast cancer with residual disease after neoadjuvant chemotherapy, and patients were randomized to either receive T-DM1 vs continuation of trastuzumab. The most recent results showed a 13.7% invasive disease-free survival benefit using T-DM1 at 7 years. And with 8.4 years of follow-up, overall survival was 70.1% in the T-DM1 arm vs 62% in the trastuzumab arm. In the setting of residual disease, T-DM1 is preventing recurrences. Unfortunately, a disproportionate number of the recurrences on T-DM1 were CNS recurrences. For that reason, ongoing trials are evaluating treatments with CNS activity in patients with residual disease after neoadjuvant chemotherapy for HER2-positive breast cancer.

What are some of these ongoing trials?

One such trial is CompassHER2 RD,⁴ which is randomizing patients with residual disease after neoadjuvant chemotherapy for HER2-positive breast cancer to T-DM1 vs T-DM1 plus tucatinib [Tukysa], which we know in the metastatic setting has excellent CNS efficacy.

Another such trial is DESTINY-Breast05 [NCT04622319], in which patients with residual disease after neoadjuvant chemotherapy for HER2-positive breast cancer are being randomized to either T-DM1 or trastuzumab deruxtecan [Enhertu; T-DXd].⁷ We know from the metastatic setting that this agent also has efficacy in the CNS. We hope with the results of these trials to be able to reach that unmet need of preventing CNS recurrences in HER2-positive breast cancer.

What is your opinion on the use of combination therapies in HER2-positive breast cancer treatment?

In general, patients with HER2-positive breast cancer always receive combination therapy. In the early-stage setting, we are adding chemotherapy to anti-HER2 drugs and antibodies as previously discussed.

In the metastatic setting, we are generally also using combination therapy. In the first-line setting, the standard of care is based on the CLEOPATRA trial [NCT00567190],⁹ which was a randomized phase 3 trial combining taxane chemotherapy with trastuzumab and either pertuzumab [Perjeta] or placebo. The landmark 8-year overall survival was 57.1 months in the pertuzumab group vs 40.8 months in the placebo group. In clinical practice, we generally use dual antibody therapy with taxane for 6 to 8 cycles or to best response, then discontinue chemotherapy and continue antibody therapy alone or in combination with an aromatase inhibitor if patients have hormone receptor-positive tumors.

The established second-line therapy for HER2-positive metastatic breast cancer is T-DXd based on the DESTINY-Breast03 trial [NCT03529110].¹⁰ This is one area where combination therapy is not needed because this is an antibody-drug conjugate, and it is highly active as a single-agent. DESTINY-Breast03 was a randomized phase 3 trial of patients with HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab who were then randomized to T-DXd vs T-DM1. The median progression-free survival was 28.8 months with T-DXd and 6.8 months with T-DM1. The National Comprehensive Cancer Network [NCCN] designates T-DXd as the preferred second-line treatment based on these results.

In the third line, the HER2CLIMB [NCT02614794]11 regimen of tucatinib, trastuzumab, and capecitabine has efficacy systemically and in the CNS. Because of the CNS [overall survival] benefit seen in HER2CLIMB, this regimen can be considered in the second line in patients with brain metastasis.

In the fourth line and beyond, there are many different options for treatment. One option is T-DM1. T-DM1 has not been well studied after T-DXd, but anecdotally, seems to have some activity. Then beyond that, the NCCN lists a number of different combination options, including margetuximab [Margenza] with chemotherapy based on the SOPHIA trial [NCT02492711], neratinib [Nerlynx] plus capecitabine based on the NALA trial [NCT01808573], or cytotoxic chemotherapy with trastuzumab.

Along the lines of personalizing treatment plans, how do you consider factors like tumor biology and patient health?

We always have to take into account each patient's particular situation when we are planning their treatment. In patients who are older [or frailer] or who may not tolerate chemotherapy well due to comorbidities, less toxic approaches are desired.

The TRAIN-3 [NCT03820063]8 trial evaluated patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using an MRI-directed approach to determine whether chemotherapy could be ended early. I think this is an interesting approach, particularly for patients that maybe do not tolerate it so well. There are patients who may not be able to tolerate chemotherapy at all. Maybe you are concerned that they are in their 80s or 90s and they have HER2-positive breast cancer, but you just do not think that they are going to be able to tolerate chemotherapy. I think there are a number of approaches there that maybe are not what we do in a usual clinical situation, but where we could consider something like adding [trastuzumab] and pertuzumab to an aromatase inhibitor for patients who are triple positive.

There was a recent publication presentation at the American Society of Clinical Oncology Annual Meeting in 2024 in the first-line metastatic setting comparing our standard-of-care taxane, trastuzumab, and pertuzumab regimen to eribulin plus trastuzumab and pertuzumab and showing no differences in efficacy. For many patients, eribulin is better tolerated than taxane, so I think this is something that we should be thinking about in patients that are concerned about tolerance.

In terms of tumor biology, that is where sometimes we do have unique situations where potentially that patient has a HER2-positive breast cancer in 1 breast and a triple-negative breast cancer in the other breast, or within the same breast, 2 components regarding tumor heterogeneity. In those rare cases where there are 2 tumors and 1 is triple negative, I would include anthracycline.

Can you discuss the mechanisms of resistance to HER2 targeted therapies? What are some of the strategies to overcome these resistances?

Over time, our patients with HER2-positive breast cancer can develop resistance to some of our traditional therapies like trastuzumab and pertuzumab. Toward that end, there have been many new drugs that have been recently approved and that are in the pipeline that are novel therapeutics. T-DXd has revolutionized the treatment of metastatic breast cancer and now is being studied in earlier phases. We have seen great efficacy across tumor types, particularly in HER2-positive breast cancer and in CNS responses.

It has been exciting to have some new drugs in the armamentarium, not only for systemic disease, but to help to address CNS disease. Tucatinib, the novel anti-HER2 tyrosine kinase inhibitor, has CNS overall survival benefits. And for our patients with brain metastases, this is a highly active agent. Knowing that trastuzumab does not have CNS activity, it is important to identify the treatments that have CNS efficacy.

What are just some of the most common adverse effects associated with HER2-targeted therapies? How do you manage them in your patients?

Different drugs in our armamentarium for HER2-positive breast cancer tend to have different [adverse] effects. Trastuzumab is our first anti-HER2-directed therapy and has a low rate of reversible cardiac function suppression with a drop in ejection fraction, which is oftentimes asymptomatic and noted on surveillance echocardiogram. These patients recover their cardiac function well when the drug is held and there is some data for reintroduction of trastuzumab in conjunction with cardio-oncology after a previous drop in ejection fraction with good success.

With pertuzumab, we tend to see diarrhea, particularly when using it in combination with carboplatin in the early-stage setting. Antidiarrheals, such as loperamide [Imodium], and good hydration can help patients significantly.

Trastuzumab deruxtecan can commonly cause nausea. It is a highly emetogenic agent, and we use triple antiemetic prophylaxis. On top of that, if further antiemetic prophylaxis is needed, we can add olanzapine [Zypreza]. We all, of course, have concerns about the pneumonitis that has been reported with T-DXd. Across pivotal clinical trials, the rate of interstitial lung disease [ILD] is about 10% at the dose level that we use in breast cancer with some grade 5 events. For that reason, vigilance is required by all members of the clinical team. The median onset of interstitial lung disease is about 4 months into therapy. I tend to see in the clinic, everybody being vigilant about this in the first month or 2, and then perhaps, some of that vigilance, decreasing over time. We need to remember to maintain vigilance throughout the time the patient is on therapy.

We perform a first restaging CAT scan at 9 weeks after initiation of T-DXd to try to identify asymptomatic-grade ILD before it becomes symptomatic. Once the patient has symptoms, it is considered grade 2, and according to the package insert for trastuzumab deruxtecan, we should be discontinuing permanently after a grade 2 ILD event. After a grade 1 ILD event, there is some data for rechallenge with T-DXd. In a recent series, about 45 patients who had grade 1 ILD with T-DXd were rechallenged. Fifteen [33%] developed recurrent ILD, but the other 30 [67%] did not, and there were robust tumor responses in those patients as well. I think if grade 1 ILD is completely and radiologically resolved, we do have data to form a basis for rechallenge. Of course, as soon as ILD is recognized, steroids should be instituted rapidly, and [oncologists should] consider pulmonary consultation.

Tucatinib can cause diarrhea and transaminitis. Overall, it is well tolerated. One issue we encounter with the HER2CLIMB regimen¹¹ is difficulty managing pill administration. A written schedule can help patients follow until they understand how the regimen works and get comfortable with using it. Other older HER2 TKIs such as neratinib [Nerlynx] and lapatinib [Tykerb] caused a lot more diarrhea than tucatinib does. Similar strategies for antidiarrheal management will work for those.

T-DM1 tends to be well tolerated. There can be thrombocytopenia and transaminitis for which one should follow the package insert and dose reduce as appropriate.

What do you see as the most promising future directions in HER2-positive breast cancer research and treatment?

The future of HER2-positive breast cancer is one of personalized medicine and of understanding the biology and mechanisms of resistance to HER2-targeting agents. I think we are doing a good job of identifying the patients who maybe do not need as intensive treatment and can achieve equal outcomes with less intensive treatments, which is much better for quality of life without trading in on efficacy.

But really, an unmet need is in terms of CNS disease, preventing CNS recurrence, and then developing more active agents in the CNS space. There are so many new agents in the pipeline. We have a lot to look forward to in HER2-positive breast cancer.

What are the key takeaways from this conversation that you would like your peers to get out of it?

My key takeaways for HER2-positive breast cancer is that there is a lot of new data coming out all the time. We are seeing that our agents are highly active and providing a lot of efficacy to our patients. It is our job to select who is the best candidate for which treatment, really being cautious not to over treat, but also not to undertreat, and personalizing every patient's treatment plan to their specific situation.

REFERENCES:

1. Tolaney SM, Tarantino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023;24(3):273-285. doi:10.1016/S1470-2045(23)00051-7

2. Tolaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emtansine versus paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A randomized clinical trial. J Clin Oncol. 2021;39(21):2375-2385. doi:10.1200/JCO.20.03398

3. A randomized phase II trial of adjuvant trastuzumab emtansine (T-DM1) followed by subcutaneous trastuzumab versus paclitaxel in combination with subcutaneous trastuzumab for stage I HER2-positive breast cancer (ATEMPT 2.0). News release. Dana-Farber Cancer Institute. Accessed July 17, 2024. https://tinyurl.com/2327n5ry

4. O'Sullivan CC, Ballman KV, McCall L, et al. Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. Future Oncol. 2021;17(34):4665-4676. doi:10.2217/fon-2021-0753

5. van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640. doi:10.1016/S1470-2045(18)30570-9

6. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

7. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). ClinicalTrials.gov. Updated June 28, 2024. Accessed July 17, 2024. https://clinicaltrials.gov/study/NCT04622319

8. van der Voort A, Louis FM, van Ramshorst MS, et al. MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024;25(5):603-613. doi:10.1016/S1470-2045(24)00104-9

9. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0

10. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial [published correction appears in Lancet. 2023 Feb 18;401(10376):556. doi:10.1016/S0140-6736(22)00045-9]. Lancet Oncol. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5

11. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis [published correction appears in Ann Oncol. 2023 Jul;34(7):630. doi:10.1016/j.annonc.2022.12.005.