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Spotlight

Erika P. Hamilton, MD, discusses antibody-drug conjugates in multiple types of breast cancer, and when to use these drugs in sequence.

Antibody-Drug Conjugates Show Unique Advantage in Breast Cancer

Erika P. Hamilton, MD, director of breast cancer and gynecologic cancer research at the Sarah Cannon Research Institute, discusses antibody-drug conjugates (ADCs) in multiple types of breast cancer, and when to use these drugs in sequence.

ADCs such as datopotamab deruxtecan (Dato-DXd), trastuzumab deruxtecan (Enhertu), and sacituzumab govitecan (Trodelvy) have been studied across breast cancer subgroups. The latter 2 drugs received indications for both hormonally driven and triple-negative breast cancer, according to Hamilton.

Typically, treatment for hormonally-driven breast cancer is endocrine therapy such as aromatase inhibition (AI) with a CDK4/6 inhibitor in the first line. Then there are different options in second line, but it is dependent on if the patient has a mutation, for example 

. After the patient progresses on endocrine therapy, ADCs can be considered as a replacement for chemotherapy that would have been used at this point.

 What's unique about the ADCs is that they aren't specific just to 1 type of breast cancer. We typically think about breast cancer as 3 types: HER2 positive, hormonally driven, and triple negative. For our ADCs, particularly trastuzumab deruxtecan and sacituzumab govitecan have indications in what we would consider hormonally driven as well as triple-negative breast cancer. I think that's really unique.

 For our patients who are hormonally driven, we typically exhaust our endocrine therapies. So, the first-line standard is an AI with CDK4/6. Second line, maybe fulvestrant [combination], PI3 or mTOR, AKT inhibitor, or maybe something like elacestrant if they have an 

 mutation. And then they continue to get endocrine therapy until their tumor shows us that it's no longer sensitive to endocrine blockade. Then when we start thinking about chemotherapy, that's where ADCs come in. So, it's important to make sure that we file ADCs as a chemotherapy substitute. It's not just, quote, a second-line or third-line therapy, especially when we're talking about patients with hormonally driven breast cancer, because their endocrine therapies come first.

Erika P. Hamilton, MD, discusses antibody-drug conjugates in multiple types of breast cancer, and when to use these drugs in sequence. 

KEY TAKEAWAYS FROM ADITYA BARDIA, MD, MPH​, FASCO

Trastuzumab deruxtecan and sacituzumab govitecan can be given to patients with metastatic HER2-low breast cancer after endocrine therapy and chemotherapy.

Progression-free survival and overall survival favor trastuzumab deruxtecan over chemotherapy in HER2-low disease.

The DESTINY-Breast06 trial showed similar outcomes for HER2-low and HER2-ultralow disease.

A 52-year-old postmenopausal woman underwent breast-conserving surgery plus radiation therapy for pT2 N1 invasive ductal carcinoma of the right breast, grade 2, estrogen receptor (ER)–positive, progesterone receptor–positive, HER2 1+ by immunohistochemistry (IHC); 21-gene recurrence score: 27​.

She received dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and completed 10 years of tamoxifen.​

Five years later, she presented with disease recurrence in the liver, hormone receptor–positive, HER2-low, no actionable mutations on tissue next-generation sequencing​.

She received first-line letrozole plus ribociclib​ (Kisqali).

​She went on to receive ​fulvestrant for 6 months to disease progression in the bone and liver, then everolimus plus exemestane for 4 months to disease progression, followed by capecitabine for 6 months until disease progression.

Repeat circulating tumor DNA next-generation sequencing at each progression showed no actionable alteration.

Targeted Oncology: Do you consider this patient with metastatic breast cancer (mBC) to be eligible for sacituzumab govitecan (Trodelvy)?

If you look at the label of sacituzumab govitecan, it says 2 prior lines of systemic therapy; it does not say which kind, so you can make a case that the endocrine-based treatment was also systemic therapy.

 But the TROPiCS-02 trial [NCT03901339], which led to approval, required 2 prior lines of chemotherapy. Purely from a trial perspective, you should give 2 lines of chemotherapy, but in routine clinical practice, after capecitabine, that's when we consider trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan.

Can you use T-DXd and sacituzumab one after another?

You can use them in sequence. There have been studies looking at the efficacy of one after the next,

 and there is some cross-resistance between these agents because they have similar payloads. In sacituzumab govitecan, SN38 is a topoisomerase-1 inhibitor. With T-DXd, deruxtecan is also a topoisomerase-1 inhibitor. But in some patients, it does work, and maybe in that setting, the disease progression is more because of the antigen, and so you're using a different antibody that works. But in some patients, you would see cross resistance.

If you look at our guidelines, you have both these drugs, T-DXd and sacituzumab govitecan. The guidelines would suggest T-DXd should be preferred for HER2-low disease.

 But if a patient is not a candidate for T-DXd, that's when you use sacituzumab. That could be either contraindication to T-DXd, or if a patient has HER2 IHC 0 mBC in that setting, you can use sacituzumab, and you can use them in sequence. If you start with one, you can use the other drug after that.

What data support the use of T-DXd in patients with HER2-low status?

This was based on DESTINY-Breast04 [NCT03734029], which looked at T-DXd vs standard chemotherapy for HER2-low, ER-positive breast cancer. It showed impressive improvement in both progression-free survival [PFS] and overall survival [OS]. We saw updated results last year, and essentially continue to see benefit with T-DXd vs a standard chemotherapy with median OS of about 24 months [vs 17.6 months for chemotherapy; HR, 0.69; 95% CI, 0.55-0.87].

 That's 2 years in the second line [and beyond] setting.

At least in DESTINY-Breast04, HER2 IHC 1+ vs 2+ didn't matter. We saw similar results, and in DESTINY-Breast04, any prior HER2-low specimen was allowed. That could be primary breast cancer. It could be the first metastatic [biopsy] specimen. Any prior specimen that was HER2-low was allowed, and they saw similar benefit. In terms of safety, the main adverse events [AEs] with T-DXd are neutropenia, alopecia, nausea, and then pneumonitis.

What is the significance of the DESTINYBreast06 trial (NCT04494425) in mBC?

DESTINY-Breast06 also included HER2-ultralow, which is IHC 0+, so just some cells with HER2 expression. The other big difference was it did not require prior chemotherapy for metastatic disease. The comparator was capecitabine, which was 60% in this trial, or taxanes.

It showed results somewhat similar to DESTINY-Breast04, maybe a bit less in terms of HR, but still meaningful [in the HER2-low subgroup]. The HR was 0.62 [95% CI, 0.51-0.74; 

 < .0002] and a 5-month improvement in PFS [median, 13.2 months vs 8.1 months with chemotherapy].

Then if we combine both HER2-low and -ultralow, in the intent-to-treat population, there were very similar results [PFS HR, 0.63; 95% CI, 0.53-0.75; 

 < .0001]. In terms of OS, there was a trend towards improvement in OS [HR, 0.83; 95% CI, 0.66-1.05] but the results are not mature at this time.

If we just look at HER2-ultralow, there were very similar results, improvement in PFS with a delta of about 5 months [median, 13.2 months vs 8.3 months for chemotherapy; HR, 0.78; 95% CI, 0.50-1.21], and a trend towards improvement in OS as well [HR, 0.75; 95% CI, 0.43-1.29].

Then if you look at response rate, it was close to 60% overall response rate with T-DXd, even with HER2-ultralow. That’s why we feel that this drug works regardless of the amount of HER2 expression.

In terms of AEs, nausea is the most common, with alopecia, and some diarrhea as well. This is a setting where you should remember to get EKGs, because you can have decrease in left ventricle ejection fraction.

1. Trodelvy. Prescribing information. Gilead Sciences, Inc; 2023. Accessed November 13, 2024. 

2. Huppert LA, Mahtanai RL, Fisch SC, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): updated data and subgroup analyses by age, sites of disease, and use of intervening therapies. 

. 2024;42(suppl 16):1083. doi:10.1200/JCO.2024.42.16_suppl.1083

3. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2024. Accessed November 13, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

4. Modi S, Jacot W, Iwata H, et al. 376O - Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Updated survival results of the randomized, phase III DESTINY-Breast04 study. 

. 2023;34(suppl 2):S334-S335. doi:10.1016/j.annonc.2023.09.553

5. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

During a Case-Based Roundtable® event, Aditya Bardia, MD, MS, FASCO, discussed data from the DESTINY-Breast04 and DESTINY-Breast06 trials for HER2-low breast cancer in the second article of a 2-part series.

HER2-Low and -Ultralow Populations Benefit from T-DXd in HR+ mBC

Trastuzumab deruxtecan (T-DXd) continued to show benefit in the updated data from the DESTINY-Breast03 trial (NCT03529110).

Special attention should be paid to the toxicities of nausea and pneumonitis with T-DXd, according to Bardia.

Tucatinib (Tukysa) demonstrated improved intracranial efficacy in patients with active brain metastases; similar data for T-DXd have been published but not from randomized trials.

Targeted Oncology: What sequence of systemic therapy options is recommended by the National Comprehensive Cancer Network for stage IV HER2-positive metastatic breast cancer?

In terms of guidelines, the first line is trastuzumab [Herceptin], pertuzumab [Perjeta], and [either docetaxel or paclitaxel].

 The second line is T-DXd. The third line [can be] tucatinib plus trastuzumab plus capecitabine or trastuzumab emtamsine [T-DM1]. You can use T-DM1 after T-DXd [but physicians] generally like to use a ‘sandwich’ technique in which you use T-DXd, then use tucatinib, capecitabine, and trastuzumab, and then after that bring in T-DM1 so you're not using antibody-drug conjugate [ADC] after ADC, but we don't have much evidence. You can use T-DM1 after T-DXd if you want. There was a trial combining T-DM1 with tucatinib that 

 but not much, so it's not something that we would use in clinical practice. Then after that, [one can use] pretty much any option. You can combine trastuzumab with something: trastuzumab plus capecitabine, docetaxel, vinorelbine, eribulin—you just combine anti-HER2 therapy with chemotherapy. Neratinib [Nerlynx] is another option in the third-line setting [and beyond].

What led to the indication for T-DXd following HER2-targeted first-line treatment in this setting, and what are the most recent updates to these data?

This was based on Destiny-Breast03. It was in the second-line setting with randomization to T-DXd vs T-DM1, so one ADC vs another. It included patients who had disease progression within 6 months after completing adjuvant therapy.

[With 43 months median follow-up], there was very impressive improvement in progression-free survival [PFS] with an HR of 0.3 [95% CI, 0.24-0.38].

 We don't generally see this in the field of oncology [as a whole], not just breast oncology. In terms of overall response rate [ORR], there was a nearly 80% ORR [with T-DXd vs 36.9% with T-DM1]. That's why, if a patient has liver disease or symptomatic disease, this is the go-to medication, including in estrogen receptor–positive breast cancer when a patient has HER2-low disease or a lot of disease burden. T-DXd is a good medication in that circumstance. There was improvement in overall survival as well [HR, 0.73; 95% CI, 0.56-0.94].

In terms of adverse events [AEs], 3 common AEs seen with T-DXd included nausea, myelosuppression, and alopecia, and pneumonitis as well [less commonly].

Nausea is the No.1 AE with T-DXd. If you look at guidelines, they say you can use a 2-drug or 3-drug antiemetic regimen.

 I usually use a 3-drug antiemetic regimen to start with, and if a patient does very well, then I back off. The other trick is to use olanzapine [Zyprexa]. For some reason, it tends to work very well with breakthrough nausea with T-DXd, as well as with sacituzumab govitecan [Trodelvy]. If none of this works…[you can] do dose reduction. It is somewhat dose related, and if you reduce the dose, the patient can feel better.

Pneumonitis is a very serious AEs with T-DXd; there have been deaths in clinical trials. You can imagine [with the patient population treated] in routine clinical practice it will be worse, and the key is early recognition. But sometimes, despite that, we tend to see severe pneumonitis.

[In terms of] AEs of special interest, we know about pneumonitis as well as decrease in left ventricular ejection fraction. That's less of a problem in terms of monitoring in HER2-positive disease, because those patients know about EKGs, and they're used to getting EKGs. This is something important to remember when T-DXd is used in hormone receptor–positive breast cancer in the HER2-low setting. Often those patients have not had EKGs before, so it’s just important to remember to get an EKG in that circumstance.

Does the presence of lung metastasis or the use of radiotherapy in the lungs increases the risk of pneumonitis?

In pooled analysis of clinical studies, they've not seen it to be a major risk factor. The risk factors are history of lung injury [such as] smoking and prior history of lung disease, or impaired renal function; that appears to be a risk factor as well, in terms of pneumonitis from T-DXd.

 Maybe it's because you have more payload that circulates around, it's usually in the first few months and the majority occurred in the first year. That's why, early on, it's important to get scans. Some would say every 8 weeks, but definitely every 12 weeks…in terms of scans initially with T-DXd.

Would you change from trastuzumab/pertuzumab to T-DXd in a patient with bone-only metastases that could be irradiated?

If you're just seeing 2 spots in the bone, and everything [else] is under control, you could consider radiation. If you just are seeing disease in the brain and everywhere else the disease is under control, you could do stereotactic radiosurgery and then continue trastuzumab/pertuzumab.

What data support treatment selection for patients with brain metastases?

There have been clinical trials looking at T-DXd in patients with brain metastases in Destiny-Breast02 [NCT03523585] and Destiny-Breast03, but it was in patients with stable brain metastases, not patients with active brain metastases. HER2CLIMB [NCT02614794] included patients who had progressive brain metastases, and that's why the level of evidence is higher with tucatinib. [We have data on] efficacy in patients with brain metastases with intracranial [confirmed ORR of 47.3%], so you have direct evidence that tucatinib does work in patients with brain metastases.

In terms of T-DXd, ¾ these are not randomized data per se—but with single-arm studies, you do see an [intracranial] ORR of 73% in the TUXEDO-1 trial [NCT04752059].

In another trial [DEBBRAH; NCT04420598], it was [44%], so it does have activity in the brain, which was surprising.

 It was not expected that ADCs would have activity in patients with [active] brain metastases, but maybe you have an impaired blood-brain barrier, which allows these ADCs to cross, or maybe the payload crosses, but it does work in that setting. Similarly, with sacituzumab govitecan, it does have activity in patients with brain metastases.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2024. Accessed October 21, 2024. 

2. Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. 

. 2024;30(8):2208-2215. doi:10.1038/s41591-024-03021-7

3. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus trastuzumab emtansine for breast cancer. 

. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022

4. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2022. Accessed October 21, 2024. 

5. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. 

. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554

6. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. 

During a Case-Based Roundtable® event, Aditya Bardia, MD, MS, FASCO discussed recent updates from the DestinyBreast03 trial and other key data on treatment for HER2+ breast cancer in the first article of a 2-part series.

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