Optimizing Outcomes With ADCs in Breast Cancer Requires a Tactical Approach

Allison Butts, PharmD, BCOP

Antibody-drug conjugates (ADCs) are innovative and effective therapeutic agents that have transformed the treatment landscape for patients with HER2-positive breast cancer and triple-negative breast cancer (TNBC). ADCs have carved out a role in third or later lines of therapy and offer solutions for patients who have been heavily pretreated. However, the agents’ toxicities pose a challenge that may limit patients’ ability to derive maximum benefit. During a recent OncLive Peer Exchange^®, a panel of breast cancer experts provided an overview of FDA-approved ADCs, including the trials that led to their approval. They used 2 case scenarios to highlight how to optimize these agents in clinical practice, including strategies for preventing some of their most common and severe toxicities.

FDA-Approved ADCs for Breast Cancer

Three ADCs that leverage antibodies targeting HER2 or Trop-2 (TABLE 1^1-3)are approved for patients with breast cancer. “These drugs are kind of like the Trojan horse of cancer care, meaning that we’re directing another drug to [patients’] cancer cells and sneaking it in,” Allison Butts, PharmD, BCOP, said. To accomplish this, Butts pointed to the design of the agents, which consists of 3 main components: the antibody, which directs the drug to its site of action; the payload, which is the cytotoxin being delivered to the cell to try to induce cell death; and the linker, which connects the cytotoxin to the antibody backbone.

T-DM1

Ado-trastuzumab emtansine (T-DM1; Kadcyla) was the first ADC approved for women with HER2-positive metastatic breast cancer. It received initial approval from the FDA in 2013.¹ Approval in this setting was based on data from the phase 3 EMILIA trial (NCT00829166). The study compared T-DM1 with lapatinib (Tykerb) plus capecitabine, which was the standard of care at the time. The study included 991 adult patients with HER2-positive unresectable, locally advanced, or metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane.

“[Treatment with T-DM1] led to a significant improvement in progression-free survival [PFS] and overall survival [OS],” Komal Jhaveri, MD, FACP, said. The median PFS was 9.6 months among those treated with T-DM1 (n = 495) vs 6.4 months for those treated with lapatinib plus capecitabine (n = 496; HR, 0.65; 95% CI, 0.55-0.77; P < .001).⁴ The median OS crossed the stopping boundary for efficacy (30.9 months vs 25.1 months, respectively; HR for death from any cause, 0.68; 95% CI, 0.55-0.85; P < .001).⁴ A descriptive analysis of the f inal OS results in 2017 showed that patients who received T-DM1 had a median OS of 29.9 months (95% CI, 26.3-34.1) with T-DM1 and 25.9 months (95% CI, 22.7-28.3) with lapatinib plus capecitabine (HR, 0.75; 95% CI, 0.64-0.88).⁵ This analysis included crossover of 136 patients in the lapatinib plus capecitabine arm to the T-DM1 arm.

Jhaveri noted that T-DM1 also showed benef it in patients who had progressed following 2 or more prior HER2-directed regimens in the phase 3 TH3RESA trial (NCT01419197).⁶ The study randomly assigned 602 patients 2:1 to receive T-DM1 (n = 404) or physician’s choice of chemotherapy (n = 198). Shortly before the enrollment period closed, the study protocol was amended to allow crossover, and 93 patients in the physician’s choice group (47%) had crossed over to T-DM1 by the data cutoff for the final OS analysis. The final OS analysis revealed a median OS of 22.7 months (95% CI, 19.4-27.5) in the T-DM1 arm vs 15.8 months (95% CI, 13.5-18.7) in the chemotherapy arm (HR, 0.68; 95% CI, 0.54-0.85; P = .0007).⁶

T-DM1 is the only ADC that thus far also has received FDA approval for the adjuvant treatment of patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. It received approval for this indication in 2019 based on data from the phase 3 KATHERINE trial (NCT01772472).^7,8 Jhaveri noted that a 3-year invasive disease survival benefit of 11% was observed with T-DM1 vs trastuzumab alone. “It improved from 77% in the control arm to 88% in the T-DM1 arm,” she said. The HR for invasive disease or death was 50% lower with adjuvant T-DM1 vs trastuzumab alone (95% CI, 39%-64%; P < .001).

Jhaveri said the KATHERINE data justify the use of T-DM1 in the adjuvant setting vs continuing anti-HER2 therapy and noted that T-DM1 is currently the standard of care. However, she noted that ongoing clinical trials are comparing T-DM1 with adjuvant fam-trastuzumab deruxtecan-nxki (Enhertu), including DESTINYBreast03 (NCT03529110) and DESTINY-Breast05 (NCT04622319), which have the potential to change the standard of care.

Trastuzumab Deruxtecan

In 2019, trastuzumab deruxtecan became the second ADC approved in the metastatic setting for patients with HER2-positive breast cancer.⁹ Whereas T-DM1 has a maytansinoid payload, trastuzumab deruxtecan has a topoisomerase 1 inhibitor payload, Jhaveri said. “When we think about the drug-to-antibody ratio—how many molecules of chemotherapy are we delivering to a cancer cell when this conjugate attaches to the target protein—trastuzumab deruxtecan delivers approximately 8, compared with T-DM1, which delivers approximately 3.5,” she explained.

The FDA’s accelerated approval of trastuzumab deruxtecan was based on data from the phase 2 single-arm DESTINY-Breast01 trial (NCT03248492),¹⁰ in which investigators evaluated the efficacy of the ADC among 184 patients who had received a median of 6 previous treatments. Updated data from the trial presented at the European Society of Medical Oncology Annual Congress 2021 demonstrated the sustained benefit of trastuzumab deruxtecan among the intention-to-treat population at a median follow-up of 26.5 months (95% CI, 0.7-39.1).¹¹ The confirmed objective response rate (ORR) was 62.0% (95% CI, 54.5%-69.0%) with a complete response rate of 7.1% and a partial response rate of 54.9%. The median duration of response was 18.2 months (95% CI, 15.0-not estimable [NE]). Further, survival data for the agent showed a median PFS of 19.4 months (95% CI, 14.1-25.0) and a median OS of 29.1 months (95% CI, 24.6-36.1) with estimated 12-month, 18-month, and 24-month OS rates of 85% (95% CI, 79%-90%), 75% (95% CI, 67%-80%), and 58% (95% CI, 51%-65%), respectively.¹²

Data from the first phase 3, randomized trial of trastuzumab deruxtecan have bolstered the excitement over the agent’s future in the armamentarium. Investigators of the DESTINY-Breast03 trial compared trastuzumab deruxtecan (n = 261) with T-DM1 (n = 263) in patients previously treated with trastuzumab and a taxane.12 The study showed a 72% reduction in risk of progression vs T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10^-22. The median PFS was not reached (95% CI, 18.5-NE) with trastuzumab deruxtecan vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 when assessed by blinded independent central review. The 12-month PFS rates were 75.8% (95% CI, 69.8%-34.1% (95% CI, 27.7%-40.5%). “That’s something we haven’t really seen in breast cancer, let alone HER2positive breast cancer,” Jhaveri said. Additional follow-up data presented at the 2021 San Antonio Breast Cancer Symposium confirmed that this benefit was consistent across all subgroups, including among those with brain metastases at baseline.¹³

Sacituzumab Govitecan

Sacituzumab govitecan is a TROP2-directed ADC that received accelerated FDA approval in 2020 and regular approval in 2021 for patients with previously treated locally advanced or metastatic TNBC.^14,15 Regular approval was based on data from the phase 3 ASCENT trial (NCT02574455), in which 529 patients with and without brain metastases were randomized 1:1 to receive sacituzumab govitecan (n = 267) or physician’s choice of singleagent chemotherapy (n = 262).¹⁶

Among all randomized patients, the median PFS was 4.8 months in the sacituzumab govitecan arm vs 1.7 months in the chemotherapy arm (HR, 0.43; 95% CI, 0.35-0.54; P < .0001). The median OS was 11.8 months vs 6.9 months, respectively (HR, 0.51; 95% CI, 0.41-0.62; P < .0001).16 An objective response was observed in 35% of patients treated with sacituzumab govitecan versus 5% treated with chemotherapy.¹⁶

Optimizing ADCs in Clinical Practice

With ADCs providing several options for investigators and showing potential to shake up standards of care, the panel discussed case scenarios to better illustrate how they use ADCs in clinical practice and manage the toxicities associated with these agents (TABLE 2^1-3).

Case 1: T-DM1 in Adjuvant Setting

The first case discussed was that of a 62-year-old woman with early-stage HER2-positive breast cancer treated with T-DM1 in the adjuvant setting after 0.6 mm of residual disease was identified in the surgical specimen. A key issue the panelists addressed was whether there was any threshold of residual disease that would lead them to continue the HER2-targeted therapy rather than use T-DM1. Jhaveri said she has no such threshold. “My practice has been to offer T-DM1 for all patients with residual disease. I’m not holding that back, given the dramatic difference in the invasive disease survival that we saw [in the KATHERINE trial],” she said.

The other panelists agreed. “If I were to see this patient in clinic, she’s going to get T-DM1 in the adjuvant setting, given her residual disease,” Kevin Kalinsky, MD, MS, said.

Regarding the toxicities associated with T-DM1, the panelists focused on the box warnings concerning cardiotoxicity and hepatotoxicity, which apply to all patients, and neuropathy, which has mostly been observed in patients treated in the neoadjuvant setting. Because the case patient had hypertension and took a baby aspirin daily, Kandra Horne, MSN, NP, WHNP-BC, said she would monitor her left ventricular ejection fraction before starting the T-DM1 and then once every 3 weeks throughout treatment. The patient’s liver enzymes would also be monitored before initiating treatment and again prior to each dose to ensure she was not developing hepatotoxicity.

“Of course, I’ll ask her if she is having any residual effects or has developed any neuropathy,” Horne said. “I’ll let her know that we’ll continue to monitor not only her cardiac ejection fraction but also adverse effects [AEs], and that we’ll continue to monitor for them every 3 weeks.”

Butts said that some AEs are even less prevalent with T-DM1 than trastuzumab alone, including cardiotoxicity and infusion reactions. However, she noted that patients treated with this agent in the adjuvant setting tend to have more difficulty tolerating it than those receiving it in the metastatic setting. “In addition to more neuropathy, which is likely residual from neoadjuvant treatment, we found [higher incidences of] of anorexia, failure to thrive, and fatigue. Some of these things we don’t run into commonly in the metastatic space,” she said.

To reduce such risks, Butts said it’s important to optimize patients’ therapy before starting the T-DM1 and to ensure they have a sufficient break between their neoadjuvant and adjuvant therapies so that their residual neuropathy has a chance to improve or resolve. “Those [steps] have been the key because we’ve had to switch a number of patients back to HP [trastuzumab plus pertuzumab] maintenance because they haven’t done well on the T-DM1 based on preexisting toxicities that have been left over,” she said.

Jhaveri estimated that she sees peripheral neuropathy in approximately 20% to 25% of her patients with early-stage breast cancer treated with T-DM1 in the adjuvant setting. “It’s hard for patients to have a lot of treatment up front, whether it’s 6 cycles of TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or AC-THP [doxorubicin hydrochloride, cyclophosphamide, docetaxel, trastuzumab, pertuzumab], plus whatever residual neuropathy they might have from the taxane-based therapy, and then 14 cycles thereafter,” she said.

When neuropathy occurs, Jhaveri said she may delay a dose or reduce the dose from the approved dose of 3.6 mg/kg to 3.0 mg/kg. When such strategies are not sufficient, she said she may try more unconventional strategies, such as gabapentin, duloxetine, or acupuncture, noting these interventions do not have the strongest evidence base but may be helpful for some patients.

Case 1 (continued): Trastuzumab Deruxtecan in Metastatic Setting

After 6 months of treatment, the case patient’s disease progressed to metastatic and she was started on trastuzumab deruxtecan (Table 3). For patients treated with trastuzumab deruxtecan, the panelists noted that nausea, fatigue, and alopecia are key AEs they discuss with their patients. “For the most part, we need to know ahead of time that these symptoms can occur, make sure that there’s an antiemetic regimen available, talk to patients, and know how to manage adverse effects,” Horne said.

Nausea and fatigue are among the most common AEs she has observed with trastuzumab deruxtecan, Horne said. Jhaveri said she has only rarely observed alopecia, noting it occurs less frequently in clinical practice than reported in the DESTINY-Breast01 trial.¹¹ To reduce the risk of nausea, she said the protocol at her institution is to administer palonosetron with dexamethasone at the time of infusion and then provide ondansetron as needed. Regarding alopecia, she stressed the importance of making patients aware of it, particularly because it can be a devastating AE to patients and it can be a delayed effect of treatment. In addition, there is no way to determine who will experience it. “Overpreparing a patient for alopecia goes a long way compared with not mentioning it or forgetting to mention it,” she said.

The panelists also discussed the more severe AEs associated with trastuzumab deruxtecan, including interstitial lung disease (ILD) and pneumonitis, which are potentially life-threatening complications. Jhaveri said she makes sure to educate her patients about these risks. “I want them to report any dry cough that’s lingering more than usual, any extreme fatigue…and any worsening shortness of breath that’s limiting their activities of daily living,” she said. Additionally, she said she keeps a close eye on the radiological findings, looking for signs such as ground-glass opacities, which may be suggestive of pneumonitis.

Jhaveri explained that several factors have been associated with an increased risk of ILD, including a decline in renal function or glomerular filtration rate, use of higher doses of trastuzumab deruxtecan, and multiple prior lines of therapy. Although lung cancer has been shown to increase the risk of pulmonary toxicities, she said that lung metastases at baseline do not appear to be a risk factor in patients with breast cancer.

To ensure that she can better identify patients at risk for developing pulmonary problems and facilitate identification of pulmonary AEs during treatment, Jhaveri said she performs pulmonary function testing (PFT) before starting trastuzumab deruxtecan treatment. “If a patient did end up having ILD or pneumonitis, and we [only] do a PFT at that particular time, we don’t have a baseline to compare,” she said.

Butts, Horne, and Kalinsky said they do not conduct PFT testing at their institutions, but they reiterated the importance of alerting patients to this AE. “We’ve learned with experience to be careful and to express to patients the importance of looking for shortness of breath and to let us know if they’re having a cough or anything like that, because if patients are having grade 2 or higher events, we should be stopping the agent,” Kalinsky said.

Case 2: Sacituzumab Govitecan for Metastatic Breast Cancer

The second case discussed was of a postmenopausal woman who received a diagnosis of metastatic triple-negative breast cancer after she discovered a lump in her left breast. After progressing on second-line treatment, she received sacituzumab govitecan.

The first question the panelists examined is when to initiate treatment with sacituzumab govitecan. The FDA-approved indication is after at least 2 prior therapies in the relapsed or refractory metastatic disease setting. Jhaveri said it was appropriate to treat the patient with this agent in the third line based on its approved indication but she said she would have been comfortable using it in the second line as well. “Based on the results that we’ve seen in the phase 3 ASCENT trial, it’s a very active drug in TNBC,” she said. Jhaveri added that some activity with this agent also has been observed in hormone receptor–positive disease but that investigators are awaiting confirmatory data from randomized trials.

The panelists then focused on tolerability. Horne said that patients tolerate the treatment well, but that patients similar to the case patient are heavily pretreated and therefore have certain vulnerabilities. She suggested that the risk of some toxicities might be reduced as the treatment moves into earlier lines. The key AEs she has observed in heavily pretreated patients include fatigue, occasional nausea, and neutropenia. To protect patients’ neutrophil counts, she said the treatment cycle may be switched from days 1 and 8 to days 1 and 15, and agents such as pegfilgrastim may be added to further support counts.

Regarding the gastrointestinal effects, Butts said she mostly sees diarrhea because prophylactic use of oral antiemetics is a widespread practice with this regimen. “We’ve not really seen consistent diarrhea. It’ll flare up in one cycle and not be too much of an issue in the next. Fortunately, we’ve been able to manage that with oral medications,” she said.

Another key AE the panelists noted is alopecia. Unlike trastuzumab deruxtecan, where it is unclear who will experience this AE, they noted it is almost universal with sacituzumab govitecan. Butts said she has only treated 1 patient with this agent who did not lose their hair, making it another important AE to warn patients about.

In their concluding remarks, the panelists expressed considerable excitement about the future of ADCs expanding the treatment paradigm for patients with breast cancer. “This is an ever-evolving field and I think where we are now is going to be different than where we are going to be in 3 to 5 years. This is very much a moving target, and that’s exciting for us and for our patients,” Kalinsky said.

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