Familiarity Eases Tolerability Challenges With Newer ADCs in Breast Cancer

Illustration of breast cancer cells: ©ReisMedia - stock.adobe.com

In the field of targeted therapies, antibody-drug conjugates (ADCs) achieve the key goal of selectively delivering the toxic components of chemotherapy directly to cancer cells. By using a monoclonal antibody linked to a payload, ADCs are able to avoid off-target toxicity. However, they still have notable challenges to tolerability, and each ADC has its own toxicities associated with the antibody or its payload that need to be monitored and managed effectively.

Over the past years, ADCs have become standard-of-care therapies and indications have widened to include more patients. In HER2-positive breast cancer, trastuzumab emtansine (Kadcyla; T-DM1) was the first ADC, approved in 2013, followed by fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for HER2-positive breast cancer in 2019.^1,2 The Trop-2–directed ADC sacituzumab govitecan-hziy (Trodelvy) was first approved for triple-negative disease in 2020.³ Now, T-DXd is also approved for the HER2-low setting,⁴ and sacituzumab govitecan is approved for HER2-negative, hormone receptor–positive disease following cyclin-dependent kinase 4/6 inhibitor therapy.⁵ These drugs have shown impressive efficacy even in patients heavily pretreated with chemotherapy who previously had few options.

“We’re all going to be inundated with the efficacy data; that’s what gets us excited. That’s what garners the FDA approval, that’s what changes the standard of care,” said Irene M. Kang, MD, in an interview with Peers & Perspectives in Oncology. “But just as important as knowing what the benefit is for your patients will be knowing what the potential toxicities are, because your patient can’t benefit from a drug if they can’t tolerate the drug.”

Differing Toxicity Profiles in ADCs

Kang, medical director of women’s health medical oncology at City of Hope Orange County in Irvine, California, said that since ADC toxicities often mirror those of chemotherapy, it’s important to recognize they can vary for each compound. Although T-DM1, which breast cancer oncologists are most familiar with due to its longer time on the market, is well tolerated, others may come with serious adverse events (AEs).

In the phase 3 DESTINY-Breast03 study (NCT03529110), T-DXd was associated with serious AEs in 19% of patients, including vomiting, interstitial lung disease (ILD), pneumonia, pyrexia, and urinary tract infection.⁶ The occurrence of ILD/ pneumonitis in 11% of patients in this trial was of particular concern and was potentially fatal; for this reason, any grade 2 toxicity of this kind requires permanent treatment discontinuation. However, life-threatening AEs are extraordinarily rare with this drug, Kang said.

With sacituzumab govitecan, the AEs of most concern were neutropenia and diarrhea. Neutropenia occurred in 64% of patients, of which 49% of cases were grade 3 or 4.⁷ Additionally, neutropenic colitis was observed in 1.4%. Diarrhea also occurred in 64%, with grade 3 or 4 diarrhea occurring in 11% of those treated in trials.

When counseling patients on ADC therapy, Kang said it requires a conversation about the patient’s goals, their risk tolerance, what AEs they expect generally, and which rare but serious AEs need to be monitored closely.

Wade M. Smith, MD, assistant clinical professor at City of Hope and director of research at its Newport Beach location, said in an interview with Peers & Perspectives in Oncology that the chemotherapy education given to patients by advanced practice providers is an important part of counseling on toxicities. Smith said they make sure patients are educated on using antidiarrheals and to be mindful of nausea, anorexia, and replacing lost fluids. They also instruct patients to report any fever during treatment.

Additionally, he said it’s important to have support from family members to take notes, check in on patients who live alone and drive them to appointments, and alert them to allergic hypersensitivity reactions, which can sometimes occur at home, even days after infusion. Other toxicities that patients should watch for include fatigue and asthenia with T-DXd, said Smith.

Breast Cancer - Female Anatomy - pain concept: © peterschreiber.media - stock.adobe.com

Toxicities of Special Concern

According to Smith, the occurrence of ILD/pneumonitis with T-DXd has led to stricter observation of patients during treatment. “We have taken a more proactive role in terms of guidelines, how we follow patients, [and] how we monitor patients for worsening lung inflammation,” he said. “We are very quick, even for patients who aren’t having symptoms [but have] findings on imaging, to immediately pause the medication and have a workup to ensure that there’s not a pneumonitis present.”

Underlying comorbidities that could add to pneumonitis can be a concern in shared decision-making with T-DXd, Kang said. “But if you’re dealing with potentially terminal disease and don’t have a lot of other good remaining options, it may be a very good option that buys you improved quality of life [and] extra time.” She has used T-DXd in the past with close monitoring in patients with underlying issues including pleural effusion and lung involvement.

Smith said that there can be additive toxicities from viral pneumonia with drug-induced pneumonitis, and for this reason he encourages his patients to be fully vaccinated against COVID-19, influenza, and pneumococcal bacteria.

In patients receiving sacituzumab govitecan, the high rate of neutropenia is a chief tolerability concern. Granulocyte colony-stimulating factor (G-CSF) was used in 49% of patients in the ASCENT trial (NCT02574455).⁸ Kang said that although growth factor support is not mandated as primary prophylaxis, it should be considered in patients who were heavily pretreated with prior cytotoxic agents or have a history of febrile neutropenia.

Studies of sacituzumab govitecan showed an increased risk of severe hematologic AEs in patients who are homozygous for the UGT1A1*28 allele.⁷ This was also observed in patients who received irinotecan, from which the payload for sacituzumab govitecan was derived.⁹ In trials of sacituzumab govitecan, patients who were homozygous for this allele had a 58% incidence of grade 3/4 neutropenia compared with 49% who were heterozygous and 43% who were homozygous for the wild-type allele.⁷ A similar trend was seen with anemia.

The increase in AEs did not lead to a contraindication of sacituzumab govitecan for these patients and did not appear to impact efficacy, but haplotype testing can provide useful knowledge to treating physicians. Kang said that it is not part of standard recommendations to pretest patients, but health systems can implement the testing protocol. Since the haplotype testing can take a long time to return results, it may be too late to inform the selection of sacituzumab govitecan.

“I still find it beneficial to order,” said Smith on the question of haplotype testing. “We know patients who are poor metabolizers may develop toxicity even into the second cycle of chemotherapy, so [we are] preferably ordering it prior to initiation, but even soon after initiation, if we can get that information, I think it is helpful.”

Kang said that she would strongly consider primary prophylaxis for neutropenia in such a patient: “It’s not part of general guidelines or the package insert yet, so maybe that’s something that [needs] a body of evidence to be developed to support that pathway.”

Dose Adjustment Considerations

Dose modification is an important strategy in managing AEs from T-DXd and sacituzumab govitecan. Kang said that much of the phase 3 data was based on patients receiving a maximally tolerated dose. “In real life…patients will run into tolerability issues, either due to time on drug or just from the get-go for the starting dose. If this is a treatment we’re embarking on for palliative intention, quality of life is an important goal here,” she said.

Kang added that interrupting or reducing the dose is an effective strategy for many toxicities in her experience and may not reduce efficacy. She said that providers should not be afraid to dose reduce. In her experience, if a patient is benefiting from a drug, generally dose modification does not take it away.

Dose modification is key to managing severe neutropenia with sacituzumab govitecan, according to Smith. For grade 4 neutropenia he may reduce the dose by 25% and give growth factor support, then reduce the dose by 50% if it reoccurs, then discontinue treatment after a third time. For diarrhea, he would interrupt dosing until it reduces to grade 1 or lower, rule out infection, and resume, and dose reduce if diarrhea recurs.

ADCs are given until disease progression or unacceptable toxicity, with some patients now receiving them for longer durations. For instance, in DESTINY-Breast03, the median duration of treatment was 18.2 months (IQR, 9.0-29.4) with T-DXd vs 6.9 months (IQR, 2.8-12.3) with T-DM1.¹⁰ With sacituzumab govitecan, the median duration of treatment tended to be shorter (4.1 months; range, 0-63).⁷

In Kang’s experience, the duration of ADC therapy has pleasantly surprised her in many cases, but cumulative toxicities such as fatigue can occur in patients on long-term treatment. She said a strategy she and others have adopted is switching from giving sacituzumab govitecan on days 1 and 8 of a 21-day cycle to giving it on days 1 and 15, which gives patients more time between doses. This can also make it easier to manage use of G-CSF with pegfilgrastim (Neulasta) or other long-lasting agents and allow time for recovery of blood cell counts.

Smith said that cumulative toxicity buildup such as the neuropathy associated with taxane chemotherapy is not seen with ADCs. “We can give the ones that are approved, for a long duration, so long as the patient is responding,” he said.

Introducing New ADCs

Because ADC toxicities can vary widely, it can be difficult to develop experience with dose and toxicity management of individual therapies, particularly as new ADCs with distinct AE profiles are approved. For instance, trastuzumab duocarmazine, investigated in the phase 3 TULIP trial (NCT03262935), showed a high rate of ocular toxicity leading to discontinuation as well as ILD/pneumonitis.¹¹ Datopotamab deruxtecan showed a lesser signal for ocular toxicity in the TROPION-Breast01 trial (NCT05104866), and a high rate of stomatitis or oral mucositis.¹² Kang and Smith cautioned that these toxicities may be unfamiliar to breast cancer oncologists and require special care.

Kang recommended that oncologists familiarize themselves with the trial data behind new FDA approvals, focusing on grade 3 or 4 AEs, AEs that led to fatalities, and how to proactively manage AEs. Meanwhile, Smith suggested coordinating with an industry representative for guidance and instructions on how to handle patient calls and what to watch for when introducing new ADCs to practice. He said that in addition to reviewing the package insert and published data for what needs to be monitored for grade 3 and 4 AEs, his practice always makes a follow-up call 48 to 72 hours after the first infusion to make sure the patient is tolerating it. Since diarrhea is an AE associated with multiple ADCs, making sure patients have the resources to manage hydration is important, particularly in patients with indwelling vascular catheters. Watching for infusion reactions is another consideration that applies across multiple ADCs, Smith said.

The role of ADCs in breast cancer is developing in other ways that could add new challenges to management. Combinations are being explored in trials, including sacituzumab govitecan plus the PARP inhibitor talazoparib (Talzenna) in triple-negative disease (NCT04039230) and the novel ADC BDC-1001 combined with pertuzumab (Perjeta) in HER2-positive disease (NCT05954143).

The question of sequencing ADCs one after another is also increasing in relevance, since some patients are eligible for both T-DXd and sacituzumab govitecan. The DESTINY-Breast02 trial (NCT03523585), which enrolled patients to receive T-DXd following T-DM1 therapy, was the first randomized study to demonstrate that an ADC with the same target can effectively overcome resistance to the prior ADC.¹³ Data are limited on this approach with other ADCs, and efficacy and tolerability may be impacted if ADCs share a molecular target or payload. “So far, there’s no contraindication to continue on to a second or third ADC, but I think we’ll all be very curious and keen to know what the benefit is for patients,” Kang observed.

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