AE Management and Prevention Strategies for ADCs, Immunotherapy in Breast Cancer

Hope S. Rugo, MD

The integration of agents such as antibody-drug conjugates (ADCs) and immunotherapies into the breast cancer treatment paradigm has underscored the need to understand their toxicity profiles and how to properly mitigate associated adverse effects (AEs), according to Hope S. Rugo, MD. She added that developing improved management strategies for chemotherapy-related toxicities remains equally critical.

“Alopecia and [peripheral] neuropathy are areas of importance to our patients, which we often don't spend enough time on, nor do we track them well enough,” Rugo said during a presentation at the 23rd Annual International Congress on the Future of Breast Cancer East.¹

During the presentation, Rugo broke down the different toxicities associated with various treatment strategies, explained management and prevention strategies for these AEs, and detailed approaches to help curb the incidence of alopecia and peripheral neuropathy in patients with breast cancer.

Rugo holds the Winterhof Family Endowed Professorship in Breast Cancer and is a professor in the Department of Medicine (Hematology/Oncology), director of Breast Oncology and Clinical Trials Education, and medical director of Cancer Infusion Services at the University of California, San Francisco.

Examining Varying Toxicities Associated With ADCs

The volume of ADCs in the breast cancer treatment paradigm has grown in recent years, and despite some similarities between agents within this class, Rugo explained that safety outcomes vary drastically between individual agents. She added that the drug-to-antibody ratio of each agent does not appear to be associated with the respective toxicity profile of each agent.

“We see marked variations in [the types of] AEs, despite the fact that we have a same backbone. [If] you have a HER2 antibody, why should you have such different toxicities?” Rugo said. “Then, you may have a similar target of the payload—for example, topoisomerase I inhibitors. However, you see hugely different toxicities.”

During her presentation, Rugo highlighted the safety profiles of 4 ADCs within the breast cancer space, including 3 agents approved by the FDA—ado-trastuzumab emtansine (T-DM1; Kadcyla), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), and sacituzumab govitecan-hziy (Trodelvy)—as well as datopotamab deruxtecan (Dato-DXd), data for which are currently under FDA review for potential approval for the treatment of patients with unresectable or metastatic hormone receptor (HR)–positive, HER2-negative breast cancer who have received prior systemic therapy for unresectable or metastatic disease.²

Rugo said all 4 ADCs have distinct AE profiles. For example, T-DM1 is associated with higher rates of thrombocytopenia and elevated liver enzymes; T-DXd has shown a higher rate of nausea/vomiting and interstitial lung disease (ILD)/pneumonitis; sacituzumab govitecan has been linked to neutropenia and diarrhea; and Dato-DXd has been associated with nausea/vomiting and stomatitis. Notably, no alopecia is expected with T-DM1, whereas T-DXd has been associated with moderate alopecia, and sacituzumab govitecan and dato-DXd can lead to significant alopecia.

T-DXd

Data from the phase 3 DESTINY-Breast04 trial (NCT03734029) showed that in patients with previously treated metastatic HER2-low breast cancer who were treated with the ADC (n = 371), the rate of any-grade nausea was 73.0% compared with 24% for patients given physician’s choice of chemotherapy (n = 172). The rates of any-grade vomiting were 34% and 10%, respectively.³

During the study, 50.9% of patients in the T-DXd arm and 37.2% of patients in the control arm received antiemetic prophylaxis, which was recommended but not mandatory per trial protocol. In the T-DXd arm, the rates of dose reductions, dose interruptions, and treatment discontinuation due to nausea were 4.6%, 1.3%, and 0.3%, respectively. These respective rates were 2.3%, 2.3%, and 0% in the chemotherapy arm. Vomiting led to dose reductions, dose interruptions, and treatment discontinuation in 0.8%, 0%, and 0.3% of patients in the T-DXd arm, respectively. Those respective rates were 0.6%, 0%, and 0% in the chemotherapy arm.⁴

When treating patients with T-DXd, 3 classes of antiemetic premedication—5-HT3 receptor antagonists, NK-1 receptors, and corticosteroids—are recommended, which Rugo noted should be selected based on a patient’s symptoms. However, even with premedication, she said that approximately 30% to 50% of patients administered a moderately emetogenic agent and guideline-directed prophylaxis experience breakthrough nausea/vomiting. These breakthrough AEs highlight the importance of educating patients about these toxicities prior to starting treatment, Rugo said, adding that standard rescue medications for these patients include ondansetron, lorazepam, and prochlorperazine.

Furthermore, findings from a pooled analysis of patients treated across 9 different clinical trials evaluating T-DXd monotherapy showed that 15.4% of patients (n = 1150) experienced ILD, including 2.2% of patients who had grade 5 ILD. Notably, 77.4% of all instances of ILD were grade 1/2.⁵

Given the potential risk of ILD for patients treated with T-DXd, Rugo said it is recommended that all patients undergo a high-resolution CT scan at least every 12 weeks, and those with respiratory symptoms should be scanned every 6 to 9 weeks. She said the ADC should be held for patients with grade 1, asymptomatic ILD, and patients with symptomatic ILD should discontinue treatment.

In another pooled analysis of patients from 9 T-DXd monotherapy clinical trials showed that in patients who experienced grade 1 ILD and were later rechallenged with the ADC (n = 45), 68.9% were retreated without dose reductions, and 24.4% were ongoing treatment at data cutoff of their respective studies. Twenty percent of patients discontinued the ADC due to recurrent ILD, and the rates of patients who continued treatment for more than 6 months and more than 12 months were 33.3% and 17.8%, respectively.

Sacituzumab Govitecan

Rugo highlighted that during the phase 3 ASCENT trial (NCT02574455), which evaluated the ADC vs physician’s choice of therapy in patients with metastatic triple-negative breast cancer (TNBC) that was relapsed/refractory to at least 2 prior chemotherapy regimens, including 1 in the metastatic setting, the rate of any-grade neutropenia was 63% for sacituzumab govitecan vs 43% for the control arm. Notably, 29% of patients in the experimental arm were given growth factors as secondary prophylaxis vs 10% of those in the control arm. Growth factors were given as treatment in 30% and 17% of patients, respectively.⁷

Within the sacituzumab govitecan arm, no patients discontinued treatment due to neutropenia. The respective rates of dose reductions and interruptions due to neutropenia/febrile neutropenia were 11% and 46% in the sacituzumab govitecan arm. In the control arm, those rates were 19% and 21%, respectively.

Fifty-five percent of patients in the experimental arm received premedication or concomitant medication to manage diarrhea vs 10% of those in the control arm. Diarrhea did not lead to treatment discontinuation in any patients in either arm. The rate of dose reductions and interruptions due to diarrhea were both 5% in the sacituzumab govitecan arm; those respective rates were less than 1% and 0% in the control arm.

Rugo explained that better understanding UGT1A1 status could help better maximize the efficacy and minimize the toxicity of sacituzumab govitecan in patients with breast cancer. Variants of the gene influence enzyme function that leads to reduced metabolic capacity, and more than 50% of individuals in the general population may harbor a UGT1A1 polymorphism.

“Patients who have the poor-metabolism phenotype of UGT1A1—the *28/*28 homozygous phenotype—actually seemed to have more neutropenia and diarrhea in the phase 3 trials [ASCENT and TROPiCS-02 (NCT03901339)] of sacituzumab govitecan,” Rugo said.

Dato-DXd

Although Dato-DXd shares the TROP-2 target with sacituzumab govitecan and has the same topoisomerase I inhibitor payload as T-DXd, the agent has its own distinct safety profile, Rugo continued.

In the phase 3 TROPION-Breast01 trial (NCT05104866) evaluating Dato-DXd vs physician’s choice of chemotherapy in patients with HR-positive, HER2-low or -negative metastatic breast cancer, the rates of any-grade nausea were 51% in the experimental arm (n = 360) vs 24% in the chemotherapy arm (n = 351). The rates of any-grade stomatitis were 50% and 13%, respectively, and the respective rates of dye eye were 22% and 8%.⁸

Rugo explained that ocular toxicities have been observed with other ADCs evaluated in other tumor types, and a key to managing these AEs is novel preventative strategies, she added.

As ADCs become more integrated into the paradigm, there will be continued questions about treatment selection, sequencing, and how to best leverage novel agents. Regardless of how those questions are answered, Rugo said clinicians will need to be familiar with the safety profiles of the different ADCs.

“[ADCs] are interesting drugs with efficacy across all the subtypes, including new subtypes of breast cancer that we hadn't identified before. However, toxicity management is critical,” she said.

The Wide Spectrum of irAEs

Although immuno-oncology agents have a smaller role in the management of specific subtypes of breast cancer, irAEs associated with immune checkpoint inhibitors can appear in a variety of forms, Rugo said. She also explained that the type of immunotherapy used affects the incidence, timing, and type of toxicity, noting that irAEs could manifest more than 1 year after the final dose of an immune checkpoint inhibitor.

In patients with early-stage breast cancer treated with immunotherapy, thyroid and skins toxicities are the most common forms of AEs, and Rugo added that primary or secondary adrenal insufficiency is the most difficult to diagnose irAE in this patient population. Although hepatitis, colitis, and pneumonitis are common irAEs, Rugo said these toxicities related to immunotherapy can affect any organ.

“In patients who have less serious [irAEs] that resolved quickly, we can rechallenge [with immunotherapy,” Rugo said. “We're not going to rechallenge every refractory disease or more serious toxicity, [such as] encephalitis pneumonitis or myocarditis. Pneumonitis is very important to identify early because this can result in permanent pulmonary toxicity and dysfunction.”

Addressing Alopecia and Peripheral Neuropathy

As a well-known AE of chemotherapy, alopecia can drive a patient’s decision to accept or decline treatment, Rugo said. However, she noted that the advent of cooling caps has helped address alopecia for patients receiving chemotherapy.

The Dignicap and Paxman caps both received FDA clearance following prospective clinical trials, and frozen cold caps can also address this AE. Rugo explained that these caps are now partially covered by many insurers, and philanthropic organizations can also help provide these devices to patients.

Chemotherapy-induced peripheral neuropathy can also be another debilitating AE for patients, Rugo continued. She explained that compression and cooling gloves can help alleviate some of these symptoms.

In the prospective, randomized POLAR trial, compression gloves and cooling gloves nearly halved the risk of grade 2 or higher chemotherapy-induced peripheral neuropathy. Furthermore, the ongoing phase 3 ICE COMPRESS trial (NCT05642611) is evaluating cryocompression, continuous compression, and low cyclic compression for the prevention of chemotherapy-induced peripheral neuropathy.

In patients who do experience chemotherapy-induced peripheral neuropathy, Rugo said duloxetine demonstrated the ability to reduce pain vs placebo in a phase 3 trial (NCT00489411). Although gabapentin, pregabalin, and anti-depressants could also be used for the treatment of chemotherapy-induced peripheral neuropathy, preventive measures are a more effective route for this particular AE, Rugo concluded.

References

1. Rugo HS. Balancing success with toxicity: ameliorating treatment-limiting toxicities. Presented at: 23rd Annual International Congress on the Future of Breast Cancer East; July 19-20, 2024; New York, NY.
2. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer. News release. AstraZeneca. April 2, 2024. Accessed July 19, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fda-accepts-dato-dxd-bla-for-breast-cancer.html
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
4. Rugo HS, Jacot W, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): a detailed safety analysis of the randomized, phase 3 DESTINY-Breast04 trial. Ann Oncol. 2023;8(suppl_4):101223. doi:10.1016/esmoop/esmoop101223
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. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554
6. Rugo HS, Tokunaga E, Iwata H, et al. Pooled analysis of trastuzumab deruxtecan (T-DXd) retreatment (RTx) after recovery from grade (Gr) 1 interstitial lung disease/pneumonitis (ILD). Ann Oncol. 2024;9(suppl_4):1-12. doi:10.1016/esmoop/esmoop103324
7. Rugo HS, Tolaney SM, Loirat D, et al. Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer. NPJ Breast Cancer. 2022;8(1):98. doi:10.1038/s41523-022-00467-1
8. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer: Primary results from the randomized phase 3 TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015