The combination of brokers resembling antibody-drug conjugates (ADCs) and immunotherapies into the breast most cancers therapy paradigm has underscored the necessity to perceive their toxicity profiles and learn how to correctly mitigate related antagonistic results (AEs), in line with Hope S. Rugo, MD. She added that creating improved administration methods for chemotherapy-related toxicities stays equally essential.
“Alopecia and [peripheral] neuropathy are areas of significance to our sufferers, which we regularly do not spend sufficient time on, nor will we monitor them effectively sufficient,” Rugo mentioned throughout a presentation on the twenty third Annual Worldwide Congress on the Way forward for Breast Most cancers East.1
Through the presentation, Rugo broke down the completely different toxicities related to varied therapy methods, defined administration and prevention methods for these AEs, and detailed approaches to assist curb the incidence of alopecia and peripheral neuropathy in sufferers with breast most cancers.
Rugo holds the Winterhof Household Endowed Professorship in Breast Most cancers and is a professor within the Division of Medication (Hematology/Oncology), director of Breast Oncology and Scientific Trials Training, and medical director of Most cancers Infusion Providers on the College of California, San Francisco.
Analyzing Various Toxicities Related With ADCs
The quantity of ADCs within the breast most cancers therapy paradigm has grown lately, and regardless of some similarities between brokers inside this class, Rugo defined that security outcomes fluctuate drastically between particular person brokers. She added that the drug-to-antibody ratio of every agent doesn’t look like related to the respective toxicity profile of every agent.
“We see marked variations in [the types of] AEs, even though we have now a identical spine. [If] you could have a HER2 antibody, why ought to you could have such completely different toxicities?” Rugo mentioned. “Then, you will have an identical goal of the payload—for instance, topoisomerase I inhibitors. Nevertheless, you see massively completely different toxicities.”
Throughout her presentation, Rugo highlighted the security profiles of 4 ADCs throughout the breast most cancers house, together with 3 brokers authorized by the FDA—ado-trastuzumab emtansine (T-DM1; Kadcyla), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), and sacituzumab govitecan-hziy (Trodelvy)—in addition to datopotamab deruxtecan (Dato-DXd), information for that are at present underneath FDA overview for potential approval for the therapy of sufferers with unresectable or metastatic hormone receptor (HR)–constructive, HER2-negative breast most cancers who’ve acquired prior systemic remedy for unresectable or metastatic illness.2
Rugo mentioned all 4 ADCs have distinct AE profiles. For instance, T-DM1 is related to increased charges of thrombocytopenia and elevated liver enzymes; T-DXd has proven the next charge of nausea/vomiting and interstitial lung illness (ILD)/pneumonitis; sacituzumab govitecan has been linked to neutropenia and diarrhea; and Dato-DXd has been related to nausea/vomiting and stomatitis. Notably, no alopecia is predicted with T-DM1, whereas T-DXd has been related to average alopecia, and sacituzumab govitecan and dato-DXd can result in vital alopecia.
T-DXd
Knowledge from the section 3 DESTINY-Breast04 trial (NCT03734029) confirmed that in sufferers with beforehand handled metastatic HER2-low breast most cancers who have been handled with the ADC (n = 371), the speed of any-grade nausea was 73.0% in contrast with 24% for sufferers given doctor’s selection of chemotherapy (n = 172). The charges of any-grade vomiting have been 34% and 10%, respectively.3
Through the examine, 50.9% of sufferers within the T-DXd arm and 37.2% of sufferers within the management arm acquired antiemetic prophylaxis, which was really helpful however not necessary per trial protocol. Within the T-DXd arm, the charges of dose reductions, dose interruptions, and therapy discontinuation as a result of nausea have been 4.6%, 1.3%, and 0.3%, respectively. These respective charges have been 2.3%, 2.3%, and 0% within the chemotherapy arm. Vomiting led to dose reductions, dose interruptions, and therapy discontinuation in 0.8%, 0%, and 0.3% of sufferers within the T-DXd arm, respectively. These respective charges have been 0.6%, 0%, and 0% within the chemotherapy arm.4
When treating sufferers with T-DXd, 3 lessons of antiemetic premedication—5-HT3 receptor antagonists, NK-1 receptors, and corticosteroids—are really helpful, which Rugo famous ought to be chosen primarily based on a affected person’s signs. Nevertheless, even with premedication, she mentioned that roughly 30% to 50% of sufferers administered a reasonably emetogenic agent and guideline-directed prophylaxis expertise breakthrough nausea/vomiting. These breakthrough AEs spotlight the significance of training sufferers about these toxicities previous to beginning therapy, Rugo mentioned, including that commonplace rescue drugs for these sufferers embody ondansetron, lorazepam, and prochlorperazine.
Moreover, findings from a pooled evaluation of sufferers handled throughout 9 completely different scientific trials evaluating T-DXd monotherapy confirmed that 15.4% of sufferers (n = 1150) skilled ILD, together with 2.2% of sufferers who had grade 5 ILD. Notably, 77.4% of all cases of ILD have been grade 1/2.5
Given the potential threat of ILD for sufferers handled with T-DXd, Rugo mentioned it is suggested that every one sufferers endure a high-resolution CT scan no less than each 12 weeks, and people with respiratory signs ought to be scanned each 6 to 9 weeks. She mentioned the ADC ought to be held for sufferers with grade 1, asymptomatic ILD, and sufferers with symptomatic ILD ought to discontinue therapy.
In one other pooled evaluation of sufferers from 9 T-DXd monotherapy scientific trials confirmed that in sufferers who skilled grade 1 ILD and have been later rechallenged with the ADC (n = 45), 68.9% have been retreated with out dose reductions, and 24.4% have been ongoing therapy at information cutoff of their respective research. Twenty % of sufferers discontinued the ADC as a result of recurrent ILD, and the charges of sufferers who continued therapy for greater than 6 months and greater than 12 months have been 33.3% and 17.8%, respectively.
Sacituzumab Govitecan
Rugo highlighted that throughout the section 3 ASCENT trial (NCT02574455), which evaluated the ADC vs doctor’s selection of remedy in sufferers with metastatic triple-negative breast most cancers (TNBC) that was relapsed/refractory to no less than 2 prior chemotherapy regimens, together with 1 within the metastatic setting, the speed of any-grade neutropenia was 63% for sacituzumab govitecan vs 43% for the management arm. Notably, 29% of sufferers within the experimental arm got development elements as secondary prophylaxis vs 10% of these within the management arm. Development elements got as therapy in 30% and 17% of sufferers, respectively.7
Inside the sacituzumab govitecan arm, no sufferers discontinued therapy as a result of neutropenia. The respective charges of dose reductions and interruptions as a result of neutropenia/febrile neutropenia have been 11% and 46% within the sacituzumab govitecan arm. Within the management arm, these charges have been 19% and 21%, respectively.
Fifty-five % of sufferers within the experimental arm acquired premedication or concomitant treatment to handle diarrhea vs 10% of these within the management arm. Diarrhea didn’t result in therapy discontinuation in any sufferers in both arm. The speed of dose reductions and interruptions as a result of diarrhea have been each 5% within the sacituzumab govitecan arm; these respective charges have been lower than 1% and 0% within the management arm.
Rugo defined that higher understanding UGT1A1 standing may assist higher maximize the efficacy and decrease the toxicity of sacituzumab govitecan in sufferers with breast most cancers. Variants of the gene affect enzyme perform that results in lowered metabolic capability, and greater than 50% of people within the basic inhabitants might harbor a UGT1A1 polymorphism.
“Sufferers who’ve the poor-metabolism phenotype of UGT1A1—the *28/*28 homozygous phenotype—truly appeared to have extra neutropenia and diarrhea within the section 3 trials [ASCENT and TROPiCS-02 (NCT03901339)] of sacituzumab govitecan,” Rugo mentioned.
Dato-DXd
Though Dato-DXd shares the TROP-2 goal with sacituzumab govitecan and has the identical topoisomerase I inhibitor payload as T-DXd, the agent has its personal distinct security profile, Rugo continued.
Within the section 3 TROPION-Breast01 trial (NCT05104866) evaluating Dato-DXd vs doctor’s selection of chemotherapy in sufferers with HR-positive, HER2-low or -negative metastatic breast most cancers, the charges of any-grade nausea have been 51% within the experimental arm (n = 360) vs 24% within the chemotherapy arm (n = 351). The charges of any-grade stomatitis have been 50% and 13%, respectively, and the respective charges of dye eye have been 22% and eight%.8
Rugo defined that ocular toxicities have been noticed with different ADCs evaluated in different tumor varieties, and a key to managing these AEs is novel preventative methods, she added.
As ADCs change into extra built-in into the paradigm, there can be continued questions on therapy choice, sequencing, and learn how to greatest leverage novel brokers. No matter how these questions are answered, Rugo mentioned clinicians will should be acquainted with the security profiles of the completely different ADCs.
“[ADCs] are fascinating medicine with efficacy throughout all of the subtypes, together with new subtypes of breast most cancers that we hadn’t recognized earlier than. Nevertheless, toxicity administration is essential,” she mentioned.
The Extensive Spectrum of irAEs
Though immuno-oncology brokers have a smaller function within the administration of particular subtypes of breast most cancers, irAEs related to immune checkpoint inhibitors can seem in a wide range of types, Rugo mentioned. She additionally defined that the kind of immunotherapy used impacts the incidence, timing, and kind of toxicity, noting that irAEs may manifest greater than 1 12 months after the ultimate dose of an immune checkpoint inhibitor.
In sufferers with early-stage breast most cancers handled with immunotherapy, thyroid and skins toxicities are the commonest types of AEs, and Rugo added that main or secondary adrenal insufficiency is probably the most tough to diagnose irAE on this affected person inhabitants. Though hepatitis, colitis, and pneumonitis are frequent irAEs, Rugo mentioned these toxicities associated to immunotherapy can have an effect on any organ.
“In sufferers who’ve much less critical [irAEs] that resolved rapidly, we will 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 essential to determine early as a result of this may end up in everlasting pulmonary toxicity and dysfunction.”
Addressing Alopecia and Peripheral Neuropathy
As a well known AE of chemotherapy, alopecia can drive a affected person’s choice to simply accept or decline therapy, Rugo mentioned. Nevertheless, she famous that the arrival of cooling caps has helped deal with alopecia for sufferers receiving chemotherapy.
The Dignicap and Paxman caps each acquired FDA clearance following potential scientific trials, and frozen chilly caps may also deal with this AE. Rugo defined that these caps at the moment are partially lined by many insurers, and philanthropic organizations may also assist present these gadgets to sufferers.
Chemotherapy-induced peripheral neuropathy can be one other debilitating AE for sufferers, Rugo continued. She defined that compression and cooling gloves may help alleviate a few of these signs.
Within the potential, randomized POLAR trial, compression gloves and cooling gloves practically halved the chance of grade 2 or increased chemotherapy-induced peripheral neuropathy. Moreover, the continuing section 3 ICE COMPRESS trial (NCT05642611) is evaluating cryocompression, steady compression, and low cyclic compression for the prevention of chemotherapy-induced peripheral neuropathy.
In sufferers who do expertise chemotherapy-induced peripheral neuropathy, Rugo mentioned duloxetine demonstrated the power to cut back ache vs placebo in a section 3 trial (NCT00489411). Though gabapentin, pregabalin, and anti-depressants may be used for the therapy of chemotherapy-induced peripheral neuropathy, preventive measures are a more practical route for this specific AE, Rugo concluded.
References
- Rugo HS. Balancing success with toxicity: ameliorating treatment-limiting toxicities. Introduced at: twenty third Annual Worldwide Congress on the Way forward for Breast Most cancers East; July 19-20, 2024; New York, NY.
- Datopotamab deruxtecan biologics license utility accepted within the US for sufferers with beforehand handled metastatic HR-positive, HER2-negative breast most cancers. Information launch. 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
- Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in beforehand handled HER2-low superior breast most cancers. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
- Rugo HS, Jacot W, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) vs therapy of doctor’s selection (TPC) in sufferers (pts) with HER2-low unresectable and/or metastatic breast most cancers (mBC): an in depth security evaluation of the randomized, section 3 DESTINY-Breast04 trial. Ann Oncol. 2023;8(suppl_4):101223. doi:10.1016/esmoop/esmoop101223
- Powell CA, Modi S, Iwata H, et al. Pooled evaluation of drug-related interstitial lung illness and/or pneumonitis in 9 trastuzumab deruxtecan monotherapy research. ESMO Open. 2022;7(4):100554. doi:10.1016/j.esmoop.2022.100554
- Rugo HS, Tokunaga E, Iwata H, et al. Pooled evaluation of trastuzumab deruxtecan (T-DXd) retreatment (RTx) after restoration from grade (Gr) 1 interstitial lung illness/pneumonitis (ILD). Ann Oncol. 2024;9(suppl_4):1-12. doi:10.1016/esmoop/esmoop103324
- Rugo HS, Tolaney SM, Loirat D, et al. Security analyses from the section 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast most cancers. NPJ Breast Most cancers. 2022;8(1):98. doi:10.1038/s41523-022-00467-1
- Bardia A, Jhaveri Ok, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast most cancers: Main outcomes from the randomized section 3 TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015
