乌鸦传媒

Antibody-drug conjugates (ADCs) have taken the field of breast cancer by storm and appear poised to expand their reach into earlier lines of therapy and early-stage disease, a breast cancer specialist said here.

ADCs offer an "exciting and effective drug delivery system" for multiple subtypes of metastatic breast cancer, and ongoing clinical trials are exploring whether the agents' benefits extend beyond the metastatic setting. The success of trastuzumab deruxtecan (T-DXd, Enhertu) and sacituzumab govitecan (Trodelvy) have helped spur development of more ADCs, some of which have begun phase III clinical evaluation, said Hope Rugo, MD, of the University of California San Francisco, at the Miami Breast Cancer Conference.

"[ADCs have] taken the world by storm, and it's really not an overstatement. It's perhaps an understatement," said Rugo. "This has had a huge impact on the treatment of patients with HER2-negative metastatic breast cancer, and it continues to expand."

ADC technology and its "smart-bomb effect" on cancer date back to the introduction of ado-trastuzumab emtansine (T-DM1, Kadcyla), which the FDA approved in 2013 for metastatic HER2-positive breast cancer. New-generation ADCs have improved technology, said Rugo: more plasma-stable linkers; more membrane-permeable toxins, which potentially allows the payload to leak out of the center cell but also makes for a more potent payload; and less cumulative toxicity.

Trastuzumab Deruxtecan

T-DXd changed the treatment landscape for HER2-positive (HER2+) breast cancer by unseating T-DM1 as the ADC choice for previously treated HER2+ disease in the DESTINY-breast 03 trial, more than doubling the 12-month progression-free survival (PFS).

Traditional HER2-targeted therapies have activity only against HER+ cells (IHC3+). The design of T-DXd incorporated a cell membrane-permeable payload that not only kills the target cell and but passes through the membrane to produce a on adjacent tumors cells, irrespective of HER2 expression level. Preclinical studies confirmed T-DXd's antitumor activity in a variety of tumor cell types, including those with low HER2 expression (IHC1/2+).

In involving patients with heavily pretreated HER-low metastatic breast cancer, T-DXd resulted in a "remarkable" median PFS of 11.1 months and an objective response rate of 37%. The trial provided the impetus for the DESTINY-breast04 trial, which showed significant improvement in overall survival (OS) and PFS in patients with metastatic HER2-low breast cancer, irrespective of hormone receptor status. The FDA subsequently made T-DXd the first targeted therapy indicated for the newly recognized HER2-low breast cancer subtype.

Subgroup analysis showed a consistent advantage with T-DXd, including a small group of patients with HER2-low triple-negative breast cancer and patients with prior CDK4/6 inhibitor treatment, Rugo noted.

The most common toxicity associated with T-DXd is nausea, which requires prophylaxis and continued antiemetic therapy after T-DXd treatment, she continued. Bone marrow suppression has been minimal thus far. Interstitial lung disease (ILD) is not common but can be severe and even life-threatening, requiring continual monitoring.

"In patients with asymptomatic ILD ... you have to hold the drug and you should consider low-dose steroids," said Rugo. "Three weeks later we repeat the noncontrast CT, and I've been able to successfully restart the drug in almost all patients. For symptomatic ILD, you must permanently discontinue the drug and immediately begin steroids and then start the work-up.You don't want to wait and do a big work-up to look for infection and wait on the steroids, because this is, I think, where we are seeing fatalities."

Testing for HER2 status remains a key issue. In DESTINY-breast04, 78% of HER2-low results by local testing were confirmed centrally by use of the PATHWAY HER2 4B5 assay. Among the discordant samples, 88% were scored as IHC0 by central testing.

"Some of them, actually 12%, were HER2-positive by central testing, so you have to be careful about testing for HER2 because we want to know who is HER2-positive," said Rugo. "Regardless of whether you use the primary sample or a metastatic sample, or even an older sample, all predicted benefit from T-DXd, so that is really encouraging for clinical practice."

Next up, T-DXd will be evaluated in HER2 "ultralow" (IHC0-1) breast cancer in the DESTINY-breast06 trial that will involve patients with hormone receptor-positive/ICH0 tumors and no prior chemotherapy.

Sacituzumab Govitecan

The Trop-2-targeted ADC sacituzumab govitecan received the first FDA-approved indication for HER-negative metastatic breast cancer and subsequently demonstrated "remarkable" PFS and OS in heavily treated metastatic TNBC, said Rugo.

Sacituzumab was evaluated in a difficult patient population in the phase III TROPiCS-02 trial: patients with metastatic HR+/HER2- breast cancer, 4 years from diagnosis, 95% with visceral metastases, a median of three prior lines of chemotherapy for metastatic disease, and prior exposure to CDK4/6 inhibition. The ADC significantly improved PFS and OS versus physician's choice of chemotherapy. The efficacy did not differ by Trop-2 expression status.

Evaluation of sacituzumab is ongoing in several clinical trials including first line for PD-L1-negative TNBC, first-line HR+ breast cancer, in combination with pembrolizumab (Keytruda) or without in metastatic TNBC and in the setting of post-neoadjuvant residual TNBC.

The most common toxicity associated with the ADC is neutropenia, which requires growth factor support about half the time. Diarrhea also is common but can be managed in most cases with dose reduction and anti-propulsive agents, said Rugo. The drug is not associated with ILD or cardiotoxicity.

Datopotamab Deruxtecan

An "intriguing and efficacious" ADC, datopotamab deruxtecan (Dato-DXd) consists of an anti-Trop-2 antibody linked to a topoisomerase inhibitor. The drug has a lower antibody:drug ratio but higher potency toxin delivery, said Rugo.

In a phase I trial of metastatic HR+ and HR-/HER2- breast cancer, dato-DXd produced a response rate of 32%, but most patients with TNBC or HR+ disease had some degree of tumor shrinkage. The study revealed a new type of toxicity with ADCs -- stomatitis, which occurred in 75%-80% of patients but was mostly grade 1/2. Two-thirds of patients had nausea and 39% of patients reported vomiting.

Dato-DXd was evaluated in combination with durvalumab (Imfinzi) as first-line treatment for TNBC. Three-fourths of patients had objective responses, which were durable in 82% of cases. Responses occurred in patients with PD-L1 low or high expression.

Ongoing and planned studies will evaluate Dato-DXd as second/third-line treatment for metastatic HR+/HER2- breast cancer, first-line treatment for metastatic, PD-L1-negative TNBC, and as post-neoadjuvant therapy in TNBC, said Rugo.

Patritumab Deruxtecan

An anti-HER3 antibody linked to a topoisomerase toxin, patritumab deruxtecan has shown antitumor activity in HR+ disease regardless of HER3 expression status. The ADC was evaluated in a of metastatic HER3+ breast cancer and produced objective responses in 23%-43% in HR+/HER2-, HER2+, and TNBC subtypes and median duration of response ranging from 5.9 to 8.3 months.

The most common toxicities in the trial were gastrointestinal and hematologic, including grade 3 thrombocytopenia (another new toxicity for ADCs) in a fourth of patients.

Current evaluation of the drug focuses on EGFR-mutated non-small cell lung cancer, but additional studies in early-stage HR+ breast cancer have been planned, said Rugo.

"Antibody-drug conjugates are an exciting and effective drug delivery system that have an established role in all of the [traditional] subsets plus a new subset of breast cancer in the metastatic setting," she said in closing. "There is a huge potential in early-stage disease, and I think that antibody-drug conjugates are likely to replace giving naked chemotherapy in the not-to-distant future. Toxicity management is critical as we treat our patients with these highly effective new drugs."

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