Sacituzumab Govitecan Becomes First ADC Approved for TNBC

In Clinical Studies News by Barbara Jacoby

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By: Rachel Narozniak, MA

From: onclive.com

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For the first time in the therapeutic landscape of metastatic triple-negative breast cancer (mTNBC), treatment options now include an antibody-drug conjugate (ADC). The aggressive subtype is associated with poor prognoses.

On April 22, 2020, the FDA granted an accelerated approval to sacituzumab govitecan-hziy (Trodelvy) for adults with mTNBC who have received at least 2 prior therapies for metastatic disease. The FDA’s decision was supported by efficacy data from the single-arm phase 1/2 IMMU-132-01 trial (NCT01631552), which showed that sacituzumab govitecan induced durable responses in the 108 patients with mTNBC who were treated with the ADC. The overall response rate was 33.3% (95% CI, 24.6%-43.1%) and the median duration of response was 7.7 months (95% CI, 4.9-10.8).

The efficacy of sacituzumab govitecan was “much higher than what you would expect with standard chemotherapy” according to Aditya Bardia, MD, MPH, lead author of the IMMU-132-01 trial. In an interview with OncLive, Bardia, director of precision medicine at the Center for Breast Cancer at Massachusetts General Hospital Cancer Center in Boston, discussed how the ADC can address the unmet need in TNBC and the toxicities seen with the therapy.

OncLive: How great was the need for a new treatment option in this breast cancer subtype?

Bardia: Triple-negative breast cancer is [a source of] major unmet need in the field of breast oncology and in oncology in general. The risk of disease recurrence in triple-negative breast cancer is much higher compared with other breast cancer subtypes, and the prognosis of patients with this disease is also much worse [than it is with] other subtypes. The response rate with standard chemotherapy is in the range of 10% to 15%, and the median progression-free survival is 3 to 4 months with standard therapies in the later-line setting.

Please discuss the efficacy data that led to the approval.

Sacituzumab govitecan was tested in a basket trial with multiple cohorts, one of which included patients with metastatic triple-negative breast cancer. Early on, the team saw signs of therapeutic efficacy in patients with triple-negative breast cancer, and after discussion with the regulatory authorities, a more homogeneous patient population was enrolled. This patient population included patients with metastatic triple-negative breast cancer who had received at least 2 prior lines of therapy. Patients received sacituzumab govitecan on day 1 and day 8, every 21 days until disease progression or unacceptable toxicity.

Patients had an ECOG performance status of 0 to 1, received a median of 3 prior systemic therapies, and 76% had visceral disease. In the metastatic setting, prior chemotherapies included carboplatin, cisplatin, gemcitabine, doxorubicin, and eribulin. Overall, 98% of patients had received prior taxanes and 86% had received prior anthracyclines, so this was a very heavily pretreated patient population. Among these patients, the overall response rate was 33.3% and the median duration of response was 7.7 months.

The efficacy was much higher than what you would expect with standard chemotherapy. If you compare [these results] to historical data with standard chemotherapy, [these findings] nearly double what you would see with that of standard chemotherapy.

What do clinicians need to know about the black box warning on the drug label?

Neutropenia is the most common adverse event [reported] with sacituzumab govitecan. The incidence of any grade of neutropenia was 64%. The incidence of grade 4 neutropenia was 13%, [but] less than 1% of patients permanently discontinued because of neutropenia.

When we talk about neutropenia, an important metric to consider is febrile neutropenia, since these patients need to be hospitalized and treated with intravenous antibiotics. The incidence of febrile neutropenia with this agent was 6%. In terms of neutropenia management, growth factor support should be considered to decrease the probability of febrile neutropenia and grade 3 or grade 4 neutropenia. In general, oncologists are comfortable with the use of growth factor support and it is [an intervention] that should be considered if grade 3 or grade 4 neutropenia is observed or even earlier in patients who are at a high risk for severe infection.

Sacituzumab govitecan is linked to SN-38 [an antineoplastic drug], which is the toxic payload associated with the antibody-drug conjugate. The most common gastrointestinal adverse event seen with SN-38 [which is also an active metabolite of irinotecan] is diarrhea. The incidence of grade 3 or grade 4 diarrhea with irinotecan is about 30%. With sacituzumab govitecan, grade 3 and grade 4 diarrhea is also observed, but the incidence of [these grades] is much lower [9%].

The usual management guidelines need to be followed to manage diarrhea, [including] use of antidiarrheal medications like loperamide. If a patient is having a cholinergic response, which can be seen with irinotecan as well and usually manifests as abdominal pain, cramping, increased secretions, then atropine can also be considered to manage the cholinergic response. Besides neutropenia and diarrhea, the other [adverse events] that were noted with this drug include hypersensitivity, nausea, and alopecia.

How does this agent advance the mTNBC paradigm?

Effective treatment options in the third-line setting and beyond are limited in metastatic triple-negative breast cancer, so this drug offers a novel therapeutic option for patients battling this devastating disease. While the drug is not perfect, it moves the needle towards better outcomes and underscores the importance of more research.

Moving forward, we need to investigate the efficacy of this agent in earlier lines of metastatic triple-negative breast cancer, [including the] first and second lines. We also need to look at combining this agent with other therapies like immunotherapy and PARP inhibitors, which could potentially further increase the efficacy of this agent.

This is the beginning and we need to build on [this] progress [by] developing better therapies and combinations to improve outcomes for our patients with triple-negative breast cancer.