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An investigational antibody-drug conjugate (ADC) achieved disease control in all but one patient with advanced or metastatic triple-negative breast cancer, results of a preliminary clinical study showed.

Nine of 21 evaluable patients had objective responses and 11 had stable disease when treated with datopotamab deruxtecan (Dato-DXd). The study population had a median treatment history of four prior systemic regimens, and 21 of 24 patients enrolled in the trial had received at least two prior regimens.

The treatment was generally well tolerated, as adverse events were mostly low-grade nonhematologic toxicities, reported Aditya Bardia, MD, of Massachusetts General Hospital Cancer Center in Boston, during the .

"Dato-DXd demonstrated a manageable safety profile, and no patients discontinued treatment due to adverse events," said Bardia. "Emerging efficacy results showed antitumor activity in heavily pretreated patients with metastatic triple-negative breast cancer. Further study in breast cancer is warranted, and enrollment of a hormone receptor-positive cohort has begun."

Dato-DXd targets TROP2, a cell-surface glycoprotein involved in multiple signaling pathways associated with cancer progression and metastasis. The ADC construct consists of a humanized anti-TROP2 antibody, a topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker. Dato-DXd had encouraging antitumor activity with manageable toxicity in patients with advanced non-small cell lung cancer, said Bardia. A study involving patients with advanced HER2-positive breast cancer resulted in an objective response rate of 61%.

Safety of Dual Anti-HER2 Therapy Supported

Dual anti-HER2 therapy before and after surgery for breast cancer led to significant heart failure events in 1% to 2% of patients with either of two concurrent chemotherapy regimens, according to long-term follow-up from a randomized trial.

Four cycles of pre- and postoperative pertuzumab (Perjeta) plus trastuzumab (Herceptin) was associated with a 1.5% incidence of class III/IV heart failure at 5 years when paired with neoadjuvant dose-dense doxorubicin-cyclophosphamide and paclitaxel. Heart failure incidence was 1.0% with FEC (fluorouracil, epirubicin, and cyclophosphamide) chemotherapy plus pertuzumab-trastuzumab and docetaxel. Symptomatic and asymptomatic declines in left ventricular ejection fraction (LVEF) occurred in 12% to 13% of patients in each treatment arm.

Across both arms of the randomized trial, the 5-year event-free survival rate was around 89% or higher, the invasive disease-free survival rate at 4 years was at least 91%, and the 5-year overall survival rate was about 94%, reported Chau Dang, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"No new safety concerns arose during long-term follow-up, with low incidences of drug-related grade 3 or greater adverse events and serious adverse events in both cohorts," she said. "We observed favorable long-term efficacy outcomes with pertuzumab-trastuzumab-based regimens. These data support the use of dual HER2 blockade with pertuzumab-trastuzumab-based regimens ... across the neoadjuvant and adjuvant treatment settings for the complete management of HER2-positive early breast cancer."

The involved 400 patients with HER2-positive, locally advanced, inflammatory, or early breast cancer and normal LVEF. Initial results showed pathologic complete response rates of 61% to 62% when pertuzumab and trastuzumab were administered preoperatively with either of the chemotherapy regimens. The primary endpoint was the incidence of class III/IV heart failure and the combination of symptomatic and asymptomatic LVEF declines ≥10 percentage points from baseline and to a value of ≤50%. Dang reported findings from a median follow-up of 64.5 months.

Reassuring Data on Lung Disease With ADC

About 16% of patients with metastatic HER2-positive breast cancer treated with trastuzumab deruxtecan developed interstitial lung disease (ILD), which was grade 1/2 in most cases, according to pooled clinical trial data.

Overall, 38 of 245 patients treated with the ADC developed ILD, which was grade 1/2 in 30 cases. Concomitant steroid use was associated with 14 of 24 cases of grade 2-4 ILD and three of six deaths associated with ILD. Most events occurred during the first 12 months of treatment. An independent adjudication committee identified 44 ILD events, and a comparative analysis showed that the adjudication committee identified ILD earlier, reported Charles Powell, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

for ILD monitoring recommend stopping treatment if a patient develops ILD. Patients with grade 1 disease may restart treatment when symptoms resolve, but patients with grade 2-4 ILD should discontinue treatment. At the recent American Association for Cancer Research virtual meeting, Powell reported findings from a pooled analysis of ILD across studies of trastuzumab deruxtecan in multiple tumor types. The results suggested that the frequency of high-grade ILD decreased after publication of the guidelines.

Trastuzumab deruxtecan has shown "significant and unprecedented activity" in HER2-positive metastatic breast cancer, said Powell. However, clinical studies had identified ILD as an important treatment-associated risk.

"Effective early detection and optimal management are critical in preventing high-grade ILD," he concluded. "The risk of ILD may decrease over time, which suggests no cumulative toxicity. The overall clinical data support the positive benefit-risk profile of trastuzumab deruxtecan."