Investigational ADC Ups Survival in Advanced Triple-Negative Breast Cancer

CHICAGO — Treatment with investigational izalontamab brengitecan (iza-bren) significantly improved progression-free survival (PFS) and overall survival (OS) in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), a randomized trial from China showed.

Median PFS by blinded independent central review (BICR) was 8.5 months with the bispecific antibody-drug conjugate (ADC) compared with 3.1 months with physician’s choice of chemotherapy (HR 0.29, 95% CI 0.22-0.38, P<0.0001), reported Jiong Wu, MD, PhD, of Fudan University Shanghai Cancer Center, at the American Society of Clinical Oncology annual meeting.

Median OS was 15.9 months with iza-bren versus 12.5 months with chemotherapy (HR 0.60, 95% CI 0.42-0.85, P=0.0019).

“Iza-bren clearly demonstrated superior, and more durable, antitumor activity,” Wu said, adding that the data “support iza-bren as a new standard of care for patients with pretreated metastatic triple-negative breast cancer.”

Invited discussant Valentina Guarneri, MD, PhD, of the University of Padova in Italy, pointed out that “the significant overall survival benefit was captured despite subsequent [anti-cancer] therapy use, including ADCs, in the control arm.”

More patients in the chemotherapy arm received at least one subsequent anti-cancer therapy (63.4% vs 38.6% in the iza-bren arm), with 42% and 16.4% of those patients receiving a subsequent ADC.

Guarneri said the study raised several questions, including whether chemotherapy was the appropriate control arm considering other ADCs have demonstrated superiority over chemotherapy in comparable patient populations, such as in the ASCENT trial.

“However, given the variability in global access and treatment availability … an additional option remains clinically valuable,” she said.

She also questioned the relevance of the data in the current era of early ADC use, and suggested the magnitude of benefit seen in the trial may not be replicated in contemporary patients. “However, this is a common challenge across many modern oncology trials as the treatment landscape rapidly evolves,” she observed.

Guarneri also pointed out that the results of this study will need to be validated globally.

In explaining why he and his team conducted the study, Wu noted that “triple-negative breast cancer remains a therapeutic challenge due to its aggressive biology and limited treatment options beyond first-line standard-of-care treatment.”

Iza-bren targets both EGFR and HER3, which are highly expressed in various epithelial cancers and are known to be associated with cancer cell proliferation and survival, Wu said. The ADC’s dual mechanism of action blocks EGFR and HER3 signaling to cancer cells, reducing proliferation and survival. In a previous early-phase study, iza-bren showed promising antitumor activity, with a manageable safety profile, in locally advanced or metastatic breast cancer.

The phase III PANKU-Breast02 trial was conducted at 81 centers across China and included 418 patients with unresectable locally advanced or metastatic TNBC whose disease progressed following one to two prior lines of systemic therapy for advanced disease, including prior taxane therapy.

Patients were randomized to receive iza-bren or physician’s choice of chemotherapy (which included eribulin, capecitabine, gemcitabine, or vinorelbine). PFS and OS were dual primary endpoints.

Median age was 53 years in the iza-bren group and 54 years in the chemotherapy arm. Eastern Cooperative Oncology Group performance status was 1 in the majority of both groups.

About 70% of patients received one prior line of treatment, while the remaining 30% received two prior lines. About a quarter of patients received prior anti-PD(L)1 therapy, and nearly every patient had stage IV disease at baseline.

In patients with HER2 immunohistochemistry 0 disease, median PFS by BICR was 8.3 months with iza-bren versus 2.6 months with chemotherapy (HR 0.28, 95% CI 0.20-0.41, P<0.0001). In those with HER2-low disease, median PFS by BICR was 9.7 versus 4.1 months, respectively (HR 0.32, 95% CI 0.22-0.46, P<0.0001).

The confirmed objective response rate assessed by BICR was 51.7% with iza-bren versus 20.5% with chemotherapy (OR 4.3, 95% CI 2.8-6.7), with a median duration of response of 8.3 months and 4.0 months, respectively.

As for safety, grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 88.9% of patients in the iza-bren arm and in 62.9% of patients in the chemotherapy arm. Serious adverse events occurred in 44% and 19%, respectively.

The most frequent grade ≥3 TEAEs in the iza-bren arm were hematologic in nature and effectively managed with standard supportive care, Wu said. Interstitial lung disease was reported in three patients in the iza-bren arm.

TEAEs leading to treatment discontinuation were rare — 1.9% with iza-bren and 0.5% with chemotherapy.

In addition to TNBC, iza-bren is in clinical development for esophageal squamous cell carcinoma, and has been granted a breakthrough therapy designation by the FDA for the treatment of advanced EGFR-mutated non-small cell lung cancer.

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