44 Results From the Phase 1/2 Study of Patritumab Deruxtecan (HER3-DXd), a HER3-Directed Antibody-Drug Conjugate (ADC), in Patients (pts) With HER3- Expressing Metastatic Breast Cancer (MBC)

Background

Human epidermal growth factor receptor 3 (HER3) is overexpressed in many types of cancer, including 30%-50% of breast cancers (BCs):

• Overexpression of HER3 in BC is associated with poor prognosis.
• No HER3-directed therapies have been approved for the treatment of any cancer.

Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate (ADC) with 3 components:

• A fully human anti-HER3 IgG1 mAb (patritumab) covalently linked to
• A topoisomerase I inhibitor payload (an exatecan derivative) via
• A tetrapeptide-based cleavable linker

U31402-A-J101 (NCT02980341/JapicCTI-163401) is an ongoing phase 1/2 study of HER3-DXd in patients with HER3-expressing metastatic breast cancer (mBC).

• Early data from the dose-escalation, dose-finding, and dose-expansion parts showed promising antitumor activity and a manageable safety profile in heavily pretreated patients.

Here, we report mature data across all study cohorts, providing consolidated data among patients with a range of BC subtypes.

Materials and Methods

U31402-A-J101 is a phase 1/2, multicenter, open-label, first-in-human study of HER3DXd in HER3-expressing advanced/ unresectable or mBC, including TNBC. Data were pooled for all 3 parts of the ongoing U31402-A-J101 study. Primary objectives included safety and efficacy.

Results

Median follow-up for all patients at data cutoff (August 16, 2021) was 31.9 mo (range,15-56 mo)

• Efficacy is reported by BC subtype: HR+/HER2− (n = 113), TNBC (n = 53), and HER2+ (n = 14).
• Safety is reported for patients who received HER3-DXd 4.8 mg/kg (n = 48), 6.4 mg/kg (n = 98), and all patients (N = 182a).

Patients with HER3-expressing mBC with poor prognostic characteristics were heavily pretreated. At 32 mo follow-up, almost all patients (97.8%) had discontinued treatment at the time of data cutoff. HER3-DXd demonstrated durable antitumor activity per blinded independent central review (BICR) across BC subtypes.

• Confirmed ORR for all patients (N = 182) was 28.6% (95% CI, 22.1%-35.7%), with a median DOR of 7.0 mo (95% CI, 5.5-8.5 mo).

HER3-DXd induced a clinically meaningful decrease in tumor size by BICR in most patients across BC subtypes. Antitumor responses by the best overall response (BOR) were observed across a broad range of pretreatment baseline HER3 membrane-expression levels. HER3 membrane expression changed dynamically, but this was not associated with clinical activity.

Conclusions

HER3-DXd demonstrated clinically meaningful and durable antitumor activity in a heavily pretreated population of patients with HER3-expressing BC.

• Durable antitumor activity was demonstrated across BC subtypes: HR+/HER2– (objective response rate [ORR], 30%; median duration of response (DOR), 7.2 months [mo]), triple-negative breast cancer (TNBC) (ORR, 23%; median DOR, 5.9 mo), and HER2+ (ORR, 43%; median DOR, 8.3 mo).
• Antitumor activity was also demonstrated across the range of HER3 expression.

The safety profile was manageable, with a low rate of discontinuation due to treatment-emergent adverse events (TEAEs) (10%).

• The rate of adjudicated treatment-related interstitial lung disease (ILD) was 7%; most cases were grades 1 and 2.
• Grade ≥3 hematological toxicities were manageable; no grade ≥3 thrombocytopenia resulted in treatment discontinuation nor in a grade ≥3 bleeding event.

As a similar safety profile was seen with 4.8 mg/kg and 6.4 mg/kg, a 5.6 mg/kg dose, currently used in non–small cell lung cancer, is being evaluated in BC to refine dose optimization. These data provide encouraging evidence of antitumor efficacy with a manageable safety profile and warrant further evaluation of HER3-DXd across clinical and histopathological BC subtypes.

AFFILIATIONS:

Ian E. Krop,¹ Norikazu Masuda,² Toru Mukohara,³ Shunji Takahashi,⁴ Takahiro Nakayama,⁵ Kenichi Inoue,⁶ Hiroji Iwata,⁷ Tatsuya Toyama,⁸ Yutaka Yamamoto,⁹ Damien Hansra,¹⁰ Masato Takahashi,¹¹ Akihiko Osaki,¹² Kumiko Koyama,¹³ Tatsuya Inoue,¹⁴ Takatoshi Yonekura,¹³ Joseph Mostillo,¹⁵ Shoichi Ohwada,¹³ Yoshimi Tanaka,¹³ David Sternberg,¹⁵ Kan Yonemori¹⁶

¹Yale Cancer Center, New Haven, CT.

²Nagoya University Graduate School of Medicine, Nagoya, Japan.

³National Cancer Center Hospital East, Kashiwa, Japan.

⁴The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

⁵Osaka International Cancer Institute, Osaka, Japan.

⁶Saitama Cancer Center, Saitama Japan.

⁷Aichi Cancer Center Hospital, Nagoya, Japan.

⁸Nagoya City University, Nagoya, Japan.

⁹Kumamoto University Hospital, Kumamoto, Japan.

¹⁰Piedmont Physicians Medical Oncology, Fayetteville, GA.

¹¹National Hospital Organization, Hokkaido Cancer Center, Sapporo, Japan.

¹²Saitama Medical University International Medical Center; Hidaka, Japan.

¹³Daiichi Sankyo Co, Ltd., Tokyo, Japan.

¹⁴Daiichi Sankyo RD Novare Co, Ltd., Tokyo, Japan.

¹⁵Daiichi Sankyo, Inc, Basking Ridge, NJ.

¹⁶National Cancer Center Hospital, Tokyo, Japan.