Abstract P6-17-02: Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study

Abstract

Background: HER2-targeted therapies have improved survival for advanced HER2-positive breast cancers (BC), but none have been approved for tumors with low levels of HER2 expression (ie, HER2 IHC 1+ or 2+/ISH-negative). Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker, which is designed to have broad antitumor activity in HER2-expressing tumors. It has a drug-to-antibody ratio of 7 to 8, a novel linker that is stable in plasma and that is selectively cleaved by lysosomal cathepsins which are upregulated in cancer cells, and its payload has a short systemic half-life. In 2015, a phase 1 study (NCT02564900) was initiated to evaluate the safety and efficacy of DS-8201a in subjects with advanced HER2-expressing or HER2-mutated solid tumors, including HER2-low expressing BC. In this study, the overall confirmed response rate (ORR) in the evaluable subjects was 49.3% (103/209) (April 2018 data cutoff; Iwata H, et al. ASCO 2018). Expanded results from the HER2-low expressing BC subjects are presented here. Methods: This ongoing phase 1 trial included 2 parts. The dose escalation part served to determine the dose-limiting toxicities, the maximum tolerated dose, and to select the recommended dose for expansion (RDE). The dose expansion part further evaluated the safety, tolerability, and efficacy of the DS-8201a at the RDE (5.4 and 6.4 mg/kg; q3wks) in various advanced HER2-expressing or HER2-mutated solid tumors, including heavily pretreated HER2-low BC (IHC 1+ or 2+, ISH-negative). Enrollment of HER2-low subjects is ongoing. Results: At the cutoff date of 18 April 2018, data from 34 HER2-low BC subjects were collected. The median age was 55.8 (range; 33, 75) years, the median number of prior endocrine therapies was 2, and the median number of prior chemotherapies was 3. In this HER2-low BC population, most patients had hormone receptor (HR)-positive disease (85.3%; 29/34); of which 17.2% (5/29) received prior treatment with a CDK4/6 inhibitor. The confirmed ORR was 50.0% (17/34), the disease control rate was 85.3% (29/34), the median time to response was 2.8 (range; 1.2, 13.8) months, the median duration of response (DOR) was 11.0 months, and the median progression-free survival (PFS) was 12.9 months. In the subgroup with HR-positive disease, the ORR was 55.2% (16/29), the median DOR was 11.0 months, and the median PFS was 13.6 months. After exclusion of 8 HER2-low subjects who received prior HER2-targeted therapy, the ORR was 46.2% (12/26). In the overall study, among the 145 BC subjects who received ≥1 dose of DS-8201a (5.4 or 6.4 mg/kg), the most frequent grade ≥3 adverse events included anemia (14.5%), and decreased counts of neutrophils (13.8%) and white blood cells (10.3%). There were 4 fatal cases of interstitial lung disease/pneumonitis in BC subjects, including 2 fatal cases in HER2-low BC subjects. Conclusions: In this study, DS-8201a showed substantial antitumor activity and acceptable safety in heavily pretreated HER2-low BC. Citation Format: Modi S, Tsurutani J, Tamura K, Park H, Sagara Y, Murthy R, Iwata H, Krop IE, Doi T, Redfern C, Moreno-Aspitia A, Redman R, Lee C, Sugihara M, Fujisaki Y, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-02.

A view on drug resistance in cancer

“…Although we acknowledge that ADCs have so far not fully delivered on their initial promise to improve therapeutic index-despite the approval of several of these agents 105 -we believe that with modern ADC chemistry this is beginning to change. This is perhaps best exemplified by the high degree of durable efficacy that is observed with the latest generation of HER2-targeted ADC, DS-8201a, in so-called HER2-low (that is, defined by amplification of HER2 that is less than that necessary for response to current anti-HER2 therapies) breast cancer 106 . DS-8201a demonstrates the ability of a modern ADC to effectively deliver chemotherapy that is based on low levels of expression of a target protein, even when the target protein is not itself an oncogene for that tumour type.…”

<p>Resistance and Overcoming Resistance in Breast Cancer</p>

“…The results of trastuzumab deruxtecan treatment in these patients have shown a response rate of 44.2%. 91 Currently, several HER2-directed ADCs are under clinical investigation for both HER2 amplified and HER2 expressing but not amplified BCs, including ARX788 and XMT-1522.ARX788, a novel next-generation anti-HER2 ADC containing an anti-HER2 monoclonal antibody sitespecifically conjugated to amberstatin, 92,93 has shown antitumor effects and rapid tumor regression in murine xenograft models of the HER2+ BC cell lines BT474 and HCC1954. 92 Furthermore, ARX788 showed a stronger inhibitory effect than T-DM1 on T-DM1-responsive BC cells and caused complete tumor regression in a trastuzumab-resistant BC xenograft model derived from JIMT-1 cells.…”

“…The results of trastuzumab deruxtecan treatment in these patients have shown a response rate of 44.2%. 91 …”

HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

“…Thirty-four patients with HER2-low breast cancer were enrolled at data cutoff (12 October 2018), with a median age of 56 years (range 33–75) and a median number of prior cancer regimens of 8 (2–18) [ 32 ]. The majority of HER2-low patients had hormone-receptor positive disease (87%) and 34% of them were pretreated with a CDK4/6 inhibitor.…”