Abstract P4-01-15: Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC)
Authors: Miller Kathy , Tolaney Sara , Emens Leisha A. , Kim Sung-Bae , Hamilton Erika , Saura Cristina , Sanz Lucia , Boni Valentina , Lynce Filipa , Cejalvo Juan Miguel , Crozier Jennifer , Wang Shirley , Uppal Hirdesh , Hannah Alison L. , Hurvitz Sara 
Published: March 2023

Background: CD166 is broadly expressed in normal epithelium and overexpressed in many types of malignancies, including breast cancer. Probody® therapeutic candidates are masked antibodies, conditionally activated by tumor-associated proteases, which restricts their activity to the tumor microenvironment and minimizes ‘off-tumor’ toxicity. CX-2009 is a conditionally activated humanized anti-CD166 monoclonal antibody conjugated to DM4 that showed clinical activity in ABC patients in a phase 1 study (Boni et al. Clin Cancer Res. 2022). This phase 2 study (NCT04596150) evaluates CX-2009 as monotherapy in patients with advanced HR+/HER2− BC (Arm A) and TNBC (Arm B), and in combination with pacmilimab (a conditionally activated PD-L1) in TNBC (Arm C). Methods: Key eligibility criteria for all cohorts include: ECOG 0-1, acceptable end-organ function, measurable disease, willingness to receive ocular prophylaxis for DM-4 related toxicity, and available tumor tissue for CD166 evaluation. Eligibility criteria for HR+ BC include: 2-4 prior regimens (excluding single-agent hormonal therapy with up to 2 prior cytotoxic regimens) and a prior CDK 4/6 inhibitor in the metastatic setting; eligibility criteria for TNBC include CD166 by IHC &gt;1% by central assessment, 1-3 prior regimens in the metastatic setting and prior taxane. All patients initially received 7 mg/kg Q3W; the protocol was subsequently amended to enroll patients at 6 mg/kg Q3W. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by central review. Other key endpoints include ORR by investigator assessment, clinical benefit rate at 24 weeks (CBR24; defined as any response, confirmed or unconfirmed, or SD for 24 weeks), duration of response, and progression-free survival by investigator. Archival tumor specimens and blood samples were collected for correlative research including genomic analyses. Results: As of 13 May 2022, 60 patients were enrolled in Arm A (all patients started at 7 mg/kg); 52 were evaluable for efficacy by investigator. Median duration of follow-up was 29.1 weeks (range: 3.6-60.7). Median age was 60.5 years (36, 83); pts received a median of 3.5 (1, 6) prior treatments for ABC. CD166 H-Score &gt; 200 was reported in 53.3% of patients. Arm A met the primary efficacy endpoint with a confirmed ORR by central radiology of 14.9% (n=47); by investigator, ORR was similar at 15.4% (n=52); an additional 9 patients (17.3%) had an unconfirmed response. CBR24 was 40.4%; using only confirmed responses, CBR24 was 23.1%. Median PFS was 11.4 weeks (95% CI 9.0, 13.9). Common treatment-related all-grade adverse events (TRAEs) included blurred vision (42%), nausea (35%), fatigue (35%), diarrhea (25%), peripheral neuropathy (27%), infusion-related reaction (23%) and decreased appetite (20%). Grade ≥3 ocular and neuropathic TRAEs were 15% and 10%, respectively. AEs resulting in treatment discontinuation (AEDC) were 25%. For Arm B and C, 55 and 10 patients were enrolled (the majority received a starting dose of 6 mg/kg). For Arm B, the futility boundary was crossed (ORR &lt; 10%). Grade ≥3 ocular and neuropathic TRAEs and AEDC at 7 mg/kg in Arm B were similar to Arm A (11%, 11% and 21% respectively); whereas at 6 mg/kg, they were reduced at 3%, 0% and 0%, respectively. Biomarker data and correlation with outcomes will be presented. Conclusions: Praluzatamab ravtansine demonstrated single-agent activity in unselected heavily pretreated patients with HR+/HER2- ABC. Time to event analyses, such as PFS, were confounded by higher-than-expected toxicity at a starting dose of 7 mg/kg. The toxicity profile was generally consistent with a DM4 payload. The lower dose of 6 mg/kg appears to be better tolerated. Additional clinical studies in HR+ABC, incorporating a starting dose of 6 mg/kg and potentially including a biomarker strategy, are warranted.

Citation Format: Kathy Miller, Sara Tolaney, Leisha A. Emens, Sung-Bae Kim, Erika Hamilton, Cristina Saura, Lucia Sanz, Valentina Boni, Filipa Lynce, Juan Miguel Cejalvo, Jennifer Crozier, Shirley Wang, Hirdesh Uppal, Alison L. Hannah, Sara Hurvitz. Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-15.