Praluzatamab Ravtansine (CX-2009) Meets Primary Endpoint of ORR in HR+/HER2- Breast Cancer in Phase 2 Study

A Phase 2 study of praluzatamab ravtansine, also known as CX-2009 (CytomX Therapeutics) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-non-amplified breast cancer (Arm A) met its primary efficacy endpoint of confirmed objective response rate (ORR) of greater than 10% by central radiology review.

Praluzatamab ravtansine is a conditionally activated antibody-drug conjugate (ADC), which includes a CD166-directed humanized monoclonal antibody conjugated to maytansinoid DM4 (N2′-deacetyl-n2′-(4-Mercapto-4-Methyl-1-oxopentyl)-6-MethylMaytansine), a tubulin inhibitor. CD166, also known as ALCAM, is a novel, ubiquitously expressed targe, over-expressed in multiple tumor types and previously considered “undruggable” given its lesser expression on normal, healthy, tissues.

Praluzatamab ravtansine is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types [1]

Probody platform technology
The investigational drug uses CytomX Probody® platform technology, which incorporates a masking peptide to cover and block the cellular binding region of the antibody. Tethered to the antibody via a protease-cleavable linker, the masking peptide is designed to be removed in a protease-rich tumor microenvironment, enabling the ADC to be unmasked and engage its target to deliver the toxic DM4 payload inside tumor cells. The goal is to have praluzatamab ravtansine remain inert while in circulation to limit binding in healthy tissues until it is activated by tumor-associated proteases.

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Praluzatamab ravtansine was evaluated in a three-arm Phase 2 study (NCT04596150) in patients with advanced solid tumors, including hormone receptor-positive/HER2-non-amplified breast cancer and patients with triple-negative breast cancer (TNBC), a disease which accounts for about 10-15%  of all breast cancers. The disease  Triple-negative breast cancer cells do not contain estrogen or progesterone receptors (ER or PR) and do not express, or express only limited HER2.  These cancers tend to be more common in women younger than age 40, who are Black, or who have a BRCA1 mutation.[2]

TNBC differs from other types of invasive breast cancer in that it tends to grow and spread faster, has fewer treatment options, and tends to have a worse prognosis (outcome).[2]

Trial design
The a three-arm Phase 2 study study included:

• Arm A of the study evaluated praluzatamab ravtansine as monotherapy (7 mg/kg, Q3W) in patients with inoperable, locally advanced or metastatic hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-non-amplified breast cancer. Patients received 0 to 2 prior cytotoxic chemotherapies in the inoperable, locally advanced, or metastatic setting, regardless of the level of CD166 expression.
• Arm B assessed praluzatamab ravtansine as a single agent (6 or 7 mg/kg, Q3W) in patients with inoperable, locally advanced or metastatic triple-negative breast cancer (TNBC). Patients received 1 to 3 prior lines of chemotherapy for inoperable, locally advanced, or metastatic disease and had CD166 expression.
• Arm C studied praluzatamab ravtansine (6 mg/kg, Q3W) in combination with pacmilimab (1200 mg, Q3W), CytomX’s proprietary conditionally activated anti-PD-L1 antibody, in patients with TNBC. Eligibility was the same as Arm B with the additional requirement that patients’ tumors were programmed death-ligand 1 (PD-L1)-positive by an FDA-approved test.

Study results
As of the data cutoff on May 13, 2022, 47 patients unselected for CD166 expression with advanced HR+/HER2-non-amplified breast cancer were evaluable for the primary efficacy endpoint. The ORR by central radiology review was 15%. Clinical benefit rate at 24 weeks by investigator (CBR24), as defined in the protocol as any response (confirmed or unconfirmed) or stable disease for 24 weeks, was 40%; median progression-free survival was 2.6 months. All patients in Arm A were treated at the initial Phase 2 starting dose of 7 mg/kg administered every three weeks. Arm B did not pass protocol-defined futility boundary (ORR was less than 10%) in patients with advanced triple-negative breast cancer (TNBC) and enrollment into Arms B and C will be discontinued.

As of this data cut, the safety profile of praluzatamab ravtansine in Arm A was generally consistent with toxicities observed in Phase 1 and with the DM4 payload; namely, high-grade toxicities or toxicities resulting in dose modifications were predominantly ocular or neuropathic in nature. Thirty percent of patients discontinued treatment for an adverse event (AE). Grade 3+ ocular and neuropathic toxicities were 15 and 10%, respectively. Arm B evaluated both 7 mg/kg and 6 mg/kg in patients with TNBC. The toxicity profile of 7 mg/kg starting dose was consistent with Arm A. In the 6 mg/kg cohort, no patients discontinued treatment for an AE and Grade 3+ ocular or neuropathic related events were lower at 3, and 0 percent, respectively. Biomarker analysis is ongoing.

“These results from our Phase 2 evaluation of praluzatamab ravtansine support single-agent activity of this novel drug candidate in hormone receptor-positive breast cancer where significant unmet need remains,” said Sean McCarthy, D.Phil., chief executive officer and chairman at CytomX Therapeutics.

“However, we do not believe the median progression-free survival at 7 mg/kg supports further evaluation at this dose. While we are encouraged by the emerging safety profile of 6 mg/kg, we do not plan to further advance this program alone given current financial market conditions and will be seeking a partnership,” McCarthy added.

“In this Phase 2 study, praluzatamab ravtansine showed single-agent activity in an unselected population of patients with advanced HR+/HER2-non-amplified breast cancer; additional clinical studies at 6 mg/kg are warranted,” noted Kathy D. Miller, MD, Ballvé Lantero Professor of Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana, and lead investigator of the Phase 2 study.

Clinical trials
Study to Evaluate the Safety and Antitumor Activity of CX-2009 Monotherapy and in Combination With CX-072 in Advanced Breast Cancer – NCT04596150

Reference
[1] Boni V, Fidler MJ, Arkenau HT, Spira A, Meric-Bernstam F, Uboha N, Sanborn RE, Sweis RF, LoRusso P, Nagasaka M, Garcia-Corbacho J, Jalal S, Harding JJ, Kim SK, Miedema IHC, Vugts DJ, Huisman MC, Zwezerijnen GJC, van Dongen GAMS, Menke van der Houven van Oordt CW, Wang S, Dang T, Zein IA, Vasiljeva O, Lyman SK, Paton V, Hannah A, Liu JF. Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial. Clin Cancer Res. 2022 May 13;28(10):2020-2029. doi: 10.1158/1078-0432.CCR-21-3656. PMID: 35165101.
[2] Types of breast cancer. Triple-negative Breast Cancer. American Cancer Society. Online. Last accessed on July 5, 2022.

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