Praluzatamab Ravtansine Generates Responses in HR-Positive, HER2-Negative Breast Cancer

The CD166-targeted antibody-drug conjugate (ADC) praluzatamab ravtansine (CX-2009) achieved a promising overall response rate (ORR) in patients with advanced hormone receptor (HR)–positive, HER2-negative breast cancer, meeting the primary end point in arm A of the phase 2 CTMX-2009-002 trial (NCT04596150).¹

At a data cutoff of May 13, 2022, praluzatamab ravtansine demonstrated an ORR of 15% in arm A. Additionally, the clinical benefit rate at 24 weeks was 40%, and the median progression-free survival (PFS) was 2.6 months.

Notably, the primary end point was not met in patients with advanced triple-negative breast cancer (TNBC) in arm B, with data showing an ORR of less than 10%. Enrollment will be discontinued in arm B and arm C for patients with TNBC.

“These results from our phase 2 evaluation of praluzatamab ravtansine support single-agent activity of this novel drug candidate in HR-positive breast cancer where significant unmet need remains,” Sean McCarthy, PhD, chief executive officer and chairman at CytomX Therapeutics, stated in a press release. “However, we do not believe the median PFS 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.”

Praluzatamab ravtansine is comprised of a CD166-directed monoclonal antibody conjugated to the maytansinoid DM4, which is a tubulin inhibitor. The ADC is linked by a protease-cleavable linker, and the masking peptide is designed to be removed in a protease-rich tumor microenvironment.

Arm A of the CTMX-2009-002 trial enrolled patients with inoperable, locally advanced or metastatic HR-positive, HER2-negative breast cancer who received no more than 2 prior lines of cytotoxic chemotherapy in the locally advanced or metastatic setting.² Patients in arms B and C were required to have inoperable, locally advanced or metastatic TNBC with high CD166 expression by immunohistochemistry. These patients were required to have received between 1 and 3 prior lines of therapy. Patients in arm C were also required to be PD-L1 positive.

In all arms, patients needed to be at least 18 years of age with measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Notably, patients with asymptomatic brain metastases no more than 1 cm in diameter and required no treatment were allowed to enroll after discussion with the medical monitor.

Patients with a history of active malignancy within 2 years were excluded, except for those with localized cancers that were not related to the current cancer being treated, that were considered to have been cured, or presented a low risk of recurrence. Other key exclusion criteria included untreated symptomatic brain and/or leptomeningeal metastases; unresolved prior therapy-related acute toxicity higher than grade 1; active or chronic corneal disorder; or serious concurrent illness.

All patients in arm A received 7 mg/kg of intravenous (IV) praluzatamab ravtansine once every 3 weeks. Those in arm B were administered either 6 mg/kg or 7 mg/kg of IV praluzatamab ravtansine once every 3 weeks. In arm C, patients were given 6 mg/kg of IV praluzatamab ravtansine plus 1200 mg of pacmilimab (CX-072), an anti–PD-L1 antibody, once every 3 weeks.

Along with the primary end point of ORR per RECIST v1.1 criteria, secondary end points included investigator-assessed PFS, duration of response, overall survival, and clinical benefit rate at 16 and 24 weeks.

Regarding safety, the profile of praluzatamab ravtansine was consistent with toxicities observed in a phase 1 trial. In Arm A, high-grade toxicities or adverse effects (AEs) leading to dose modifications were predominately ocular or neuropathic. Thirty percent of patients discontinued treatment due to AEs. The rates of grade 3 or higher ocular and neuropathic toxicities were 15% and 10%, respectively.

Notably, safety data were similar for patients who received 7 mg/kg of praluzatamab ravtansine in arms A and B. However, among patients who were given 6 mg/kg of praluzatamab ravtansine in arm B, no patients discontinued treatment due to AEs. Additionally, the rates of grade 3 or higher ocular and neuropathic AEs were 3% and 0%, respectively, with the 6 mg/kg dose.

“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,” lead trial investigator Kathy D. Miller, MD, the Ballvé Lantero Professor of Oncology at the Indiana University Simon Comprehensive Cancer Center, stated in a press release.

A biomarker analysis is ongoing, and CytomX Therapeutics expects to submit data from the phase 2 trial for presentation at a medical conference in the second half of 2022.

References

1. CytomX Therapeutics announces phase 2 results for praluzatamab ravtansine in breast cancer. News release. CytomX Therapeutics. July 6, 2022. Accessed July 7, 2022. https://bit.ly/3yno2eC
2. Study to evaluate the safety and antitumor activity of CX-2009 monotherapy and in combination with CX-072 in advanced breast cancer. ClinicalTrials.gov. Updated March 29, 2022. Accessed July 7, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04596150