Phase 2 Data Point to Potential Predictive Biomarkers for Benefit With Second-Line CM24 Combo in PDAC

Baseline levels of the serum NET marker myeloperoxidase (MPO), high CEACAM1 expression in tumor cells, and a low PD-L1 combined positive score (CPS) were all associated with improved survival in patients with advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) who received second-line CM24 plus nivolumab (Opdivo) and chemotherapy, indicating their utility as potential predictive biomarkers for benefit with CM24-based therapy, according to biomarker data from a phase 2 study (NCT04731467).¹

Data presented at the 2024 AACR Special Conference: Pancreatic Cancer showed that patients with serum MPO levels below 350 ng/mL (n = 18) experienced a 62% reduction in the risk of death (HR, 0.38), when treated with CM24 in combination with nivolumab and Nal-IRI (liposomal irinotecan)/5-FU (fluorouracil)/LV (leucovorin) therapy (n = 9). This group also showed a prolongation in median overall survival (OS) of 3.3 months vs standard chemotherapy alone.

Analysis of outcomes in the overall patient population (n = 31) demonstrated a more modest 25% reduction in death risk (HR, 0.75) and a median OS prolongation of 2.1 months with CM24/nivolumab–based therapy (n = 16), suggesting that lower MPO levels might better identify patients who will benefit from this therapy. When two potential biomarkers for CM24/nivolumab therapy, such as serum NET marker MPO and low CPS, were combined, there was a 91% reduction in the risk of death (HR, 0.09) and a median OS prolongation of 3.3 months (P = .01).²

Moreover, tumor cells with high CEACAM1 expression (H-score > 115) were associated with a 45% reduction in the risk of death (HR, 0.55), whereas low PD-L1 expression (CPS ≤ 1) corresponded with a 65% reduction in the risk of death (HR, 0.35). When both biomarkers are considered together, patients with high CEACAM1 and low PD-L1 experienced a 90% reduction in the risk of death (HR, 0.10) and a median OS extension of 4.1 months (P = .013). This combined biomarker approach appears to significantly enhance the predictive value for CM24-based therapy, suggesting it could substantially improve patient selection and treatment outcomes in PDAC.

“We are excited to present additional positive interim data from our phase 2 study with CM24. CEACAM1 as a novel target in oncology continues to be supported by these data, underscoring its potential given its high expression on cancer cells, tumor infiltrating leucocytes and on NETs, suggesting the potential multiple roles of CM24 in overcoming immune evasion,” Gil Efron, chief executive officer of Purple Biotech, stated in a news release.¹ “Moreover, these data enable us to potentially design biomarker-guided studies for CM24 for the treatment of[patients with] PDAC, as well as other cancers.”

Overall, these biomarker data suggest that NETs could provide both a new mechanism of action and potential tool for patient selection for CM24-based therapy, along with CEACAM1 and PD-L1 expression in tumors.

“A serum biomarker for patient selection is a major advantage for cancer patients in general and [patients with] PDAC in particular. The additional interim data suggesting serum NET levels as a potential biomarker for improving the outcome of CM24-based therapy, together with the ability of this therapy to reduce serum NET levels in [patients with] PDAC and to inhibit NET-related activities in vitro, add supporting evidence for NETs as a new mechanism of action and potential biomarker for CM24-based therapy,” Hadas Reuveni, PhD, vice president of research and development at Purple Biotech, added in the news release. “Additional encouraging results suggesting that the CM24/nivolumab/chemotherapy effect is most pronounced among patients with high CEACAM1 expression and low PD-L1 also relate to the CM24/nivolumab mechanism of action and support the CM24/nivolumab combined treatment. This may open a new opportunity for patients who are not eligible for anti–PD-1 therapy in various indications. A larger sample size is required to confirm the results and better define the cutoff values.”

Mechanism of Action

CM24 is a humanized monoclonal antibody that targets and blocks CEACAM1 interactions, is a component of the NET complex and plays a crucial role in tumor progression, immune escape, and metastasis. The NET complex itself has been implicated in tumor immune evasion, metastasis, and cancer-associated thrombosis, impacting patient survival.

Prior data have shown that CM24 binding suppresses NET-induced tumor cell migration and inhibits tumor metastasis in vivo. The current analysis further shows that CM24 inhibits NET-induced platelet aggregation in an in-vitro assay designed to mimic thrombosis.

Study Overview

The open-label, multicenter, multi-dose–escalation and dose-expansion phase 2 study is evaluating CM24 in combination with nivolumab and standard chemotherapy as a second-line treatment vs chemotherapy alone in patients at least 18 years of age with solid tumors (part A) or histologically confirmed advanced metastatic PDAC (parts C and D).³

In parts C and D of the study, patients must have progressed on or after 1 standard first-line chemotherapy regimen in the metastatic setting, have at least 1 measurable lesion per RECIST 1.1 criteria with progressing or new tumors since last antitumor therapy, an ECOG performance status of 0 or 1, and stable brain metastases.

Upon enrollment, patients in parts C and D will receive intravenous CM24 and nivolumab followed by either gemcitabine/nab-paclitaxel or Nal-IRI/5-FU/LV. The respective primary end points in part C and D are safety and OS. Key secondary end points include maximum serum concentration, time of maximum concentration, area under the serum concentration curve, half life, drug clearance, volume of distribution, and serum antidrug-antibody parameters. Other end points included objective response rate, disease control rate, median duration of response, median time to response, progression-free survival, and OS—all when CM24 was used in comination with nivolumab.

A total of 63 patients have been enrolled onto the study across 18 centers in the United States, Spain, and Israel. In the current analysis, pre-dose biopsies and serum samples were collected from 26 and 30 patients in the overall population, respectively. As of May 2024, statistical analyses included receiver operating characteristic analysis to evaluate the predictive utility of each biomarker for outcomes with therapy as well as to define a tentative threshold for OS benefit.²

References

1. Purple Biotech reports additional positive interim data from its randomized Phase 2 study with its lead oncology therapeutic candidate CM24. News Release. Purple Biotech. September 18, 2024. Accessed September 19, 2024. https://www.globenewswire.com/news-release/2024/09/18/2948051/0/en/Purple-Biotech-Reports-Additional-Positive-Interim-Data-from-its-Randomized-Phase-2-Study-with-its-Lead-Oncology-Therapeutic-Candidate-CM24.html
2. Macarulla T, Cecchini M, Garcia-Carbonero R, et al. Biomarker results of the randomized Phase 2 of CM24 in combination with nivolumab and chemotherapy. Presented at the 2024 AACR Special Conference: Pancreatic Cancer; September 15-18, 2024; Boston, Massachusetts. Poster C005.
3. A study of CM24 in combination with nivolumab in adults with advanced solid tumors. ClinicalTrials.gov. Updated on June 7th, 2024. Accessed September 19, 2024. https://clinicaltrials.gov/study/NCT04731467