During the upcoming annual meeting American Society of Clinical Oncology (ASCO) in June 2019, Sanofi’s oncology franchise will present a renewed strategy to address difficult-to-treat and difficult-to-eradicate cancers, including certain types of multiple myeloma, skin cancer, breast cancer, and lung cancer.

Among the updated data to be presented is the latest data for a phase I trial with SAR408701.[1]

SAR408701 is an antibody-drug conjugate (ADC) which consists of anti-CEACAM5 antibody conjugated to the cytotoxic agent maytansinoid DM4, a chemical derivative of maytansine, a potent and selective cytotoxic agent with promising anticancer properties.

Upon administration of the anti-CEACAM5 antibody-drug conjugate, the antibody moiety targets CEACAM5 on tumor cells. Following antibody/antigen binding and internalization, the immunoconjugate releases the cytotoxic agent, which results in tumor cell death.

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The agent is currently being investigated in a phase I open-label, dose-escalation, dose-expansion trial and is estimated to enroll about 313 patients.[1]

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types, including non-squamous non-small cell lung cancer (NSQ NSCLC).

CEACAM5, a member of the CEA family of proteins that plays a key role in cell migration, cell invasion, and cell adhesion, is overexpressed by a variety of cancer cell types. Approximately 20% of lung cancers have a high expression of CEACAM5.

Trial Design
The phase I study investigated SAR408701 in patients with advanced solid tumors. During dose escalation, maximum tolerated dose (MTD) was 100 mg/m2 IV once every 2 weeks in 14-day cycles. Interim analysis of an ongoing expansion cohort in patients with non-squamous non-small cell lung cancer with CEACAM5 expression in ≥ 50% of the tumor cell population. [1]

The investigational drug was administered at the maximum tolerated dose.

The primary objective of the phase I study was overall response rate (ORR) in which researchers wanted to determine the maximum tolerated dose (MTD) administered as monotherapy once every 2 weeks (with and without a loading dose at Cycle 1) in patients with advanced solid tumors (the escalation phase) and to assess the efficacy of the investigational agent according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) (the expansion phase) when SAR408701 was administered once every 2 weeks with or without a loading dose at Cycle 1.

The secondary objectives included characterize the overall safety profile of SAR408701 and to characterize the pharmacokinetic (PK) profile of the trial drug and of its potential circulating derivatives. The secondary objectives of the study also included identification of the recommended phase 2 dose (RP2D) and assess the potential immunogenicity.  Tumor assessments were performed every 4 cycles (8 weeks).

Study Results
As of August 2, 2018, a total of 22 patients with a median age of 60 years of age ( male: 72.7%; ECOG PS (n = 21): 0 = 38.1%, 1 = 61.9%) diagnosed with non-squamous non-small cell lung cancer (21 adenocarcinoma; 1 not yet reported) received SAR408701 at the maximum tolerated dose level.

The median number of prior anticancer therapies for advanced disease was 3. A total of 66.7% (14/21) of participating patients received ≥ 3 lines with 59.1% of patients receiving prior anti-tubulin-based treatments.

The participating patients received a median of 6.5 cycles of SAR408701. Fifteen patients discontinued treatment due to progressive disease and 1 due to peripheral neuropathy, a commonly reported adverse event (AE). Six patients remain on study.

The overall response rate was estimated at 22.7% (5/22 pts; 90% CI 11.5–39.9); A total of 40.9% of the participating patients had stable disease.

Most frequently occurring all-grade treatment-emergent adverse events (TEAEs) included corneal events (40.9%; including keratitis 22.7% [1 Grade 3] and keratopathy 18.2%), dyspnea (31.8%; 5 Grade ≥ 3), asthenic conditions (31.8%) and diarrhea (27.3%).

Six patients required ≥ 1 dose modification due to a treatment-emergent adverse events . Pharmacokinetic analysis was performed in 14 patients at Cycle 1 and demonstrated mean Cmax, AUC, clearance and t1/2z were 53.1 µg/mL, 297 µg.day/mL, 0.685 L/day and 6.19 days, respectively.

In patients with non-squamous non-small cell lung cancer and CEACAM5 expression in ≥ 50% of tumor cells, SAR408701 had a favorable safety profile. Interim analysis of 22 patients achieved the predefined boundary for efficacy (≥ 4 of 30 patients).

According to the researchers, these data support further development in non-squamous non-small cell lung cancer.

[1] Evaluation of SAR408701 in Patients With Advanced Solid Tumors – NCT02187848
[2] Gazzah A, Cousin S, Boni V, Ricordel C, Kim TM, Kim JS, Helissey C, Gardeazabal I, Chadjaa M, et al. First-in-human Phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) (Poster Display #395, Sunday, June 2, 8:00-11:00 AM. J Clin Oncol 37, 2019 (suppl; abstract 9072)

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