Biomarker analysis from a Phase 1/1b study of tusamitamab ravtansine in patients with advanced non-small cell lung cancer
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Anas Gazzah1, Nils Ternès2, Joon Sang Lee3
1Drug Development Department, Gustave Roussy, Villejuif, France.
Background:
Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.
Methods:
We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (n=64) and ME (n=28). Patients received tusamitamab ravtansine 100 mg/m2 intravenously every 2 weeks.
Results:
cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1-8809] versus 12.4 µg/L [0.5-684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (P = 0.0027). EGFR and KRAS alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively.
Conclusions:
In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers.
Clinical Trial Registration:
NCT02187848.
Insights
Tusamitamab ravtansine showed antitumor activity in non-small cell lung cancer. High circulating CEA levels in patients with high CEACAM5 expression correlated with a greater objective response rate (ORR).
Area of Science:
- Oncology
- Medical Biomarkers
- Pharmacology
Background:
- Tusamitamab ravtansine demonstrated antitumor activity in advanced non-squamous non-small cell lung cancer (NSCLC) with high (HE) or moderate (ME) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression.
- The study explored CEACAM5 expression, biomarker associations, and their predictive value for objective response rate (ORR).
Purpose of the Study:
- To evaluate the association between CEACAM5 expression, circulating biomarkers (cCEA, cCEACAM5), and their correlation with the objective response rate (ORR) to tusamitamab ravtansine in advanced NSCLC.
- To investigate the relationship between CEACAM5 expression and oncogenic drivers in NSCLC patients.
Main Methods:
- Patients with HE (n=64) or ME (n=28) CEACAM5 expression received tusamitamab ravtansine 100 mg/m² intravenously every 2 weeks.
- Assessed CEACAM5, circulating CEACAM5 (cCEACAM5), and circulating CEA (cCEA) using immunohistochemistry (IHC) and blood samples.
- Analyzed associations between biomarkers and ORR, and investigated EGFR/KRAS alterations.
Main Results:
- Strong association between cCEA and cCEACAM5 (ρ=0.99); moderate associations between IHC CEACAM5 and cCEA/cCEACAM5 (ρ=0.43/0.38).
- In HE patients, ORR was higher with high cCEA (≥100 µg/L) (41.7%) compared to low cCEA (8.1%).
- Elevated CEACAM5 mRNA in HE vs. ME (P=0.0027); EGFR/KRAS alterations differed between HE and ME groups.
Conclusions:
- In CEACAM5 HE NSCLC, high cCEA correlated with a greater ORR to tusamitamab ravtansine.
- Observed associations between various CEACAM5-related biomarkers (IHC, mRNA, circulating) but not with oncogenic drivers.
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