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ADCs Targeting CEACAM5 in NSCLC
The Potential of Antibody‒Drug Conjugates Targeting CEACAM5 in NSCLC

Released: June 30, 2023

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Key Takeaways
  • CEACAM5 is an emerging biomarker with targeted therapies including an antibody‒drug conjugate currently under investigation in nonsquamous NSCLC.
  • Corneal toxicity—particularly keratopathy/keratitis—is a notable adverse event associated with tusamitamab ravtansine, an investigational antibody‒drug targeting CEACAM5 that has shown preliminary evidence of efficacy in patients with advanced NSCLC.

It is critical that patients with advanced non-small-cell lung cancer (NSCLC) undergo molecular testing to identify the presence of actionable biomarkers. Advances over the past decade have led to a range of therapeutic approvals for patients with targetable alterations in ALK, ROS1, BRAFV600E, NTRK, RET, METex14, KRASG12C, EGFR (including del19/L858R and exon 20ins), and HER2mut. Emerging biomarkers include CEACAM5, with antibody‒drug conjugates (ADCs) targeting this protein currently under investigation.

What is CEACAM5, and how is it measured?
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a protein that is overexpressed in multiple tumor types, including nonsquamous NSCLC. CEA interactions promote tumor progression and metastasis. The best and most likely simplest way to measure CEACAM5 expression is via immunohistochemistry. Because agents targeting CEACAM5 are currently investigational, routine testing for CEACAM5 is not recommended at present.

What data currently support CEACAM5 as a therapeutic target in NSCLC?
Tusamitamab ravtansine is an ADC that binds CEACAM5 to deliver a maytansinoid cytotoxic payload that has been studied in patients with advanced solid tumors, including NSCLC. A phase II expansion trial of tusamitamab ravtansine at a dose of 100 mg/m2 every 2 weeks included patients with nonsquamous NSCLC: 64 with high (≥2+ in ≥50% of tumor cells) and 28 with moderate (≥2+ in ≥1% and <50% of tumor cells) CEACAM5 expression by immunohistochemistry. The primary endpoint of overall response rate was most promising (20.3%) in those with high expression of CEACAM5, as was the duration of response (5.6 months).

The phase II CARMEN-LC05 trial (N = 25) evaluated tusamitamab ravtansine in combination with pembrolizumab with or without platinum-based chemotherapy in patients with advanced NSCLC, any PD-L1, moderate/high CEACAM5 expression, and no prior immune checkpoint inhibitor therapy. Overall, 13 patients had partial responses. The response rate was 36% in high expressors of CEACAM5 vs 20% in moderate expressors. As these are early data, we must be cautious pending duration of response and progression-free survival to confirm the magnitude of benefit and the role of this combination in the first-line treatment of advanced nonsquamous NSCLC.

What are the most notable adverse events (AEs) with ADCs targeting CEACAM5?
Among the NSCLC cohorts including moderate and high expressors of CEACAM5 within the phase I expansion trial, the tolerability profile was generally favorable, with primarily grade 1/2 toxicities. The most significant treatment-emergent AEs (TEAEs) were corneal, with all-grade keratopathy/keratitis affecting 38.0% of patients and grade ≥3 occurring in 10.9%. Ocular events are related to the DM4 payload of tusamitamab ravtansine and are reversible noninflammatory deposits starting at the periphery of the cornea. The first occurrence was noted within the initial 4 cycles of treatment for 28 patients (80%). It was manageable with dose delay and/or dose reduction, with a median time to recovery of 18.5 days. Similar findings were reported recently from a pooled analysis with 186 patients with lung and gastrointestinal malignancies receiving every-2-week dosing, with corneal TEAEs affecting 56 patients (30.1%) and grade 3 occurring in 16 (8.6%). Again, most events occurred within the initial 4 cycles, were manageable with dose delay and/or reduction, and resolved with a median time to recovery of 20.5 days.

Primary prophylaxis is not effective for corneal toxicity; treatment with topical ophthalmologic corticosteroids when it occurs is recommended. Therapy may be continued for grade 1 toxicity but must be discontinued for grade ≥3. In my experience, dose reducing is effective at improving tolerability and mitigating corneal toxicity.

In the CARMEN-LC05 study, the most frequent TEAEs were nausea (44%), diarrhea (36%), and asthenia (32%). Grade ≥3 TEAEs were observed in 68.0% of patients, and grade 5 events occurred in 16.0%. Corneal TEAEs of any grade were reported in 24.0% of patients and were manageable with dose modification.

What is the potential future role of investigational ADCs targeting CEACAM5 in nonsquamous NSCLC?
Looking at the data thus far in nonsquamous NSCLC, tusamitamab ravtansine appears to have the greatest benefit in those with high expression of CEACAM5. The optimal setting and potential combinations are yet to be determined. We await data from the confirmatory phase III CARMEN-LC03 trial (NCT04154956) to determine a potential role in the second-line setting, which is evaluating tusamitamab ravtansine vs docetaxel in patients with metastatic nonsquamous NSCLC and high expression of CEACAM5 following previous treatment with platinum-based chemotherapy and an immune checkpoint inhibitor. Ongoing phase II studies with tusamitamab ravtansine include in combination with pembrolizumab (NCT04524689) or ramucirumab (NCT04394624).

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