CEACAM5 Shows Great Potential as Therapeutic Target in NSCLC

Paul Bunn, MD

Research examining novel treatment options for patients with non–small cell lung cancer (NSCLC) actionable mutations has drastically expanded the treatment landscape for smaller subsets of patients. Soon that may include those with carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5)-expressing tumors. The target has recently displayed great potential for investigators as a therapeutic target.

CEACAM5 is a cell surface glycoprotein that is not highly expressed in several normal tissues, including colon, esophagus, and head and neck. However, the protein is often highly expressed in a few tumor types, such as gastrointestinal, breast, and lung. Approximately 20% of patients with NSCLC exhibit overexpression of CEACAM5.^1,2

“[CEACAM5] is expressed primarily on adenocarcinomas but does have some expression in squamous tumors, as well,” Paul Bunn, MD, the James Dudley Chair in Cancer Research and a distinguished professor of medicine–medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, said during an OncLive^® scientific interchange and workshop. “This antigen is associated with tumor progression. It promotes cell proliferation and migration. It is expressed much more in lung tumors than in normal lung [tissue]. Therefore, it is amenable to development of antibody-drug conjugates [ADCs].”

Investigators have reported that high CEACAM5 expression may be associated with cell proliferation and migration.³ CEACAM5 can be detected using immunohistochemical (IHC) assays. Positive staining has been defined as any partial or complete tumor cell plasma membrane staining at a minimum of 2+ intensity.⁴ The definition is being used for patient selection and stratification in ongoing phase 2 and phase 3 clinical trials of the potential first-in-class CEACAM5-targeted agent tusamitamab ravtansine (formerly SAR408701).

Novel CEACAM5-Targeted Agent Displays Promising Early Regulst in NSCLC

Tusamitamab ravtansine is an ADC consisting of a humanized monoclonal antibody and a cytotoxic maytansinoid, DM4. The monoclonal antibody binds to CEACAM5 and the maytansinoid targets CEACAM5-expressing tumor cells. In preclinical studies, the agent was proven to selectively bind to CEACAM5 in human tissue and displayed cytotoxic activity, leading investigators to tab it as a promising candidate for the development as a treatment option for patients with CEACAM5positive tumors.^1,3

“This drug in preclinical models has had very good efficacy,” Bunn said. “Tumor reduction—not only tumor stasis, but actually reduction in tumor size—[was observed] in this in vivo animal model.”

Tusamitamab ravtansine is under investigation in patients with solid tumors in a phase 1/2 trial (NCT02187848). Eligible adult patients must have locally advanced/metastatic solid tumors that expressed or are likely to express CEACAM5 and have an ECOG performance status of 1 or less.

In the dose-escalation phase 1 portion of the trial, 31 patients received tusamitamab ravtansine at doses ranging from 5 to 150 mg/m², given every 2 weeks intravenously (IV). The dose-limiting toxicity of reversible grade 3 microcystic keratopathy was reported in 3 of the 8 patients who received tusamitamab ravtansine 120 mg/m² and in 2 of the 3 patients who were treated at 150 mg/m2. Investigators determined the maximum tolerated dose (MTD) of tusamitamab ravtansine to be 100 mg/m² IV every 2 weeks.¹

As of January 2020, ninety-two patients were treated at the MTD in the nonsquamous NSCLC cohort of the trial. Twenty-eight of these patients were moderate expressors of CEACAM5 (IHC ≥ 2+ on 1%-50% of tumor cells) and 64 were high expressors (IHC ≥ 2+ on ≥ 50% of tumor cells). The median age of the treated patients was 62.5 years (range, 31-91) and the median number of prior lines of therapy for advanced disease was 3 (range, 1-10). Most patients were men (51.1%) and most had an ECOG performance status of 1 (71.7%).⁵

Findings from the trial showed that the overall response rate (ORR) among moderate expressors was 7.1% (95% CI, 1.98%-22.65%), with all responses being confirmed partial responses (PRs). Additionally, 53.6% of patients experienced stable disease (SD), the disease control rate (DCR) was 60.7%, and 35.7% had progressive disease (PD). One patient in this subgroup was not evaluable (NE) at the time of the analysis.

Comparatively, patients in the high-expressor cohort achieved an ORR of 20.3% (95% CI, 12.27%-31.71%), with all responses being PRs again. Patients in this subgroup experienced SD at a rate of 43.8%, a DCR of 64.1%, and 32.8% had PD. Two patients were NE.

In the overall nonsquamous NSCLC cohort, the most common treatment-emergent adverse effects (TEAEs) were asthenia (38.0%), keratopathy/ keratitis (38.0%), peripheral neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%). Common hematologic toxicities included leukopenia (14.4%), thrombocytopenia (13.3%), and neutropenia (4.4%). Dose modifications due to TEAEs occurred in 33.7% of patients, 10.9% of which were associated with keratopathy/keratitis. Grade 3 or greater TEAEs were reported in a little less than half of patients (47.8%).

Corneal TEAEs leading to dose modification occurred in 27.2% of patients. Ten of these patients experienced at least 1 dose reduction and 1 patient was forced to discontinue treatment. The median time to recovery from this type of TEAE was 18.5 days (range, 2-82). “This keratitis is most likely due to the DM4,” Bunn said. “There are noninflammatory deposits at the cornea. Usually, it did not occur in the first couple cycles, but at cycle 4, this seemed to be manageable with dose delay and dose reduction. It does take a couple weeks for it to go away, so dose delay was very frequent. This is not something where prophylaxis works, but if [a patient] gets it, a treatment with topical steroids is recommended.”

Additional data from the phase 1/2 trial encompassing patients treated over a long term were presented at the 2022 American Society of Clinical Oncology Annual Meeting. In this analysis, the study authors focused on patients who had undergone treatment with tusamitamab ravtansine for at least 12 months as of December 2021.⁶

Findings showed that 24 patients were treated for at least 6 months, 15 patients for at least 9 months, 11 patients for at least 12 months, 6 patients for at least 24 months, and 2 patients for at least 42 months (FIGURE).⁶ Five patients remained on treatment at the data cutoff, 1 of whom has remained on treatment for over 52 months. Among patients who were treated for at least a year, the median duration of treatment was 26.6 months (range, 12.1-45.3).

Patients in this cohort had a median age of 61 years (range, 41-91) and 81% had high CEACAM5 expression. The median number of prior regiments for advanced disease was 2 (range, 1-6), with 54.5% of patients having received prior anti–PD-1/PD-L1 therapy and 45.5% having received antitubulin therapy.⁶

Of the patients who experienced a PR in the January 2020 analysis (n = 15), PR was still reported in 67% of patients who were treated for at least 6 months, 53% of patients who were treated for at least 9 months, and 47% of patients who were treated for at least a year. Additionally, patients who were treated for at least a year had better ECOG performance status and underwent fewer prior treatment regimens compared with the overall group. PR was also found to occur regardless of CEACAM5 expression level in patients who received tusamitamab ravtansine for at least a year.

In terms of safety, investigators noted that only 1 patient who was treated for at least 12 months was forced to discontinue treatment due to a TEAE, which was breast cancer. The most common TEAEs were corneal events; any-grade corneal TEAEs occurred in 73% of patients with 36% of these being grade 3 or greater. Treatment was delayed or the dose was reduced in 7 patients and no corneal TEAEs were deemed serious or led to treatment discontinuation.

Investigators concluded that heavily pretreated patients exhibited a durable and frequently sustained response to treatment with tusamitamab ravtansine. They also concluded that further clinical development of the agent is therefore warranted.

A Multitude of Tusamitamab Ravtansine Trials Are Now Underway

In response to the positive findings among patients with NSCLC and increased CEACAM5 expression who were treated with tusamitamab ravtansine, multiple clinical trials are actively recruiting to further examine the safety and efficacy of the agent. These include the phase 3 CARMEN-LC03 trial (NCT04154956), the phase 2 CARMEN-LC04 trial (NCT04394624), and the phase 2 CARMEN-LC05 trial (NCT04524689).

In CARMEN-LC03, approximately 554 patients with nonsquamous NSCLC and a CEACAM5 expression of at least 2+ in a minimum of 50% of tumor cells will be randomly assigned 1:1 to receive either tusamitamab ravtansine or the standard-of-care docetaxel. Patients in the tusamitamab ravtansine arm will receive the agent at a dose of 100 mg/m² IV every 2 weeks and docetaxel will be given at a dose of 75 mg/m² IV every 3 weeks.²

The primary end points of the study are progression-free survival (PFS) by RECIST 1.1 criteria as assessed by an independent blinded review committee and overall survival. Secondary end points include ORR, duration of response, health-related quality of life, and safety.

CARMEN-LC04 will examine tusamitamab ravtansine in combination with monoclonal antibody ramucirumab (Cyramza) in approximately 36 pretreated patients with nonsquamous NSCLC with high CEACAM5 expression. Ramucirumab will be given IV prior to the IV administration of tusamitamab ravtansine every 2 weeks.⁷

The primary outcome in the safety run-in (part 1) will be to assess the tolerability of the combination and confirm the recommended dose of tusamitamab ravtansine when it is given with ramucirumab. Part 2 will evaluate the antitumor activity of the combination, as well as safety, durability of response, PFS, pharmacokinetic profile, and immunogenicity.

Finally, CARMEN-LC05 will enroll approximately 96 patients with nonsquamous NSCLC with high CEACAM5 expression. Patients will be sorted into 1 of 4 experimental arms: (1) tusamitamab ravtansine plus pembrolizumab (Keytruda), (2) tusamitamab ravtansine plus pembrolizumab plus carboplatin, (3) tusamitamab ravtansine plus pembrolizumab plus cisplatin, or (4) tusamitamab ravtansine plus pembrolizumab plus carboplatin plus pemetrexed.⁸

The primary objective of the trial is to assess each combination’s tolerability and to determine the recommended dose of tusamitamab ravtansine in each combination. Secondary objectives include evaluating the safety, antitumor activity, pharmacokinetics, and immunogenicity of each combination.

References

1. Gazzah A, Bedard PL, Hierro C, et al. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. Ann Oncol. 2022;33(4):416-425. doi:10.1016/j.annonc.2021.12.012
2. Johnson ML, Chadjaa M, Yoruk S, Besse B. Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. J Clin Oncol. 2020;38(suppl 15):TPS9625. doi:10.1200/JCO.2020.38.15_suppl. TPS9625
3. Decary S, Berne PF, Nicolazzi C, et al. Preclinical activity of SAR408701: a novel anti-CEACAM5-maytansinoid antibody-drug conjugate for the treatment of CEACAM5-positive epithelial tumors. Clin Cancer Res. 2020;26(24):6589-6599. doi:10.1158/1078-0432. CCR-19-4051
4. LaPointe N, Hertle N, Hsu SC, et al. Validation of an immunohistochemical assay, CEACAM5 IHC 769, under development for use with the antibody-drug conjugate tusamitamab ravtansine (SAR408701). J Clin Oncol. 2021;39(suppl 15):e21030. doi:10.1200/ JCO.2021.39.15_suppl.e21030
5. Gazzah A, Ricordel C, Cousin S, et al. Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). J Clin Oncol. 2020;38(suppl 15):9505. doi:10.1200/ JCO.2020.38.15_suppl.9505
6. Ricordel C, Barlesi F, Cousin S, et al. Safety and efficacy of tusamitamab ravtansine (SAR408701) in long-term treated patients with nonsquamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). J Clin Oncol. 2022;40(suppl 16):9039. doi:10.1200/ JCO.2022.40.16_suppl.9039
7. SAR408701 in combination with ramucirumab in pre-treated patients with non squamous non-small cell lung cancer (NSQ NSCLC) (CARMEN-LC04). ClinicalTrials.gov. Updated May 12, 2022. Accessed August 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04394624
8. Tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed in patients with NSQ NSCLC (CARMEN-LC05) (CARMEN-LC05). ClinicalTrials.gov. Updated August 12, 2022. Accessed August 15, 2022. https://clinicaltrials.gov/ct2/show/ NCT04524689

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