Abstract B237: Clinical experience of IMGN901 (BB-10901, huN901-DM1) in patients with Merkel cell carcinoma (MCC)

Abstract

Background: MCC is a neuroendocrine cancer of the skin that predominantly occurs in older individuals of northern European ancestry. While localized disease can often be treated with surgery and radiation therapy, there is a need for effective, well-tolerated chemotherapeutic options for patients with progressive or metastatic disease. Among patients with metastatic MCC, overall 5-year survival rate is 11% and median survival is in the range of 7 to 9 months. To date, no chemotherapeutic agent has been able to demonstrate a significant improvement in survival. Toxicity also is a major concern with these older patients. IMGN901 is a novel CD56-targeting anticancer agent. CD56 is expressed on virtually all MCC tumors. IMGN901 consists of a potent maytansinoid cytotoxic agent, DM1, attached to a CD56-binding monoclonal antibody, huN901, using an engineered linker. Once bound to CD56, IMGN901 is internalized into the cancer cell and the DM1 is released to kill the cell via inhibition of the polymerization of tubulin. Objective: Study 002 is an ongoing phase I trial established to determine the maximum tolerated dose (MTD), pharmacokinetics (PK) and activity of IMGN901 in patients with CD56-expressing solid tumors, including patients with MCC. Methods: IMGN901 is administered intravenously as monotherapy daily for 3 consecutive days every 3 weeks. Results: Six patients with MCC have been enrolled in Study 002 in addition to patients with other types of CD56+ solid tumors. Clinical benefit has been observed in 3 of these 6 patients including one complete response (CR), one partial response (PR) and one stable disease (SD). The patient who experienced a CR has remained disease free for more than 4 years. The patient who experienced a PR received 1 cycle of IMGN901 treatment, but had a serious adverse event and declined further treatment. This patient had sustained clinical benefit for more than 5 months, including additional tumor shrinkage. The patient who experienced SD entered Study 002 with bone metastases and had received 3 prior therapies. This patient had SD lasting approximately 3 months. Overall, a clinical benefit rate (CR+PR+SD) of 50% has been observed. The 6 MCC patients received IMGN901 at doses ranging from 36 to 75 mg/m2/day. The MTD of IMGN901 has not been defined in Study 002 and a dose level of 94 mg/m2/day will be evaluated next. Earlier this year, we reported pooled data from two studies in CD56+ solid tumors summarizing the encouraging experience with IMGN901 for the treatment of small-cell lung cancer (SCLC). SCLC and MCC have shared morphologic characteristics and a common clinical course. Conclusion: There are encouraging findings to date with IMGN901 for the treatment of MCC. The findings are supportive of the initial findings with the compound for the treatment of SCLC and vice versa. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B237.

Investigational antibody drug conjugates for solid tumors

“…In three of six patients with metastatic Merkel cell carcinoma (mMCC), clinical responses were seen which consisted of one durable CR (> = 4 years in remission), one durable partial response (PR) and stable disease [56]. Further, two PRs (1 unconfirmed) and 15 patients with clinically meaningful stable disease were noted from the 68 patients with SCLC from among the 113 total patients treated in the two Phase I solid tumor trials [56][57][58]. The acceptable safety profile and encouraging clinical activity in solid tumors warrants further investigation of this agent.…”

Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program

“…IMGN901 is an ADC that combines the pharmacological potency of the maytansinoid DM1 with the specificity of an anti‐CD56 monoclonal antibody. IMGN901 has demonstrated activity in early phase adult clinical trials against CD56 positive malignancies such as Merkel cell carcinoma and SCLC . Although CD56 is expressed in some normal tissues, localization of the highly potent cytotoxic payload to the CD56 antigen has been sufficient to reduce the systemic toxicities expected with a potent inhibitor of tubulin polymerization including nausea, diarrhea, and neuropathy .…”

Mechanisms of action of therapeutic antibodies for cancer

“…Lorvotuzumab mertansine is a humanized IgG1 targeting CD56 conjugated to DM1 that received FDA orphan status approval for treatment of Merkel-cell carcinoma in light of early evidence of its activity in that rare malignancy[274]. However, its potential as treatment for a broad range of malignancies is also promising.…”