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Antibody drug conjugate shows promise for metastatic colorectal cancer
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Labetuzumab govitecan monotherapy appeared safe and demonstrated activity in heavily pretreated patients with metastatic colorectal cancer, according to phase 1/phase 2 study results published in Journal of Clinical Oncology.
Labetuzumab govitecan (IMMU-130, Immunomedics) is a slowly internalizing humanized antibody designed to target carcinoembryonic antigen (CEA)-related cell adhesion molecule 5, which is expressed on many solid cancers.
“We developed labetuzumab govitecan, an antibody drug conjugate that uses a proprietary linker to site-specifically couple SN-38 to labetuzumab,” Efrat Dotan, MD, director of the hematology/oncology fellowship training program at Fox Chase Cancer Center, and colleagues wrote. “This results in the delivery of much higher amounts of active SN-38 to tumors than systemic irinotecan, while producing lower serum levels of glucuronidated SN-38 potentially reducing the occurrence of diarrhea.”
A phase 1 study of labetuzumab govitecan showed doses given every 14 days induced disease stabilization among patients with metastatic colorectal cancer who had been treated previously with an irinotecan-based regimen. Preclinical studies suggested that more frequent dosing may be more effective.
Dotan and colleagues conducted the open-label, multicenter phase 1/phase 2 trial to evaluate two intensified dosing regimens in 86 heavily pretreated patients with relapsed or refractory metastatic colorectal cancer who received at least one line of an irinotecan-containing regimen.
Patients received labetuzumab govitecan twice weekly at a dose level of 4 mg/kg (n = 23) or 6 mg/kg (n = 20), or once weekly at a dose level of 8 mg/kg (n = 21) or 10 mg/kg (n = 22).
Safety and tolerability of the dosing schedules served as the primary endpoint. Secondary endpoints included efficacy, pharmacokinetics and immunogenicity.
The most frequent adverse events included nausea, fatigue, vomiting and diarrhea. The most common severe adverse events included neutropenia (16%), leukopenia (11%), anemia (9%) and diarrhea (7%).
Toxicity events appeared similar between the four dosing cohorts.
Of the 72 patients with CT-assessable responses, 38% demonstrated tumor reductions from baseline to posttreatment, including one patient who achieved a partial response with a sustained response spanning more than 2.7 years.
Forty-two patients showed stable disease as best overall response. Twenty-nine patients had disease progression at the first postbaseline assessment.
In addition, 38% of 66 patients with elevated plasma CEA levels who underwent sequential CT scans demonstrated reductions in their posttreatment serum levels.
Twenty-four patients had stable disease for at least 4 months for a clinical benefit rate of 29%.
Among all 86 patients, median PFS was 3.6 months (95% CI, 2-4), which included three patients who were progression free for at least 1 year. Median OS was 6.9 months (95% CI, 5.7-7.8), including three patients who survived for at least 2 years.
Exploratory analyses found plasma CEA levels predicted improved PFS and OS; however, this association did not exist with tumor size or KRAS status.
Of the 14 patients with pharmacokinetics profiles, the mean half-life of labetuzumab govitecan appeared to last 16.5 ± 4 hours.
Residual labetuzumab in the serum at the time of the second dose increased peak labetuzumab levels by approximately 42% among patients treated biweekly. Peak levels only increased by approximately 20% among patients treated once weekly.
The researchers evaluated 460 samples for antibody responses against labetuzumab and SN-38; all samples were negative for antibodies to both.
“These initial results suggest that additional study of this agent in combination with other therapies would be appropriate, especially because preclinical studies indicated that its combination with bevacizumab (Avastin, Genentech) is effective,” Dotan and colleagues wrote.
Aside from the convenience of dosing less often, the researchers found no loss of activity with once-weekly dosing or increased safety concern with twice-weekly dosing. The researchers chose the two once-weekly dose schedules for further study to define the optimal dose.
“Additional clinical studies, especially those in which labetuzumab govitecan is combined with other agents (eg, replacing irinotecan FOLFOXIRI), are warranted,” they added. – by Kristie L. Kahl
Disclosures: Dotan reports research funding from Bayer AG, Biocompatibles, OncoMed Pharmaceuticals and Pfizer. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
Back to TopDeepa R. Magge
Metastatic colorectal cancer portends a poor prognosis and is the main determinant of patient survival in solid tumor metastases. In colorectal cancer — of which 160,000 cases occur annually in the United States — the liver is the sole or dominant site of metastases in 15% to 20% of patients. Only 10% to 20% of this subgroup reaps the benefits of surgical “cure” (5-year OS, up to 58%) when disease is resectable.
For unresectable colorectal cancer liver metastases, first-line systemic chemotherapy can yield response rates of up to 70% — with a median OS of up to 2 years — and may convert patients to resectable status in up to 38% of cases. Its use in the salvage setting, however, yields poor results with reported response rates of 4% to 28% and survival of less than 13 months. This worsens with third- and fourth-line therapy.
On the other side of the coin, 10% of patients with metastatic colorectal disease have evidence of peritoneal disease at time of diagnosis. Among those patients with metachronous disease, peritoneal carcinomatosis is the sole evidence of disease in 25% of the cohort. Unfortunately, peritoneal carcinomatosis from colorectal cancer can represent a terminal event. There are locoregional options in the management of both isolated hepatic metastases or peritoneal carcinomatosis including isolated hepatic perfusion and cytoreductive surgery/hyperthermic intraperitoneal chemotherapy. However, the majority of patients present when these options are precluded. More treatment options are necessary to treat patients with metastatic colorectal cancer, and the phase 1/phase 2 trial examining the safety and efficacy of labetuzumab in this setting is showing promising results.
However, the results are somewhat limited. Only one patient had a partial response according to RECIST criteria, but the agent appeared to induce stable disease. The majority of patients included in the study had already received a median of five prior lines of therapy, and labetuzumab was used as a last-line agent.
Given the safety profile of the agent, I believe the next step would be to use this antibody in combination with other effective agents, such as FOLFOX or as an earlier line of therapy to determine whether it offers added benefit when not encountering end-stage disease. The CEA-related cell adhesion molecule 5 antigen is present in more than 85% of patients with colorectal cancers. Therefore, using the targeted antibody earlier in the patient’s disease course may be helpful. New agents are needed to improve OS and PFS among patients with advanced metastatic colorectal cancer, and clinical trials offer the most potential in treatment development.
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