An interim analysis of a mid-stage clinical study showed that labetuzumab govitecan, also known as  (IMMU-130)a novel antibody-drug conjugates or ADC being developed by clinical-stage biopharmaceutical company Immunomedics, produced encouraging survival results in patients previously treated with at least one prior irinotecan-containing regimen for their metastatic colorectal cancer (mCRC).[1]

For decades, 5-fluorouracil (FU)/5-FU was the sole active agent for the treatment of advanced or metastatic colorectal cancer.

With the approval of irinotecan (Camptosar®; Pfizer), oxaliplatin (Eloxatin®; Sanofi) the humanized monoclonal antibody bevacizumab (Avastin®; Genentech/Roche) designed to target vascular endothelial growth factor or VEGF as well as cetuximab (Erbitux®; ImClone/Eli Lilly and Bristol-Myers Squibb/BMS) and panitumumab (Vectibix®; Amgen Oncology) targeting the epidermal growth factor receptors or EGFRs, more treatment options became available, improving the outcomes for many patients. However, there still remained an urgent need for better therapies to control this disease.*

Clinical trial
For the 33 patients participating in a clinical trial who received labetuzumab govitecan at the 8 or 10 mg/kg dose levels, the interim median progression-free survival (PFS), a measure of the length of time the patient is living without their disease getting worse from the beginning of their treatments, was 4.4 months, with 22% of these patients still benefiting from their cancer not progressing.

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“Compared to what has been reported in the medical literature,this result is very encouraging for patients with mCRC,” commented Efrat Dotan, MD, Fox Chase Cancer Center, Philadelphia, PA, who presented a multicenter study at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) as one of the Principal Investigators. [2][3]

In terms of treatment response, in 32 patients with at least one evaluation following treatments with labetuzumab govitecan at the 8 or 10 mg/kg level, 1 patient had a partial response and 24 patients reported stable disease as their best response, to give a combined disease control rate of 78%. Treatment response was evaluated in accordance with the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1) using computed tomography as the imaging tool for tumor size measurements.

Well tolerated
In clinical trials Labetuzumab govitecan was well tolerated by a majority of patients. At the optimal once-a-week doses of 8 and 10 mg/kg, grades 3 and 4 adverse events with occurrence of 5% or more included neutropenia (5% for both dose levels), and mild diarrhea (5% in the 8 mg/kg group only). Despite repeated dosing, no antibody against labetuzumab or its SN-38 conjugate was detected in blood samples from 74 patients over a 16-month period.

At the time of analysis, 87 patients have been enrolled to receive the ADC in the first 2 weeks of a 21-day cycle. In addition to the 8 and 10 mg/kg once-weekly dose, other dosing levels and schedule evaluated included 4, 6, 9, and 12 mg/kg, each at a frequency of twice a week.

“We have chosen the once-a-week dose of 10 mg/kg for future studies,” noted Cynthia L. Sullivan, President and Chief Executive Officer of Immunomedics. “At this year’s ASCO conference, we have met with key opinion leaders in colorectal cancer to discuss the future development plan for labetuzumab govitecan, either as a standalone therapy or in combination with other treatment regimes,” Sullivan added.

A moderate toxic drug
Researchers at Immunomedics created labetuzumab govitecan by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to labetuzumab, a humanized antibody that recognizes the carcinoembryonic antigen (CEA; CEACAM5 or CD66e) expressed in many solid cancers, including more than 90% of colorectal cancer. SN-38 is the active metabolite of irinotecan, which is used to treat certain solid cancers, particularly metastatic colorectal cancers, as a part of combination therapies, so its pharmacology and properties are well-known and understood.

Note: More recently intravenous aflibercept, a fully-humanized recombinant fusion protein consisting of vascular endothelial growth factor (VEGF) binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, and regorafenib, an orally active inhibitor of angiogenic (including the VEGF receptors 1 to 3), stromal, and oncogenic kinases have become available for the treatment of patients with mCRC. Additionally, orally active fluoropyrimidines (capecitabine, S-1, UFT) are also available.


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