Sacituzumab govitecan also known as IMMU-132, an antibody-drug conjugate being developed by Immunomedics, a clinical-stage biopharmaceutical company, continues to produce durable responses in patients with metastatic lung cancer who had relapsed or were refractory to their last cancer therapy.
Sacituzumab govitecan is a first-in-class antibody-drug conjugate in which the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody (DAR= 7.6), is conjugated to a humanized monoclonal antibody that targets the TROP-2 receptor which is widely expressed in most epithelial cancers, including non-small and small-cell lung cancers (NSCLC and SCLC).
SN-38 is the active metabolite of irinotecan (Camptosar®; Pfizer), which is used as a first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum and in the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Being part of existing combination therapies, the pharmacology and properties of the active compound irinotecan are well-known.
Both in vitro and in vivo preclinical data suggest that sacituzumab govitecan delivers up to 136-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft.
Highly tolerable
In addition to durable responses, repeated cycles of sacituzumab govitecan monotherapy are well tolerated. Sacituzumab govitecan also continues to demonstrate a highly tolerable and easily managed toxicity profile.
Objective response rate (ORR) and progression-free survival (PFS) data in previously-treated metastatic lung cancer (5.4 months in NSCLC) are encouraging and warrant further evaluation of IMMU-132 in these lung cancers.
In one study in which 31 lung cancer patients received sacituzumab govitecan at the dose of 10 mg/kg, the major toxicity reported was 10% Grades 3 and 4 neutropenia. Remarkably, there was no reported incidence of Grade 3 or 4 diarrhea, which is a major side effect with irinotecan. At 10 mg/kg 13% of lung cancer patients required a dose reduction in sacituzumab govitecan.
Clinical Trial
At the time of the interim analysis of the Phase II data, a total of 57 patients with metastatic lung cancer (28 non-small-cell lung cancer (NSCLC) and 29 small-cell lung cancer (SCLC)) had been enrolled into this multicenter study at doses ranging from 8-18 mg/kg given on days 1 and 8 every 21 days. The median number of prior lines of therapy in the NSCLC and SCLC patients was 3 and 2.5, respectively. Across all tumor types, 12 mg/kg was declared the maximal tolerated dose and 10 mg/kg declared the recommended Phase II dose. Accrual at 10 mg/kg continues. [2]
Treatment response in lung cancer patients administered doses of ≤12 mg/kg was assessed by computed tomography using the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1).
Response
In NSCLC, the most common type of lung cancer, 6 of 19 patients achieved an objective response (ORR = 32%). In SCLC, 6 of 20 patients achieved an objective response (ORR = 30%). In the 10 mg/kg cohorts, the objective response (partial response) rates in NSCLC and SCLC were 3/10 (30%) and 3/5 (60%), respectively.
In NSCLC, the interim median progression-free survival (PFS), which is the length of time patients are living without their cancer progressing, was 5.4 months for those patients receiving sacituzumab govitecan at the dose level of 10 mg/kg. At the time of analysis, fifty-six percent of NSCLC patients in this dose group had experienced a PFS event. For patients with SCLC, interim median PFS was 4.6 months at the 10 mg/kg dose level. At the time of analysis, eighty- three percent of SCLC patients in this dose group had experienced a PFS event. Overall survival (OS) data were too early to report.
Early compelling results
“These results, while still early, seem to show noticeable activity of this drug in a heavily pretreated lung cancer population,” commented D. Ross Camidge, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, who presented these data in an Oral Session at the 16th World Conference on Lung Cancer (WCLC) being held September 6 – 9, 2015 [1]
“Based on these compelling results, we consider both NSCLC and SCLC to be of primary interest, along with triple-negative breast, esophageal, urothelial, and colorectal cancers, for further study with sacituzumab govitecan,” remarked Cynthia L. Sullivan, President and Chief Executive Officer of Immunomedics. “Updated results in these other solid cancers are expected at future national and international cancer conferences,” Sullivan added.
According to the American Cancer Society, lung cancer accounts for more deaths than any other cancer in both men and women. An estimated 158,040 deaths are expected to occur in 2015, accounting for about 27% of all cancer deaths.
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