NEW YORK (Reuters Health) Nov 02 - Researchers are reporting modest activity against advanced Ewing sarcoma from mid-stage studies of two monoclonal antibodies against insulin-like growth factor type 1 receptor (IGF-1R).
Despite the promising results, however, the future of the IGF-1R inhibitors is in doubt because drug company interest in waning.
The results of both trials were published online October 24 in the Journal of Clinical Oncology.
Dr. Laurence H. Baker from University of Michigan, Ann Arbor, who headed a phase II trial of R1507, told Reuters Health by email, "The pre-clinical excitement about the role of inhibition of this signaling pathway is validated by these clinical studies."
"Considering the scant toxicity in patients treated with R1507, the potential to treat successfully sarcoma without devastating short and long term side effects is beginning to be realized," he said.
Dr. Baker's team tested the fully human IGF-1R monoclonal antibody R1507 in 115 patients with recurrent or refractory ESFT (Ewing sarcoma family of tumors). The overall response rate was 10% (with one complete response and 10 partial responses), and the median duration of response was 29 weeks (range, 12 to 94 weeks). Eighteen patients had stable disease lasting a median 11.4 weeks (range, 5.6 to 30.1 weeks). Median overall survival was 7.6 months.
Grade 3 and 4 toxicities included pain in 15% of patients, anemia in 8%, thrombocytopenia in 7%, and fatigue in 5%. Three patients had grade 3 or 4 hyperglycemia, none of them attributable to the study treatment.
Primary site in bone (as opposed to extraskeletal), a higher Karnofsky/Lansky performance status, and a total IGF-1 level of at least 110 ng/mL were independently associated with better overall survival.
"We have been in discussion with two companies regarding follow up studies," Dr. Baker said. Roche/Genentech is no longer interested in this compound, nor are most other major pharmaceutical companies, he said.
This past November, an article in the National Cancer Institute's Cancer Bulletin noted that there are no biomarkers yet to identify the patients likely to benefit from IGF-1 drugs, and "that reality has raised doubts in some corners about whether these agents can complete the often perilous journey to the clinic."
In the Cancer Bulletin article, Dr. Baker compared the effect of IGF-1R inhibitors in Ewing sarcoma to that of trastuzumab (Herceptin) in breast cancer. But Ewing sarcoma affects only 400 to 500 mostly younger patients a year in the United States, the article notes.
The second paper on the topic published last month alongside Dr. Baker's reports on treatment of ESFT with figitumumab.
In a phase I/II study, Dr. Antonio Gualberto from Pfizer Oncology, New London, Connecticut, and colleagues identified a 30 mg/kg dose as most worthwhile for testing and then treated 107 patients every 4 weeks for a median of two cycles (range, 1 to 16).
Fifteen patients had partial responses and 25 had stable disease. The median duration of response was 4.7 months. The median progression-free survival was 1.9 months, and the median overall survival was 8.9 months.
As in the R1507 study, total IGF-1 level influenced response to treatment. Overall survival was significantly longer with baseline free IGF-1 levels of 0.65 ng/mL than with lower levels (10.4 vs 3.65 months) and significantly higher with baseline levels of at least 110 ng/mL vs lower levels (10.6 vs 4.4 months).
"Our data suggests that total IGF-1 is an indicator of good prognosis and a weak predictor of anti-IGF-1R activity," Dr. Gualberto told Reuters Health by email.
Figitumumab (CP-751,871) no longer appears on Pfizer's list of drugs in its development pipeline, however.
Dr. Baker said that companies such as Roche/Genentech and Pfizer, "which dropped out of development in this area, should more carefully examine the role of pharma in modern society."
One of Dr. Gualberto's coauthors, Dr. Heribert Juergens from University Children's Hospital, Muenster, Germany, offered this hope in an email message to Reuters Health: "IGF-1R antibody therapy remains my 'Midsummer Night's Dream' in Ewing sarcoma, to be moved forward into combination with conventional chemotherapy - with a partner with - truly - sustained interest in rare malignant diseases, such as sarcomas and other entities in particular in pediatric oncology."
Despite the promising results, however, the future of the IGF-1R inhibitors is in doubt because drug company interest in waning.
The results of both trials were published online October 24 in the Journal of Clinical Oncology.
Dr. Laurence H. Baker from University of Michigan, Ann Arbor, who headed a phase II trial of R1507, told Reuters Health by email, "The pre-clinical excitement about the role of inhibition of this signaling pathway is validated by these clinical studies."
"Considering the scant toxicity in patients treated with R1507, the potential to treat successfully sarcoma without devastating short and long term side effects is beginning to be realized," he said.
Dr. Baker's team tested the fully human IGF-1R monoclonal antibody R1507 in 115 patients with recurrent or refractory ESFT (Ewing sarcoma family of tumors). The overall response rate was 10% (with one complete response and 10 partial responses), and the median duration of response was 29 weeks (range, 12 to 94 weeks). Eighteen patients had stable disease lasting a median 11.4 weeks (range, 5.6 to 30.1 weeks). Median overall survival was 7.6 months.
Grade 3 and 4 toxicities included pain in 15% of patients, anemia in 8%, thrombocytopenia in 7%, and fatigue in 5%. Three patients had grade 3 or 4 hyperglycemia, none of them attributable to the study treatment.
Primary site in bone (as opposed to extraskeletal), a higher Karnofsky/Lansky performance status, and a total IGF-1 level of at least 110 ng/mL were independently associated with better overall survival.
"We have been in discussion with two companies regarding follow up studies," Dr. Baker said. Roche/Genentech is no longer interested in this compound, nor are most other major pharmaceutical companies, he said.
This past November, an article in the National Cancer Institute's Cancer Bulletin noted that there are no biomarkers yet to identify the patients likely to benefit from IGF-1 drugs, and "that reality has raised doubts in some corners about whether these agents can complete the often perilous journey to the clinic."
In the Cancer Bulletin article, Dr. Baker compared the effect of IGF-1R inhibitors in Ewing sarcoma to that of trastuzumab (Herceptin) in breast cancer. But Ewing sarcoma affects only 400 to 500 mostly younger patients a year in the United States, the article notes.
The second paper on the topic published last month alongside Dr. Baker's reports on treatment of ESFT with figitumumab.
In a phase I/II study, Dr. Antonio Gualberto from Pfizer Oncology, New London, Connecticut, and colleagues identified a 30 mg/kg dose as most worthwhile for testing and then treated 107 patients every 4 weeks for a median of two cycles (range, 1 to 16).
Fifteen patients had partial responses and 25 had stable disease. The median duration of response was 4.7 months. The median progression-free survival was 1.9 months, and the median overall survival was 8.9 months.
As in the R1507 study, total IGF-1 level influenced response to treatment. Overall survival was significantly longer with baseline free IGF-1 levels of 0.65 ng/mL than with lower levels (10.4 vs 3.65 months) and significantly higher with baseline levels of at least 110 ng/mL vs lower levels (10.6 vs 4.4 months).
"Our data suggests that total IGF-1 is an indicator of good prognosis and a weak predictor of anti-IGF-1R activity," Dr. Gualberto told Reuters Health by email.
Figitumumab (CP-751,871) no longer appears on Pfizer's list of drugs in its development pipeline, however.
Dr. Baker said that companies such as Roche/Genentech and Pfizer, "which dropped out of development in this area, should more carefully examine the role of pharma in modern society."
One of Dr. Gualberto's coauthors, Dr. Heribert Juergens from University Children's Hospital, Muenster, Germany, offered this hope in an email message to Reuters Health: "IGF-1R antibody therapy remains my 'Midsummer Night's Dream' in Ewing sarcoma, to be moved forward into combination with conventional chemotherapy - with a partner with - truly - sustained interest in rare malignant diseases, such as sarcomas and other entities in particular in pediatric oncology."
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