Alternative endpoints needed for osteosarcoma trials

Pediatric and young adult patients with recurrent or refractory osteosarcoma demonstrated uniformly poor EFS outcomes, according to a retrospective analysis of seven phase 2 trials.

Because use of overall response rate as the primary endpoint can be problematic for osteosarcoma trials, researchers may be able to conduct future trials that use the EFS data from this study as a historical benchmark, according to researchers.

“Osteosarcoma is a distinct and biologically aggressive cancer,” Joanne P. Lagmay, MD, clinical assistant professor of pediatric hematology and oncology at University of Florida and director of the pediatric solid tumor program at UF Health, told HemOnc Today. “Outcomes for patients with osteosarcoma have not improved over the past 3 decades compared with other pediatric cancers. This made us question why that is.”

Joanne Lagmay

Joanne P. Lagmay

The use of radiographic response in phase 2 osteosarcoma trials may limit the detection of disease response due to the calcified tumor matrix. Lagmay and colleagues sought to determine whether time to progression could serve as a suitable primary endpoint for future osteosarcoma studies.

The researchers analyzed seven trials conducted over a 10-year period (1997-2007) by the Children’s Cancer Group, the Pediatric Oncology Group and the Children’s Oncology Group, representing 96 patients.

All trials used radiographic response, by WHO or RECIST criteria, as the primary endpoint for response rate.

Researchers calculated the historical disease control rate for patients with fully resected disease using data from an additional phase 2 trial with EFS and biologic endpoints, in which patients received inhaled granulocyte colony–stimulating factor with first pulmonary recurrence.

All drugs studied in the seven trials were found to be ineffective based on radiographic response.

Disease progressed in 83 patients receiving a study drug. Ten of the remaining 13 patients discontinued treatment — due to personal preference or toxicity — and subsequently died; the researchers considered death an event for the purposes of this analysis.

The researchers had access to some follow-up data from 95 patients, 93 of whom experienced an event. Two patients — both enrolled in a trial studying oxaliplatin — remained alive and without an EFS event at 8 months and 46 months from enrollment.

EFS at 4 months was 12% (95% CI, 6-19).

Researchers evaluated factors including age, sex, trial, number of prior chemotherapy regimens, and race or ethnicity were evaluated for their impact on EFS. However, covariates did not appear to have an impact on EFS in any trials.

Patients with fully resected disease had a 12-month EFS rate of 20% (95% CI, 10-34). The study evaluating inhaled G-CSF found that the treatment failed to meet the primary outcome measure of biologic response.

“By characterizing EFS from prior studies in which agents were not considered efficacious according to conventional response criteria, this analysis allows for the introduction of benchmarks that can be used in the design of single-arm phase 2 trials that use EFS as an endpoint in osteosarcoma,” Lagmay and colleagues wrote. “Introduction of alternative endpoints, such as EFS or PFS in lieu of radiographic response, have previously been proposed for other diseases, such as metastatic melanoma.”

Study limitations included the lack of standardized schedules for routine evaluation across trials and the potential that agents with limited activity may have been included.

“To change the outcome of patients with osteosarcoma, it is especially important for cooperative groups to pursue novel therapies in patients with recurrent and refractory osteosarcoma in the context of a trial design with statistical design, eligibility criteria and outcome measures which take into account the unique aspects of osteosarcoma,” Lagmay said. “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase 2 trials in osteosarcoma.

“With our proposed design for future osteosarcoma trials, we hope that this will permit rapid screening of drug activity in patients with recurrent osteosarcoma,” she added. – by Cameron Kelsall 

For more information:

Joanne P. Lagmay, MD, can be reached at jplagmay@peds.ufl.edu.

Disclosure: Lagmay reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.

Pediatric and young adult patients with recurrent or refractory osteosarcoma demonstrated uniformly poor EFS outcomes, according to a retrospective analysis of seven phase 2 trials.

Because use of overall response rate as the primary endpoint can be problematic for osteosarcoma trials, researchers may be able to conduct future trials that use the EFS data from this study as a historical benchmark, according to researchers.

“Osteosarcoma is a distinct and biologically aggressive cancer,” Joanne P. Lagmay, MD, clinical assistant professor of pediatric hematology and oncology at University of Florida and director of the pediatric solid tumor program at UF Health, told HemOnc Today. “Outcomes for patients with osteosarcoma have not improved over the past 3 decades compared with other pediatric cancers. This made us question why that is.”

Joanne Lagmay

Joanne P. Lagmay

The use of radiographic response in phase 2 osteosarcoma trials may limit the detection of disease response due to the calcified tumor matrix. Lagmay and colleagues sought to determine whether time to progression could serve as a suitable primary endpoint for future osteosarcoma studies.

The researchers analyzed seven trials conducted over a 10-year period (1997-2007) by the Children’s Cancer Group, the Pediatric Oncology Group and the Children’s Oncology Group, representing 96 patients.

All trials used radiographic response, by WHO or RECIST criteria, as the primary endpoint for response rate.

Researchers calculated the historical disease control rate for patients with fully resected disease using data from an additional phase 2 trial with EFS and biologic endpoints, in which patients received inhaled granulocyte colony–stimulating factor with first pulmonary recurrence.

All drugs studied in the seven trials were found to be ineffective based on radiographic response.

Disease progressed in 83 patients receiving a study drug. Ten of the remaining 13 patients discontinued treatment — due to personal preference or toxicity — and subsequently died; the researchers considered death an event for the purposes of this analysis.

The researchers had access to some follow-up data from 95 patients, 93 of whom experienced an event. Two patients — both enrolled in a trial studying oxaliplatin — remained alive and without an EFS event at 8 months and 46 months from enrollment.

EFS at 4 months was 12% (95% CI, 6-19).

Researchers evaluated factors including age, sex, trial, number of prior chemotherapy regimens, and race or ethnicity were evaluated for their impact on EFS. However, covariates did not appear to have an impact on EFS in any trials.

Patients with fully resected disease had a 12-month EFS rate of 20% (95% CI, 10-34). The study evaluating inhaled G-CSF found that the treatment failed to meet the primary outcome measure of biologic response.

“By characterizing EFS from prior studies in which agents were not considered efficacious according to conventional response criteria, this analysis allows for the introduction of benchmarks that can be used in the design of single-arm phase 2 trials that use EFS as an endpoint in osteosarcoma,” Lagmay and colleagues wrote. “Introduction of alternative endpoints, such as EFS or PFS in lieu of radiographic response, have previously been proposed for other diseases, such as metastatic melanoma.”

Study limitations included the lack of standardized schedules for routine evaluation across trials and the potential that agents with limited activity may have been included.

“To change the outcome of patients with osteosarcoma, it is especially important for cooperative groups to pursue novel therapies in patients with recurrent and refractory osteosarcoma in the context of a trial design with statistical design, eligibility criteria and outcome measures which take into account the unique aspects of osteosarcoma,” Lagmay said. “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase 2 trials in osteosarcoma.

“With our proposed design for future osteosarcoma trials, we hope that this will permit rapid screening of drug activity in patients with recurrent osteosarcoma,” she added. – by Cameron Kelsall 

For more information:

Joanne P. Lagmay, MD, can be reached at jplagmay@peds.ufl.edu.

Disclosure: Lagmay reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.