Based on this study, the monoclonal antibody is being investigated in an ongoing phase 3 study and has received an FDA Breakthrough Therapy Designation.
The addition of olaratumab to the chemotherapy doxorubicin improved overall survival by nearly one year in patients with advanced soft tissue sarcoma, according to final results of a phase 1b/2 study. These data were presented at the 2015 Connective Tissue Oncology Society (CTOS) Annual Meeting, a gathering of nearly 1,000 physicians and other oncology professionals.
Based on this study, the monoclonal antibody is being investigated in an ongoing phase 3 study and has received an FDA Breakthrough Therapy Designation, which will expedite the development and review of the drug.
“This is striking for us in the sarcoma community because we have yet to put any combination with doxorubicin against doxorubicin or any drug [as monotherapy] against doxorubicin, which has shown any form of survival advantage,” said William D. Tap, the lead author on the study and chief, Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, in an interview with CURE.
In the intent-to-treat population (129 patients), median overall survival was 26.5 months with the combination of olaratumab and doxorubicin compared with 14.7 months with doxorubicin alone.
In the phase 1b study, 15 patients were enrolled who had advanced soft tissue sarcoma that was not amenable to surgery or radiotherapy. Patients were deemed eligible if they had a performance status of 2 or lower and had available tumor tissue to determine PDGFRalpha status. Eligible patients could have received any number of prior treatments, but no prior anthracyclines.
On the trial, patients received 15 mg/kg of olaratumab on days 1 and 8 and 75 mg/m2 of doxorubicin on day 1 for eight cycles (21 days). During cycles 5 through 8, patients could receive dexrazoxane at the investigator’s discretion prior to doxorubicin on day 1, according to Tap. After eight cycles, patients could receive olaratumab alone if benefit was seen from the combination. The primary endpoint on the trial was safety.
In the phase 2 trial, eligibility criteria remained the same but patients were stratified by PDGFRalpha status, lines of prior treatment, performance status and disease histology. In total, 133 patients were randomized evenly to receive 75 mg/m2 of doxorubicin on day 1 for eight cycles (21 days) or the combination of that doxorubicin regimen with 15 mg/kg of olaratumab on days 1 and 8 for eight cycles (21 days). As in the phase 1 trial, patients could receive dexrazoxane during cycles 5 through 8 at the investigator’s discretion prior to doxorubicin on day 1.
After eight cycles, patients on the doxorubicin arm (67 patients) were able to receive olaratumab monotherapy after progression while patients on the combination arm (66 patients) received the olaratumab monotherapy until progression.
The phase 2 trial’s primary endpoint was progression-free survival, with secondary endpoints focused on overall survival, objective response rate, and progression-free survival at three months.
Patients were well balanced between the arms with regard to age, race, performance status, PDGFRalpha status and histological subtype (leiomyosarcoma vs other). There were slightly more females on the combination arm.
Patients on the combination arm (64 patients) received a median number of seven infusions of doxorubicin (ranging from one to eight), 16.5 infusions of olaratumab (ranging from one to 83) and five infusions of olaratumab monotherapy post-combination (ranging from one to 68). Patients on the doxorubicin arm (65) received a median number of four infusions (ranging from one to eight). In total, 30 patients on this arm received olaratumab post-progression and received a median number of four infusions (ranging from one to 60).
The objective response rate was 18.2 percent in the combination arm (9.8 percent complete response [CR] + 29.6 percent partial response [PR]) compared with 11.9 percent in the doxorubicin arm (5.3 percent CR + 22.2 percent PR), though the data were not statistically significant.
Progression-free survival improved by over 50 percent with the addition of olaratumab. Median progression-free survival was 4.1 months (ranging from 2.8 to 5.4) in the doxorubicin arm compared with 6.6 months (ranging from 4.1 to 8.3) in the combination arm. Median overall survival was 14.7 months (ranging from 9.2 to 17.1) in the doxorubicin arm compared with 26.5 months (ranging from 20.9 to 31.7) in the combination arm.
As a monoclonal antibody, Tap maintained that olaratumab is very specific in nature, which resulted in both positive results in this trial and hope for the future.
“If we actually have drugs that target mesenchymal aspects of the cancer cell, we also hope that they may also be infecting the tumor microenvironment,” Tap said. “So it’s a very exciting time and hopefully there are a lot of novel therapies that are beginning to come into the field.”
In total, there were six adverse events of grade 3 or greater that were seen in at least 5 percent of the population: neutropenia, anemia, febrile neutropenia, fatigue, thrombocytopenia and infections. In his presentation, Tap pointed out that three of those AEs occurred at a significantly higher rate in the combination arm compared with the doxorubicin arm: neutropenia (51.5 vs 33.8 percent), anemia (12.5 vs 7.7 percent) and fatigue (9.4 vs 3.1 percent).
The tolerability of olaratumab provides even more reason to study the drug in future trials, according to Tap.
“It’s a very nontoxic drug, in and of itself, and it really didn’t add a tremendous amount of toxicity to standard chemotherapy,” Tap said. “One thought is that: Could you use this drug as a backbone with other chemotherapies? If it is doing something in the tumor microenvironment, could this drug remain a backbone through sequential different types of therapies?”
“We’re really excited about the potential of combining this drug with other novel inhibitors in disease-specific, or sarcoma-specific, trials.”
Tap WA, Jones R, Chmielowski B, et al. A randomized phase 1b/2 study evaluating the safety and efficacy of doxorubicin (Dox) with or without olaratumab (IMC-3G3), a human anti-platelet-derived growth factor α (PDGFRα) monoclonal antibody, in advanced soft tissue sarcoma (STS). Presented at: 2015 CTOS Annual Meeting; November 4-7; Salt Lake City, UT. Abstract 020.