Addition of Olaratumab to Doxorubicin Extends Survival by Nearly One Year in Soft Tissue Sarcoma

The addition of olaratumab to doxorubicin improved overall survival (OS) by nearly 1 year in patients with advanced soft tissue sarcoma, according to final results of a phase Ib/II study.

William D. Tap, MD

The addition of olaratumab to doxorubicin improved overall survival (OS) by nearly 1 year in patients with advanced soft tissue sarcoma (STS), according to final results of a phase Ib/II study presented at the 2015 Connective Tissue Oncology Society (CTOS) Annual Meeting.

Based on this study, the monoclonal antibody is being investigated in an ongoing phase III study and has received an FDA Breakthrough Therapy Designation.

“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, MD, the lead author on the study and chief, Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, in an interview withTargeted Oncology.

In the intent-to-treat population (n = 129), median OS was 26.5 months with the combination of olaratumab and doxorubicin compared with 14.7 months with doxorubicin alone (HR, 0.46; 95% CI, 0.30-0.71;P= .0003).

In the phase Ib study, 15 patients were enrolled who had advanced STS that was not amenable to surgery or radiotherapy. Patients were deemed eligible if they had an ECOG performance status (PS) £2 and had available tumor tissue to determine PDGFRa 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/m2of 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, with the secondary endpoint focused on pharmacokinetics.

In the phase II trial, eligibility criteria remained the same but patients were stratified by PDGFRa status, lines of prior treatment, ECOG PS, and disease histology. In total, 133 patients were randomized 1:1 to receive 75 mg/m2of 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 I 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 (n = 67) were able to receive olaratumab monotherapyafterprogression while patients on the combination arm (n = 66) received the olaratumab monotherapyuntilprogression.

The phase II trial’s primary endpoint was progression-free survival (PFS), with secondary endpoints focused on OS, objective response rate, and PFS at 3 months.

Patients were well balanced between the arms with regard to age, race, ECOG PS, PDGFRa status, and histological subtype (leiomyosarcoma vs other). There were slightly more females on the combination arm.

Patients on the combination arm (n = 64) received a median number of seven infusions of doxorubicin (range, 1-8), 16.5 infusions of olaratumab (range, 1-83), and five infusions of olaratumab monotherapy post-combination (range, 1-68). Patients on the doxorubicin arm (n = 65) received a median number of four infusions (range, 1-8). In total, 30 patients on this arm received olaratumab post-progression and received a median number of four infusions (range, 1-60).

>The objective response rate was 18.2% in the combination arm (9.8% complete response [CR] + 29.6% partial response [PR]) compared with 11.9% in the doxorubicin arm (5.3% CR + 22.2% PR), though the data were not statistically significant (P= 0.34).

PFS improved by over 50% with the addition of olaratumab. Median PFS was 4.1 months (range, 2.8-5.4) in the doxorubicin arm compared with 6.6 months (range, 4.1-8.3) in the combination arm (HR, 0.67; 95% CI, 0.44-1.02;P= .0615). Median OS was 14.7 months (range, 9.2-17.1) in the doxorubicin arm compared with 26.5 months (range, 20.9-31.7) in the combination arm (HR, 0.46; 95% CI, 0.30-0.71;P= .0003).

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 grade ³3 adverse events (AEs) that were seen in ³5% 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%), anemia (12.5 vs 7.7%), and fatigue (9.4 vs 3.1%).

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.”