Article

Adding Olaratumab to Chemo Improves Survival in Soft Tissue Sarcoma

Author(s):

Combining olaratumab with doxorubicin reduced the risk of death by 54% versus doxorubicin alone in patients with advanced soft tissue sarcoma.

William D. Tap, MD

Combining olaratumab with doxorubicin reduced the risk of death by 54% versus doxorubicin alone 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.

The median overall survival (OS) in the intent-to-treat population (n = 129) was 11.8 months higher with the olaratumab combination versus doxorubicin alone (HR, 0.46; 95% CI, 0.30-0.71; P = .0003). Based on the phase Ib/II data, the FDA granted olaratumab a breakthrough therapy designation in STS.

“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 with OncLive.

The human IgG1 monoclonal antibody olaratumab binds to PDGFRα and blocks the PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to the receptor, according to Eli Lilly and Company, the developer of the drug.

The phase Ib olaratumab study presented at CTOS included 15 patients with advanced STS that was not amenable to surgery or radiotherapy. Eligible had to have an ECOG performance status <2 and available tumor tissue to determine PDGFRα status. Patients could not have received prior anthracyclines, but previous treatment was allowed.

Patients received 15 mg/kg of olaratumab on days 1 and 8 and 75 mg/m2 of doxorubicin on day 1 for 8 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 8 cycles, patients could receive olaratumab alone if a benefit was seen from the combination. The primary endpoint on the trial was safety.

In the phase II study, eligibility criteria remained the same but patients were stratified by PDGFRα status, lines of prior treatment, ECOG PS, and disease histology. Patient characteristics were well balanced between the arms. By a small margin, there were more females who received the combination.

Overall, 133 patients were randomized 1:1 to receive 75 mg/m2 of doxorubicin on day 1 for 8 cycles (21 days; n = 67) or the combination of the same doxorubicin regimen with 15 mg/kg of olaratumab on days 1 and 8 for 8 cycles (21 days; n = 66). 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.

Following 8 cycles, patients on the doxorubicin arm were able to receive olaratumab monotherapy after progression while patients on the combination arm received the olaratumab monotherapy until progression.

The primary outcome measure of the phase II study was progression-free survival (PFS), with second endpoints including OS, objective response rate (ORR), and PFS at 3 months.

Evaluable patients in the olaratumab arm (n = 64) received a median of 7 infusions of doxorubicin (range, 1-8), 16.5 infusions of olaratumab (range, 1-83), and 5 infusions of olaratumab monotherapy post-combination (range, 1-68). Patients on the doxorubicin arm who were evaluable (n = 65) received a median of 4 infusions (range, 1-8). In total, 30 patients on this arm received olaratumab post-progression and received a median number of 4 infusions (range, 1-60).

The addition of olaratumab reduced the risk of disease progression by 33% versus doxorubicin alone (HR, 0.67; 95% CI, 0.44-1.02; P = .0615). Median PFS was 6.6 versus 4.1 months, respectively. Median OS was 26.5 months with the combination versus 14.7 months with doxorubicin alone.

ORR was 18.2% in the combination arm compared with 11.9% in the doxorubicin arm (P = .34).

There were 6 grade 3 adverse events (AEs) that were observed in at least 5% of the population: neutropenia, anemia, febrile neutropenia, fatigue, thrombocytopenia, and infections. In his presentation, Tap said that 3 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%).

Overall, however, Tap considered the drug to be well tolerated and is optimistic about its potential going forward.

“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, ‘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.”

Based on the positive phase Ib/II data, the olaratumab/doxorubicin combination is being compared with doxorubicin alone in the ongoing phase III ANNOUNCE trial (NCT02451943).

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.

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.
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