Among them, the Phase Ib/II ANNOUNCE-2 trial has been designed in order to assess safety and efficacy of the chemotherapy association of gemcitabine and docetaxel with or without olaratumab in patients with pretreated advanced STSs. OS is the primary end point of the Phase II portion, and the study is still recruiting patients.52
Moreover, this drug is being evaluated in Phase II trials regarding other cancer histotypes, such as advanced non-small cell lung cancer (NSCLC), GIST, and ovarian cancer.53,54
The Phase II study of olaratumab in previously treated patients with metastatic GIST by Wagner et al showed a statistically different disease control rate in two different cohorts including patients with or without PDGFRα mutations. The clinical benefit rate at 12 weeks was 50.0% and 14.3%, respectively.53
AGENCIES’APPROVAL AND REGULATORY AFFAIRS
In October 2014, the FDA granted olaratumab, in combination with doxorubicin, orphan drug status for the treatment of STS patients not amenable to curative treatment with surgery or radiotherapy.55The same indication was also given by the EMA in February 2015.56
Owing to the impressive results in terms of OS improvement observed in the Phase Ib/II study, in October 2016, the FDA also granted first accelerated approval to use olaratumab in combination with doxorubicin for treatment of adult patients with advanced STS, and the same approval was also given by the EMA in November 2016.
Both regulatory agencies’ approval is contingent upon confirmation of a significant clinical benefit in the ongoing randomized, Phase III ANNOUNCE trial.52
Olaratumab has an approximate molecular weight of 154 kDa and is produced in genetically engineered mammalian NS0 cells. Olaratumab is supplied in single-use vials containing 500 mg/50 mL (10 mg/mL) solution, and it is administered at a dose of 15 mg/kg via intravenous infusion over 60 min; for patients requiring higher doses, the duration of infusion should be increased such that the maximum infusion rate of 25 mg/minute is not exceeded. The approved recommended dose and schedule of treatment is 15 mg/kg administered by intravenous infusion over 60 minutes on day 1 and day 8 of each 21-day cycle, in combination with 75 mg/m2 of doxorubicin on day 1 following the olaratumab infusion, for up to eight cycles of treatment or until the patient experiences an unacceptable toxicity or disease progression, followed by olaratumab monotherapy until disease progression or unacceptable toxicity.57,58 Premedication with intravenous diphenhydramine and dexamethasone can be administered on day 1 of the first cycle.
Maximum serum concentrations (Cmax) are reached in a median time of 2 hours after the start of the infusion, and the drug reaches steady state during the third cycle. At the steady state, the volume of distribution (Vd) is 7.7 L and the estimated elimination half-life is ~11 days (range 6–24 days). No differences in pharmacokinetics are noticed in patients treated by a combination of olaratumab and doxorubicin.57,58
A recent review59 described the pharmacokinetic properties of olaratumab using data from four Phase II clinical studies in NSCLC, glioblastoma, STSs, and GIST populations. This study substantially confirmed the data from Tap et al analysis, showing a linear drug disposition due to full target saturation at the dose levels tested. Moreover, tumor burden seemed to be associated with a higher clearance (CL).
The mechanism of action of olaratumab has been well defined, as a specific PDGFRα ligand and receptor dimerization and signaling blocker. Moreover, the internalization of olaratumab-bound PDGFRα dimer may further contribute to drug activity.
As demonstrated by preclinical sarcoma models, the PDGFRα inhibition is necessary but not sufficient for durable control of cell growth. In fact, the antitumor activity of olaratumab is enhanced by co-administration with doxorubicin or cisplatin. Thus, combination with other targeted agents or chemotherapy drugs may be the future scenario of olaratumab clinical application.60,61
An additional possible mechanism under investigation is the increased tumor cell permeability to doxorubicin due to olaratumab inhibition of PDGFRα in stromal cells.62
This pharmacodynamic interaction may reduce the number of doxorubicin plus olaratumab cycles compared to the eight administrations of doxorubicin expected from the trial of Tap et al.26 In fact, this schedule leads to 600 mg doxorubicin/m2 cumulative dose, which is not recommended in clinical practice.
Olaratumab, a first-in-class monoclonal antibody blocking the PDGF/PDGFRα cellular signaling pathway, is the first agent in many years to show a survival advantage for patients with advanced STSs.
In their randomized, double-blind Phase II trial, Tap et al26 showed a clinically meaningful OS improvement in patients treated with olaratumab and doxorubicin combination vs patients receiving doxorubicin alone, with a median survival gain of 11.8 months, with manageable toxicity: although an increased rate of neutropenia, mucositis, vomiting, diarrhea, and musculoskeletal pain was observed, these AEs were primarily of grade 2 and, with the exception of febrile neutropenia, severe events were not observed. By contrast, PFS, the primary end point of the study, was extended by only 2.5 months in the olaratumab arm (6.6 months vs 4.1 months in the control arm). These findings suggest a change to the treatment strategy in patients with high-grade, advanced or metastatic, anthracycline-naive STSs in the first-line setting: this was the first time that a monoclonal antibody in combination with doxorubicin was able to influence OS in soft-tissue sarcomas (perhaps also owing to the survival gain obtained by olaratumab maintenance therapy after primary induction with the combination).
These results appear remarkable also because previous studies evaluating the superiority of combination chemotherapy regimens or histology-tailored therapies vs doxorubicin alone in the first-line setting of advanced/metastatic STSs failed to show any survival advantage.9,10 However, OS is a composite end point, influenced by all subsequent treatment administered in the metastatic setting, and the exact effect of various post-study treatments is not easy to define. This aspect will certainly require further investigation, also because PFS for patients enrolled in the study was only marginally influenced, indicating that the greatest benefit for patients enrolled in the combination treatment arm consisted mostly of survival benefits in post-progression survival (PPS).
Furthermore, PFS, particularly when assessed by RECIST criteria in patients treated with a drug that targets mainly angiogenic pathways, is usually not the best parameter to evaluate the survival gain of the population, as it can be usually observed also in other settings where antiangiogenic drugs are more extensively used, such as in colorectal cancer.63
Moreover, some issues, such as the reduced power of the study and the small number of patients included, remain and will be hopefully solved by the Phase III ANNOUNCE study, which has recently completed accrual.
Another unanswered question is the reason behind the disparity between PFS and OS study end points. Some interesting hypotheses could explain this topic, such as olaratumab may display a long-term modulatory effect on the tumor and stromal microenvironment or possess a synergistic antitumor effect with doxorubicin, even if supporting evidence is currently lacking. To date, studies investigating olaratumab mechanism of action, both as a single-agent therapy and in combination, are required to improve the efficacy of this drug. Several ongoing clinical trials are evaluating olaratumab in combination with other drugs, such as gemcitabine and docetaxel, which may help to clarify if the postulated synergic effect of olaratumab plus chemotherapy is restricted to anthracyclines or could be extended also to other chemotherapeutics.