It was studied in a Phase Ib and in a randomized Phase II study (randomization between doxorubicin alone and in combination with olaratumab plus doxorubicin) in previously anthracycline-naive STS patients, showing both a statistically significant improvement in PFS and an improvement in OS to 26.9 months. This is the first randomized trial to show a significant improvement in OS compared to doxorubicin alone.26

This review aims at providing a comprehensive overview on this innovative drug that represents an important therapeutic novelty in the treatment of advanced STSs, in particular focusing on its clinical development and its application in clinical practice.


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PLATELET-DERIVED GROWTH FACTOR AXIS

The PDGFR ligands, ie, PDGF-A, PDGF-B, PDGF-C, and PDGF-D, are a family of disulfide-bound polypeptide chains that form hetero- and homodimers before binding and activating two structurally related tyrosine kinase receptors, PDGFRα and PDGFRβ.27,28 These receptors are transmembrane proteins containing an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. After binding to the receptor, PDGF induces homodimerization or heterodimerization, resulting in the formation of PDGFRαα, PDGFRαβ, or PDGFRββ.29 After dimerization, the receptors phosphorylate each other on tyrosine residues: this process increases the kinase activity of the receptor and creates a high-affinity docking site for Src homology 2 (SH2) domain-containing adapter molecules (such as growth factor receptor-bound protein 2 [Grb2], Grb7, Crk, Nck, and Shc) that work as a link to other downstream effectors. Thus, phosphorylation of the receptors activates signaling pathways that promote growth and regulate stromal-derived fibroblasts30–32 and angiogenesis.33,34 Moreover, PDGFRα regulates stromal fibroblasts’ production of VEGF, an essential growth factor for angiogenesis and tumorigenesis.35

If unbalanced, this pathway could play a role in influencing tumor microenvironment in promoting diffusion and growth of cancer cells, hence further suggesting the need for development of drugs targeting the PDGF/PDGFRα axis as means of antitumor development.36

PRECLINICAL EVIDENCE FOR OLARATUMAB

Monoclonal antibodies directed against the ligand-binding site of PDGFRα have been demonstrated to be potent antagonists against receptor function. Neutralizing antibodies to PDGFRα have been reported previously.37,38

Olaratumab (LY3012207; formerly IMC-3G3; Eli Lilly and Company, Indianapolis, IN, USA) is an IgG1 monoclonal antibody identified as the most potent PDGFRα-neutralizing antibody (Figure 1). Olaratumab binds to the extracellular domain of PDGFRα with a high affinity (Kd 0.04 nM) and specificity, as it does not cross-react with PDGFR-β isoform.39 High-affinity binding of olaratumab to PDGFRα blocks ligand (PDGF-AA, PDGF-BB, PDGF-CC) binding in a dose-dependent manner with a 50% inhibitory concentration (IC50) of 0.24–0.58 nM. By blocking ligand binding, olaratumab inhibits ligand-induced receptor autophosphorylation and subsequent cellular events such as phosphorylation of the downstream signaling molecules (Akt and mitogen-activated protein kinase) and cell mitogenesis.40 In addition, olaratumab induces internalization of surface PDGFR into intracellular space and down modulation of PDGF/PDGFR signaling.39

It is interesting to note that the potent anti-PDGFRα neutralizing activity of olaratumab is likely due to the affinity for receptor lying in the picomolar range, higher than the PDGF itself (Kd 0.2 nM), and the receptor binding site, since autoantibodies binding specific PDGFRα epitopes with nanomolar affinity (Kd 71–17 nM) have been cloned from memory B cells of patients affected by systemic sclerosis and shown to be potent receptor agonists in vitro and in vivo.41–44

The first evidence of antimitogenic activity of olaratumab in cancer cell lines was provided by the significant inhibition of growth of human leiomyosarcoma (SKLMS-1) xenografts in mice (p<0.0001) compared to the control group.39 Later, it was also shown that olaratumab enhances the antitumor activity of doxorubicin against the same human soft-tissue sarcoma xenograft model.45

The study by Loizos et al39 established that plasma olaratumab concentrations should be maintained in the 155–258 μg/mL range to obtain antitumor activity; tested doses of 6, 20, and 60 mg/kg administered twice per week resulted in statistically significant tumor growth inhibition. Monoclonal antibodies are not metabolized by cytochrome P450 enzymes; thus, co-administered drug do not affect the pharmacokinetic properties of olaratumab.46

These data represent the preclinical rationale for the dose cohorts in Phase I studies.

CLINICAL DEVELOPMENT

Phase I studies

Based on the favorable preclinical data, olaratumab monotherapy has been studied in two Phase I trials (the first one in predominantly Caucasian and the second one in Asian patients’ population) in order to assess its pharmacokinetic properties.47,48

The first trial47 was an open-label, dose-escalation study conducted in Caucasian and Black patients with advanced solid tumors. The aim of this study was to assess the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab. Patients were enrolled into five dose-escalating cohorts of three to six patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1–3) or once every other week at 15 or 20 mg/kg (cohorts 4–5), with 4 weeks/cycle. The study was conducted from December 2006 to March 2009, and totally, 19 patients were treated in five cohorts. Among all cohorts, the median number of infusions was 9 (range 1.0–54.0) and the median treatment duration was 12.1 weeks (range 1.0–57.9 weeks). Interestingly, no dose-limiting toxicities (DLTs) were observed during the study, and therefore, the MTD was not identified. The most common adverse events (AEs) considered at least possibly, probably, or definitely related to olaratumab were fatigue and infusion-related reactions (IRRs; 10.5% each). With the exception of one patient (enrolled in the 20 mg/kg cohort) experiencing two grade 3 drug-related AEs (increased alkaline phosphatase) after assessment period of DLTs, all drug-related AEs were of grade 1 or 2. Following multiple doses, the trough concentrations (Cmin) for 16 mg/kg weekly and 20 mg/kg biweekly were >155 μg/mL, which was the efficacious concentration in animal xenograft models. Regarding efficacy measurements, there were no complete responses (CRs) or partial responses (PRs) in this study, but 12 (63.2%) patients had a best response of stable diseases (SDs) with a median duration of 3.9 months (95% CI 2.3–8.7 months). The authors concluded that olaratumab was well tolerated and showed preliminary antitumor activity. Identified RP2Ds were both 16 mg/kg weekly and 20 mg/kg biweekly.

The second Phase I trial48 was a single-center, open-label, dose-escalation study conducted in Japanese patients with advanced/refractory solid malignancies. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Three to six patients were enrolled into each of three cohorts: patients received intravenous olaratumab at 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1), 20 mg/kg every 2 weeks (cohort 2), and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. A total of 16 patients were treated across three cohorts, and the median duration of treatment was 13.1 weeks (range 7.0–13.6 weeks), 6.0 weeks (range 3.0–13.4 weeks), and 7.0 weeks (range 7.0–25.1 weeks) in cohort 1, cohort 2, and cohort 3, respectively.

Similar to the previous Phase I trial conducted in Caucasian patients, there were no DLTs; thus, the MTD was not reached. The most frequently reported olaratumab-related events across the three cohorts included proteinuria (25.0%) and increased aspartate aminotransferase levels (12.5%), while no IRRs were reported. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Regarding efficacy, like in the other Phase I trial, the best overall response was SD. The disease control rate (CRs + PRs + SDs) was 66.7% in cohort 1, 42.9% in cohort 2, and 33.3% in cohort 3. The median duration of SD was 2.8 months in cohort 1 and cohort 2 and 4.9 months in cohort 3. Thus, the authors concluded that olaratumab had an acceptable safety profile and was well tolerated, and the aforementioned two doses represent an acceptable schedule for future trials in Japanese patients.

Therefore, olaratumab safety profile emerging from Phase I monotherapy trials was consistent with its toxicology profile and the toxicity profile observed in patients with advanced-stage solid tumors.