Margaret von Mehren, MD
The current plethora of drugs in development for oncology is leading to the testing of novel agents in common as well as rare diseases. Targeted therapies have been a focus of great interest in soft-tissue sarcomas, with testing of a variety of oral tyrosine kinase inhibitors leading to the approval of several agents for the treatment of gastrointestinal stromal tumor as well as pazopanib (Votrient) for soft-tissue sarcomas.1,2 Olaratumab (Lartruvo), a fully human IgG1 monoclonal antibody that targets platelet-derived growth factor (PDGF) receptor-alpha, has undergone phase I testing as a single agent3,4 as well as in combination with doxorubicin in a phase Ib and a randomized phase II study.5 As reviewed in this issue of The ASCO Post, Tap and colleagues reported an improvement in both progression-free and overall survival for olaratumab in combination with doxorubicin as compared with standard single-agent doxorubicin,5 which supported the recent accelerated approval of olaratumab by the U.S. Food and Drug Administration (FDA) for the treatment of advanced soft-tissue sarcomas.
Why Target PDGF Receptor-Alpha?
Why might PDGF receptor-alpha be an important target in soft-tissue sarcomas? PDGF receptor-alpha is expressed by malignancies as well as peritumoral stroma.6 Both the receptor and its ligands have been shown to have fundamental roles in development, notably of mesenchymal stem cells, as well as in the pathogenesis of disease, including cancers.7 It has a role in angiogenesis and metastasis.8-10 There are also data to support autocrine and paracrine loops in malignant tissues.11,12 Olaratumab binds to PDGF receptor-alpha and blocks binding of its ligands, which in preclinical studies of PDGF receptor-alpha–expressing tumors led to the downregulation of downstream mediators such as AKT and S6 kinase, as well as decreased proliferation of tumor cells.13
Phase I Experience
The phase I experience of olaratumab did not identify a maximum tolerated dose.3,4 As compared with other PDGF receptor-alpha–targeted agents, no evidence of fluid retention was observed. Infusion reactions were noted, as would be anticipated with an antibody treatment; also seen were proteinuria, fever, diarrhea/constipation, nausea/vomiting, liver function test abnormalities, and thrombocytopenia—without a clear correlation between the dose and the observed toxicities. One episode of tumor hemorrhage occurred outside the dose-limiting toxicity window.
In the phase I experience, several patients with sarcoma (n = 1) and gastrointestinal stromal tumor (n = 2) were enrolled. The patient with sarcoma remained on study for 24 weeks, whereas the patients with gastrointestinal stromal tumor discontinued therapy at the first disease assessment. Overall, 7 of 16 and 12 of 19 patients, respectively, achieved stable disease in the 2 phase I trials conducted. Dosing at 15 mg/kg on days 1 and 8 in a 3-week cycle as well as 20 mg/kg every 2 weeks achieved trough concentrations of olaratumab above the efficacious dose identified in preclinical models.
Data Supporting Accelerated Approval
The phase Ib/II study that supported the recent accelerated approval of doxorubicin with olaratumab enrolled adult patients with advanced or metastatic sarcomas who were anthracycline naive, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and had tumor samples available to assess the expression of PDGF receptor-alpha by immunohistochemistry. Fifteen patients were enrolled in the phase Ib portion of the study, and 133 patients were randomized in a 1:1 fashion in the phase II portion, with 66 patients receiving the combination therapy and 67 receiving doxorubicin alone. Factors used for randomization were performance status, line of therapy, and PDGF receptor-alpha expression, as well as histologic tumor type (leiomyosarcoma vs synovial sarcoma vs other).
In both the phase Ib and II portions, treatment cycles were 21 days, with doxorubicin given at standard doses of 75 mg/m2 on day 1 and olaratumab given at 15 mg/kg on days 1 and 8, with a total of 8 cycles of doxorubicin allowed; dexrazoxane was permitted as a cardioprotectant. In the phase II portion, patients randomized to the olaratumab arm continued on maintenance single-agent antibody therapy if their disease was stable or responding. Those randomized to receive doxorubicin were allowed to cross over to single-agent olaratumab at the time of disease progression, whether that occurred during the 8 cycles of planned therapy or later under observation.
Toxicity of the combination compared with single-agent doxorubicin included an increase in grade 3 and 4 hematologic toxicities. For example, grade 3 and 4 neutropenia was 53% for the combination vs 33% for doxorubicin alone; however, this did not translate into an increase in grade 3/4 febrile neutropenia (12.6% vs 14%) or infections (8% vs 11%). It is important to note that there was no significant difference in the rate of patients discontinuing therapy due to adverse events (13% vs 18%). There did not appear to be a significant increase in cardiac toxicities with the addition of olaratumab (8% vs 6%) or in the percentage of patients whose left ventricular ejection fraction was less than 50% after beginning therapy (12% vs 9%). An increase in peripheral edema was noted in the combination arm, which was not unanticipated given the known effects of PDGF receptor-alpha inhibitors.
Although none of the patients in the phase Ib portion of the study had a response, in the randomized portion of the trial, the objective response rate increased when doxorubicin was combined with olaratumab. Based on investigator assessment, response rates were 11.9% for doxorubicin and 18.2% with the combination; the majority of responses were partial responses. An independent radiology assessment indicated response rates of 18.2% vs 7.5% for doxorubicin alone. The results for the standard arm fall within the range of recent trial results in patients with advanced or metastatic soft-tissue sarcomas that incorporated doxorubicin as a single agent, with the objective response rate ranging from 0% to 14%.14,15
Notable Study Findings
What is particularly notable regarding the outcomes of this study are the improvements in progression-free and overall survival. The investigators reported median progression-free survival of 4.1 months with doxorubicin alone compared with 6.6 months with the olaratumab combination, with a more striking difference on independent radiology review (4.4 months vs 8.2 months). It should be noted that those in the combination arm continued to receive maintenance treatment with olaratumab if their disease was stable or responding; per investigator assessment, the ongoing maintenance treatment with single-agent olaratumab therapy did not add meaningfully to progression-free survival. Remarkably, overall survival improved by nearly 1 year (14.7–26.5 months), with the overall survival for doxorubicin echoing that reported in two recently published randomized trials using doxorubicin.14,15
Other drugs in sarcoma trials have suggested benefits in the phase II setting when compared with historical data, or even in randomized study designs, to find no such benefits in larger phase III experiences. Results of the phase III trial of doxorubicin and olaratumab vs doxorubicin alone are awaited eagerly.— Margaret von Mehren, MD
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Certainly, overall survival is a cumulative measure of treatment, and a larger proportion of patients on the combination arm received further therapy (67% vs 49%). Regimens utilized more frequently in patients who had received olaratumab with doxorubicin included gemcitabine and docetaxel (21.2% vs 11.9%), as well as single-agent therapy with gemcitabine (22.7% vs 16.4%), pazopanib (22.7% vs 14.9%), docetaxel (21.2% vs 11.9%), dacarbazine (18.2% vs 11.9%), trabectedin (16.7 % vs 3.0%), and investigational therapies (12.1 % vs 3.0%). Additional doxorubicin was more frequently used in the single-agent arm (1.5% vs 9%), likely because the olaratumab patients reached the cumulative lifetime dose of the agent prior to disease progression on study therapy. In addition, this likely reflects the limited available treatment options for this patient population, as it would seem likely that those who were re-treated with doxorubicin likely progressed on it or had discontinued it due to toxicity prior to completing the planned 8 cycles, given the known risk of cardiac toxicity with increasing cumulative dosing. There was comparable usage of single-agent therapy with ifosfamide (12.1% vs 11.9 %) and eribulin (Halavan; 4.5% vs 3.0%). Although olaratumab was allowed at disease progression for patients who received doxorubicin alone, the length of therapy was not reported.
Improved initial disease control afforded by doxorubicin and olaratumab does appear to have allowed more patients to have the opportunity for treatment when their disease progressed (67% vs 49%). To date, none of the agents utilized following protocol assigned treatment has been associated with an improvement in overall survival, with the exception of eribulin, which demonstrated a 2-month improvement compared with treatment with dacarbazine when used as a second- or higher-line treatment in patients with advanced leiomyosarcoma and liposarcoma; the study found the survival benefit was relegated to those patients with liposarcoma.16 The number of liposarcoma patients entered onto the randomized phase II study of olaratumab and doxorubicin was higher in the doxorubicin arm (12% vs 22%).
Liposarcoma is a broad category, and the particular subtype could have influenced outcome with subsequent therapies, particularly myxoid liposarcomas, which have been shown to exhibit prolonged disease control with trabectedin.17 Other histologic differences between the arms were more patients with pleomorphic sarcoma (15% vs 21%) in the doxorubicin alone arm and more patients classified as other (26% vs 9%) in the olaratumab arm. Sensitivity analyses conducted censoring at the time of subsequent chemotherapy administration or at the initiation of selected therapies (pazopanib, erlotinib [Tarceva], gemcitabine, docetaxel, doxorubicin, and trabectedin) persisted in demonstrating an improvement in overall survival and argue against the suggestion that the results are the effects of a summation of benefit from subsequent therapies. The investigators did find a correlation between the highest quartile of olaratumab serum drug exposure and improved progression-free and overall survival; there was no comparison of subsequent therapy in this group of patients compared with those whose olaratumab concentrations were in the lower quartiles.
Expression of PDGF Receptor-Alpha
As olaratumab targets PDGF receptor-alpha, tumor tissue was assessed for expression of the receptor by immunohistochemistry and used as a factor for randomization. Tumors with weak expression of PDGF receptor-alpha in more than 30% of tumors cells or one with intermediate to strong staining in more than 5% on tumor cells were considered positive. At study entry, the initial antibody that prospectively assessed PDGF receptor-alpha expression categorized 88% of both cohorts as positive for PDGF receptor-alpha. The antibody used was found to cross-react with PDGF receptor-beta, and this led to a retrospective reassessment of tumors. Using a more specific antibody for PDGF receptor-alpha, 33% and 34% of tumors in the combination and single-agent cohorts were shown to express the receptor; not all tumor samples were available for this secondary assessment.
When analyzing progression-free or overall survival, there was no association between positive or negative expression of PDGF receptor-alpha, but no information was provided on how the two antibodies compared. Were all those cases of PDGF receptor-alpha expression in the retrospective analysis identified by the prospective analysis? No data were provided on the distribution or intensity of expression patterns in tumor tissue or whether this was evaluated in terms of outcomes. Lastly, expression of PDGF receptor-alpha in peritumoral tissue was not described; certainly, the effects of olaratumab on the tumor stroma may have been a component of the benefit observed.
Second Study to Show Survival Benefit
This is the second study in advanced soft-tissue sarcomas that has demonstrated an overall survival benefit, the gold standard for efficacy in oncology drug development. In the phase III randomized trial of eribulin compared with dacarbazine in patients with advanced, previously treated leiomyosarcoma or liposarcoma, eribulin demonstrated a 2-month benefit in survival; the benefit appeared to be in patients with advanced liposarcoma.16 Strikingly, the improvement in overall survival seen with eribulin recapitulated a benefit seen in breast cancer trials, as in both disease settings, there was no progression-free survival advantage for eribulin over its comparator.
In the case of eribulin, and I think we could also argue with olaratumab, the benefit of the agent may be more complex than a direct cytotoxic effect on tumor. Eribulin is a microtubular agent that prevents mitosis and leads to apoptosis and affects the microenvironment, with remodeling of microvasculature leading to enhanced perfusion.18-23 In the case of olaratumab, the effect might be related in part to improved delivery of doxorubicin due to effects on the vasculature, leading to a higher response rate, as well as to alterations of autocrine and paracrine interactions between stroma and tumor cells, which persist after progression of disease. Additional data on the mechanism of olaratumab will be of interest to understand the benefits observed in this study.
Olaratumab and doxorubicin demonstrated an increase in response rate, progression-free survival, and overall survival compared with doxorubicin alone in this randomized phase II trial. The findings are indeed impressive but generated from 130 patients. Other drugs in sarcoma trials have suggested benefits in the phase II setting when compared with historical data, or even in randomized study designs, to find no such benefits in larger phase III experiences.24,25 The phase III trial of doxorubicin and olaratumab vs doxorubicin alone has completed accrual, and the results are awaited eagerly. Patients and physicians fortunately have the opportunity to access olaratumab while we await confirmation of the phase II findings. ■
Disclosure: Dr. von Mehren is a member of the scientific steering committee for the published phase III trial of trabectedin vs dacarbazine and was a member of the data safety monitoring board for the phase III trial of eribulin vs dacarbazine.
Dr. von Mehren is Chief, Sarcoma Program; Physician Director; Clinical Trials Office Associate Director, Clinical Research; Professor, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia.
1. Somaiah N, von Mehren M: New drugs and combinations for the treatment of soft-tissue sarcoma: A review. Cancer Manag Res 4:397-411, 2012.
2. Vadakara J, von Mehren M: Gastrointestinal stromal tumors: Management of metastatic disease and emerging therapies. Hematol Oncol Clin North Am 27:905-920, 2013.
3. Doi T, Ma Y, Dontabhaktuni A, et al: Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci 105:862-869, 2014.
4. Chiorean EG, Sweeney C, Youssoufian H, et al: A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol 73:595-604, 2014.
5. Tap WD, Jones RL, Van Tine BA, et al: Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: An open-label phase 1b and randomised phase 2 trial. Lancet 388:488-497, 2016.
6. Shah GD, Loizos N, Youssououfian H, et al: Rationale for the development of IMC-3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet-derived growth factor receptor alpha. Cancer 116(4 suppl):1018-1026, 2010.
7. Ng F, Boucher S, Koh S, et al: PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells. Blood 112:295-307, 2008.
8. Chen CY, Liu SH, Chen CY, et al: Human placenta-derived multipotent mesenchymal stromal cells involved in placental angiogenesis via the PDGF-BB and STAT3 pathways. Biol Reprod 93:103, 2015.
9. Henriksen R, Funa K, Wilander E, et al: Expression and prognostic significance of platelet-derived growth factor expression and its receptors in epithelial ovarian neoplasms. Cancer Res 53:4550-4554, 1993.
10. Sulzbacher I, Birner P, Träxler M, et al: Expression of platelet-derived growth factor-alpha receptor is associated with tumor progression in clear cell renal cell carcinoma. Am J Clin Pathol 120:107-112, 2003.
11. Dong J, Grunstein J, Tejada M, et al: VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J 23:2800-2810, 2004.
12. Adams SF, Hickson JA, Huto JY, et al: PDGFR-alpha as a potential therapeutic target in uterine sarcomas. Gynecol Oncol 104:524-528, 2007.
13. Loizos N, Xu Y, Huber J, et al: Targeting the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts. Mol Cancer Ther 4:369-379, 2005.
14. Judson I, Radford JA, Harris M, et al: Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: A study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 37:870-877, 2001.
15. Chawla SP, Papai Z, Mukhametshina G, et al: First-line aldoxorubicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissue sarcoma: A phase 2b randomized clinical trial. JAMA Oncol 1:1272-1280, 2015.
16. Schöffski P, Chawla S, Maki RG, et al: Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, multicentre, phase 3 trial. Lancet 387:1629-1637, 2016.
17. Grosso F, Jones RL, Demetri GD, et al: Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: A retrospective study. Lancet Oncol 8:595-602, 2007.
18. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011.
19. Kaufman PA, Awada A, Twelves C, et al: Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601, 2015.
20. Twelves C, Cortes J, Vahdat L, et al: Efficacy of eribulin in women with metastatic breast cancer: A pooled analysis of two phase 3 studies. Breast Cancer Res Treat 148:553-561, 2014.
21. Towle MJ, Salvato KA, Wels BF, et al: Eribulin induces irreversible mitotic blockade: Implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 71:496-505, 2011.
22. Funahashi Y, Okamoto K, Adachi Y, et al: Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 105:1334-1342, 2014.
23. Kawano S, Asano M, Adachi Y, et al: Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res 36:1553-1561, 2016.
24. Verschraegen CF, Chawla SP, Mita MM, et al: A phase II, randomized, controlled trial of palifosfamide plus doxorubicin versus doxorubicin in patients with soft tissue sarcoma (PICASSO). 2010 ASCO Annual Meeting. Abstract 10004.
25. Chawla SP, Ganjoo KN, Adkins D, et al: TH-302 in combination with doxorubicin in patients with first line advanced soft tissue sarcoma previously untreated with chemotherapy. 2011 Combined Meeting of the Connective Tissue Oncology Society and the Musculoskeletal Tumor Society. Paper 13. Presented October 27, 2011.
William D. Tap, MD
As reported by William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, and colleagues in The Lancet, the addition of the anti-PDGFRα (platelet-derived growth factor receptor alpha) antibody olaratumab to doxorubicin resulted in prolonged progression-free and...!-->!-->