Other concerns are raised by possible differences in disease biology between treatment groups, which may impact on the findings of relatively small studies. Some differences between cohorts in the study arms were noticed; for example, the proportion of patients with undifferentiated pleomorphic sarcoma, an aggressive STS subtype, was higher in the doxorubicin monotherapy arm vs the combination arm (21% vs 15%, respectively). Another imbalance also occurred in the “other” disease category (26% in the combination arm vs 9% in the monotherapy arm), and finally, more women were included in the combination arm (61% vs 51%, respectively). These differences between groups might account for the differences observed in terms of OS.

The effect of olaratumab on the PDGFR pathway also seems to be interesting, even if in the Phase Ib/II study, PDGFRα expression in tumor samples did not show any predictive value on efficacy and, indeed, the authors reported that negative expression of this marker was associated with a favorable outcome, which does not support PDGFRα inhibition in the tumor as the main mechanism of action. However, as confirmed by the authors, the immunohistochemistry assay used to assess PDGFRα expression was not specific; therefore, this issue would require further investigation.


Continue Reading

Olaratumab represents a promising and well-tolerated new anticancer therapy that has demonstrated an unexpected survival benefit in combination with doxorubicin in patients with advanced or metastatic STSs who have poor prognosis. Although in the future this combination seems to have the potential to become the new standard of care for first-line treatment of STS patients, the results of the ANNOUNCE confirmatory Phase III trial are warranted in order to confirm these optimistic perspectives and solve the unanswered questions.

Disclosure

The authors report no conflicts of interest in this work.

References

1.

Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11(4):187–202.

2.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

3.

Clark MA, Fisher C, Judson I, Thomas JM. Soft-tissue sarcomas in adults. N Engl J Med. 2005;353(7):701–711.

4.

Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5(6):840–850.

5.

Knepper TC, Saller J, Walko CM. Novel and expanded oncology drug approvals of 2016-PART 1: new options in solid tumor management. Oncology (Williston Park). 2017;31(2):110–121.

6.

Shirley M. Olaratumab: first global approval. Drugs. 2017;77(1):107–112.

7.

von Mehren M, Randall RL, Benjamin RS, et al. Soft tissue sarcoma, version 2. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(6):758–786.

8.

Bramwell VHC, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline.Sarcoma. 2000;4(3):103–112.

9.

Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.Lancet Oncol. 2014;15(4):415–423.

10.

Seddon BM, Whelan J, Strauss SJ, et al. GeDDiS: a prospective randomised controlled phase III trial of gemcitabine and docetaxel compared with doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft tissue sarcomas (EudraCT 2009-014907-29). J Clin Oncol. 2015;33(suppl):abstr10500.

11.

Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: a phase III, placebo-controlled study of doxorubicin with or without Palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol. 2016;34(32):3898–3905.

12.

Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017;18(8):1089–1103.

13.

Montironi R, Cheng L, Mazzucchelli R, et al. Immunohistochemical detection and localization of somatostatin receptor subtypes in prostate tissue from patients with bladder outlet obstruction. Cell Oncol. 2008;30(6):473–482.

14.

Florio T, Montella L, Corsaro A, et al. In vitro and in vivo expression of somatostatin receptors in intermediate and malignant soft tissue tumors. Anticancer Res. 2003;23:2465–2471.

15.

Crespo-Jara A, González Manzano R, Lopera Sierra M, Redal Peña MC, Brugarolas Masllorens A. A patient with metastatic sarcoma was successfully treated with radiolabeled somatostatin analogs. Clin Nucl Med. 2016;41(9):705–707.

16.

George D. Platelet-derived growth factor receptors: a therapeutic target in solid tumors. Semin Oncol. 2001;28(5 suppl 17):27–33.

17.

Board R, Jayson GC. Platelet-derived growth factor receptor (PDGFR): a target for anticancer therapeutics. Drug Resist Updat. 2005;8(1–2):75–83.

18.

Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004;15(4):275–286.

19.

Ehnman M, Missiaglia E, Folestad E, et al. Distinct effects of ligand-induced PDGFRalpha and PDGFRbeta signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res. 2013;73(7):2139–2149.

20.

Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors.Science. 2003;299(5607):708–710.

21.

Mir O, Brodowicz T, Italiano A, et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1732–1742.

22.

George S, Merriam P, Maki RG, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27(19):3154–3160.

23.

Maki RG, D’Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009;27(19):3133–3140.

24.

van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879–1886.

25.

Kilvaer TK, Valkov A, Sorbye SW, et al. Platelet-derived growth factors in non-GIST soft-tissue sarcomas identify a subgroup of patients with wide resection margins and poor disease-specific survival. Sarcoma. 2010;2010:751304.

26.

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 Ib and randomised phase II trial. Lancet. 2016;388(10043):488–497.

27.

Heldin CH, Eriksson U, Ostman A. New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys. 2002;398(2):284–290.

28.

Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 2004;15(4):197–204.

29.

Seifert RA, Hart CE, Phillips PE, et al. Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem. 1989;264(15):8771–8778.

30.

Svegliati S, Cancello R, Sambo P, et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS and Ras in systemic sclerosis fibroblasts. J Biol Chem. 2005;280(43):36474–36482.

31.

Smaldone S, Olivieri J, Gusella GL, Moroncini G, Gabrielli A, Ramirez F. Ha-Ras stabilization mediates pro-fibrotic signals in dermal fibroblasts. Fibrogenesis Tissue Repair. 2011;4(1):8.

32.

Spadoni T, Svegliati Baroni S, Amico D, et al. A reactive oxygen species-mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. Arthritis Rheumatol. 2015;67(6):1611–1622.

33.

Alvarez RH, Kantarjian HM, Cortes JE. Biology of platelet-derived growth factor and its involvement in disease.Mayo Clin Proc. 2006;81(9):1241–1257.

34.

Dong J, Grunstein J, Tejada M, et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004;23(14):2800–2810.

35.

Crawford Y, Kasman I, Yu L, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34.

36.

Shah GD, Loizos N, Youssoufian H, Schwartz JD, Rowinsky EK. Rationale for the development of IMC-3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet-derived growth factor receptor α. Cancer. 2010;116(4 suppl):1018–1026.

37.

Lokker NA, O’Hare JP, Barsoumian A, et al. Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies. J Biol Chem. 1997;272(52):33037–33044.

38.

LaRochelle WJ, Jensen RA, Heidaran MA, et al. Inhibition of platelet derived growth factor autocrine growth stimulation by a monoclonal antibody to the human a platelet-derived growth factor receptor. Cell Growth Differ. 1993;4(7):547–553.

39.

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: implications as a potential therapeutic target. Mol Cancer Ther. 2005;4(3):369–379.

40.

Dolloff NG, Russell MR, Loizos N, Fatatis A. Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor. Cancer Res. 2007;67(2):555–562.

41.

Moroncini G, Grieco A, Nacci G, et al. Epitope specificity determines pathogenicity and detectability of anti-platelet-derived growth factor receptor alpha autoantibodies in systemic sclerosis. Arthritis Rheumatol. 2015;67(7):1891–1903.

42.

Moroncini G, Cuccioloni M, Mozzicafreddo M, et al. Characterization of binding and quantification of human autoantibodies to PDGFRalpha using a biosensor-based approach. Anal Biochem. 2017;528:26–33.

43.

Svegliati S, Amico D, Spadoni T, et al. Agonistic anti-PDGF receptor autoantibodies from patients with systemic sclerosis impact human pulmonary artery smooth muscle cells function in vitro. Front Immunol. 2017;8:75.

44.

Luchetti MM, Moroncini G, Jose Escamez M, et al. Induction of scleroderma fibrosis in skin-humanized mice by administration of anti-platelet-derived growth factor receptor agonistic autoantibodies. Arthritis Rheumatol. 2016;68:2263–2273.

45.

Tonra J, Deevi D, Carrick F, et al. Enhanced antitumour activity of anti-platelet derived growth factor receptor alpha antibody, IMC-3G3, in combination with doxorubicin against a human soft-tissue sarcoma xenograft model. AACR-NCI-EORTC MolecularTargets and Cancer Therapeutics International Conference; 2005 Nov 14–18. Philadelphia, PA: 2005:A67.

46.

Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493–507.

47.

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. 2014;73(3):595–604.

48.

Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A. Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(7):862–869.

49.

NIH [homepage on the Internet]. A Study of Doxorubicin Plus Olaratumab (LY3012207) in Participants with Advanced or Metastatic Soft Tissue Sarcoma. 2018. Available from: http://www.mayo.edu/research/clinical-trials/cls-20193937. Accessed January 17, 2018.

50.

Oakley GJ 3rd, Wijayawardana S, Marchal C. Expression of pdgfrα, ligands, and related genes versus clinical outcomes in a phase 1b/2 study of olaratumab plus doxorubicin in soft tissue sarcoma. CTOS 2017 Annual Meeting, Maui, Hawaii: Poster 217 #2768598.

51.

Barker S, Peterson P, Ilaria RL, et al. Olaratumab after treatment with olaratumab + doxorubicin: monotherapy (mono) outcomes from the jgdg phase 2 clinical trial. CTOS 2017 Annual Meeting, Maui, Hawaii: Poster 202 #2778170.

52.

NIH [homepage on the Internet]. A Study of Olaratumab (LY3012207) in Participants with Advanced Soft Tissue Sarcoma. 2018. Available from: http://www.utswmedicine.org/cancer/clinical-trials/fact-detail.html?primarypurpose=10&studyId=STU%20012016-032. Accessed January 17, 2018.

53.

Wagner AJ, Kindler H, Gelderblom H, et al. A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors. Ann Oncol. 2017;28(3):541–546.

54.

Gerber DE, Swanson P, Lopez-Chavez A, et al. Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC. Lung Cancer. 2017;111:108–115.

55.

FDA [webpage on the Internet]. Orphan Drug Designations and Approvals. 2018. Available from:https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed January 17, 2018.

56.

EPAR Summary for the Public. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004216/human_med_002036.jsp&mid=WC0b01ac058001d124. Accessed January 17, 2018.

57.

Lartruvo® (olaratumab) injection [FDA prescribing information] [homepage on the Internet]; 2016. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761038lbl.pdf. Accessed January 17, 2018.

58.

Lartruvo® (olaratumab) injection [EMA prescribing information] [homepage on the Internet]; 2016. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004216/WC500216869.pdf. Accessed January 17, 2018.

59.

Mo G, Baldwin JR, Luffer-Atlas D, et al. Population pharmacokinetic modeling of olaratumab, an anti-PDGFRa human monoclonal antibody, in patients with advanced and/or metastatic cancer. Clin Pharmacokinet. Epub 2017 Jun 15.

60.

Lowery CD, Blosser W, Dowless M, et al. Olaratumab exerts anti-tumor activity in preclinical models of pediatric bone and soft tissue tumors through inhibition of platelet-derived growth factor receptor & alpha. Clin Cancer Res. Epub 2017 Nov 30.

61.

Koos B, Jeibmann A, Lünenbürger H, et al. The tyrosine kinase c-Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors. Cancer. 2010;116(21):5075–5081.

62.

Vincenzi B, Badalamenti G, Napolitano A, et al. Olaratumab: PDGFR-α inhibition as a novel tool in the treatment of advanced soft tissue sarcomas. Crit Rev Oncol Hematol. 2017;118:1–6.

63.

Giampieri R, Scartozzi M, Del Prete M, et al. The “angiogenetic ladder”, step-wise angiogenesis inhibition in metastatic colorectal cancer. Cancer Treat Rev. 2014;40(8):934–941.