Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

PDGFRα monoclonal antibody: Assessment of toxicity in juvenile mice administered a murine surrogate antibody of olaratumab.

BACKGROUND: Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. In order to support use of Lartruvo in pediatric patients, a definitive juvenile animal study in neonatal mice was conducted with a human anti-mouse PDGFRα antibody analog of olaratumab (LSN3338786). METHODS: A pilot study was used to set doses for the definitive juvenile mouse study. In the definitive study, juvenile mice were administered vehicle, 50, 100, or 150 mg/kg LSN3338786 by subcutaneous (SC) injection every 3 days between postnatal days (PND) 1 and 49, for a total of 17 doses. Blood samples were collected on PND 49 for antibody analysis and toxicokinetic evaluation. Tissues were collected on PND 52 for histopathologic examination. RESULTS: Results of the pilot study indicated that dosing neonatal mice starting on PND 1 via SC administration every 3 days was logistically feasible, produced exposures consistent with prior animal studies, and the selected dose levels were well tolerated by juvenile mice. In the definitive juvenile study, there were no LSN3338786-related deaths, clinical findings, and no effects on mean body weights, body weight gains, or food consumption. Additionally, there were no adverse LSN3338786-related hematology findings, and no macroscopic, organ weight, or microscopic findings of note. The highest dose evaluated, 150 mg/kg, was considered the NOAEL for juvenile toxicity. CONCLUSIONS: In conclusion, the juvenile animal studies did not identify any new toxicities or increased sensitivities for the intended pediatric patient population. The use of the surrogate antibody approach in a standard rodent model enabled the de-risking of theoretical concerns for toxicity in pediatric patients due to disruption of the PDGFRα pathway during early human development, such as pulmonary development.

Quality of life of patients with soft tissue sarcoma treated with doxorubicin in the ANNOUNCE phase III clinical trial.

BACKGROUND: Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy. METHODS: ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0-100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0-10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline. RESULTS: The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial (n = 460, 90.4% EORTC QLQ-C30; n = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months. CONCLUSION: Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.

Olaratumab's failure in soft tissue sarcoma.

Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26-75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3-37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28-10.45), and mean OS was 12.26 months (95% CI 8.47-16.05) Median OS was 9.8 months (95% CI 6.07-13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.

Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors.

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

Olaratumab plus anthracyline in advanced/metastatic soft tissue sarcoma : Data of real-world utilization in Austria.

BACKGROUND: Olaratumab is a humanized monoclonal antiplatelet-derived growth factor receptor alpha antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria. METHODS: Retrospectively collected longitudinal data from patients treated between November 2016 and September 2018 at 9 Austrian centers were obtained from the respective medical charts. All patients who received at least one dose of olaratumab were eligible. Parameters of most interest were response rates, progression-free survival (PFS) and overall survival (OS). RESULTS: Altogether 55 patients were included in the analysis. The median age was 58 years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first, second or ≥third line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); one patient received olaratumab as upfront monotherapy. The median PFS and OS were 2.6 and 11.4 months, respectively. The objective response rate was 11.4% and the disease control rate was 40.9%. CONCLUSION: In this real-world analysis the outcome was less pronounced compared to the results of both the phase Ib/II approval trial and the confirmatory phase III trial. The latter failed to show an improvement in OS and PFS for the doxorubicin/olaratumab combination. As such, olaratumab should not be used anymore in patients with STS.

Real-world experience with doxorubicin and olaratumab in soft tissue sarcomas in England and Northern Ireland.

BACKGROUND: A randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone. The recently presented phase III study of doxorubicin and olaratumab in advanced soft tissue sarcoma was discordant with this finding. METHODS: We performed a retrospective analysis of adult patients with advanced-/metastatic STS treated with at least two cycles of doxorubicin and olaratumab at eight sarcoma units across England and Northern Ireland between May 2017 and March 2019. RESULTS: 172 patients were evaluable and 40 patients (23.3%) had died at the time of analysis. Median ECOG performance status (PS) was 1. Median progression free survival (PFS) was 6.8 months (95% CI 5.9-7.7 months). Leiomyosarcoma was the most common histological subtype (75 patients, 43.6%), followed by liposarcomas (19, 11.0%). The mean number of cycles was 5 (doxorubicin range 2-6; olaratumab range 2-23). Two patients (1.2%) had a complete response and 34 (19.8%) had a partial response. 79 (45.9%) had stable and 58 (33.7%) progressive disease. 57 patients (33.1%) experienced grade ≥ 3 neutropenia and 7 patients (4.1%) grade ≥ 3 febrile neutropenia. Grade ≥ 3 anaemia was seen in 21 patients (12.2%). Grade ≥ 3 non-haematological toxicities were seen in 35 patients (20.3%). A clinically significant drop in left ventricular ejection fraction was seen in 6 patients (3.5%). 48 patients (27.9%) required a dose reduction. Overall survival (OS) is pending. CONCLUSIONS: Our results are in keeping with the phase III study findings: response rate, PFS and OS were similar to those reported in the phase III ANNOUNCE trial.

Metastatic Hepatic Epithelioid Hemangioendothelioma Treated with Olaratumab: A Falling Star Rising?

Epithelioid hemangioendothelioma (EHE) is a rare vascular malignant tumor with indolent course. Liver transplantation for local disease is the treatment of choice. In the metastatic setting there is no consensus regarding the appropriate systemic treatment. We present two cases of metastatic hepatic epithelioid hemangioendothelioma (hEHE) treated with the combination of Doxorubicin and Olaratumab. Both patients showed Stable Disease (SD) as a response, after the completion of six cycles of this combination therapy.

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience.

BACKGROUND: The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context. METHODS: Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019. RESULTS: Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD. CONCLUSIONS: This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.

Pharmacokinetics of doxorubicin following concomitant intravenous administration of olaratumab (IMC-3G3) to patients with advanced soft tissue sarcoma.

BACKGROUND: Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin. METHODS: This open-label randomized phase 1 trial enrolled 49 patients ages 27 to 83 with metastatic or locally advanced soft tissue sarcoma (STS). Patients participated in 21-day treatment cycles (up to 8) until they met discontinuation criteria. In cycles 1 and 2, patients received olaratumab (15 mg/kg in Part A, 20 mg/kg in Part B) and doxorubicin (75 mg/m2 ). In cycles 3 through 8, patients continued combination treatment (15 mg/kg olaratumab + doxorubicin). Effect of olaratumab on PK of doxorubicin was determined in patients who received all doses in cycles 1 and 2. RESULTS: PK properties of doxorubicin administered alone or in combination with olaratumab (15 or 20 mg/kg) were similar for AUC(0-tlast ), AUC(0-∞), and Cmax . PK properties of olaratumab (15 or 20 mg/kg) were also similar when administered alone or in combination with doxorubicin. Three patients died (2 of disease progression and 1 of neutropenic enterocolitis). Fatigue and nausea (>75% of patients) were the most common treatment-emergent adverse events (TEAEs). Other common TEAEs included musculoskeletal pain, mucositis, constipation, and diarrhea. CONCLUSIONS: Olaratumab at 15 or 20 mg/kg before doxorubicin infusion had no clinically relevant effect on systemic exposure to doxorubicin compared with doxorubicin alone in patients with metastatic or locally advanced STS.

Advances in soft-tissue sarcoma - There are no mistakes, only lessons to learn!

BACKGROUND: In this decade the treatment of advanced sarcoma has seen many highs and lows in terms of successful trials and failed trials. This is possible due to great collaborations, newer therapies and histology focused trials. METHODS: In ASCO 2019 many sarcoma trials were presented and we chose 3 challenging clinical trials that widen our perspective on soft tissue sarcoma. We have critically analyzed the data and have discussed the implications of these trials on current practice. First trial was ANNOUNCE trial which was done to confirm the efficacy of olaratumab after its dramatic success in advanced soft tissue sarcoma in a phase 2 trial. Another trial STRASS trial, which was unique because of being first successfully conducted randomized trial addressing preoperative radiotherapy in retroperitoneal soft tissue sarcoma. Third trial was phase 2 trial SARC 028 trial exploring the role of immunotherapy in pleomorphic undifferentiated sarcoma and liposarcoma subgroup. RESULT: ANNOUNCE trial failed to show OS benefit in olaratumab/doxorubicin arm as compared to doxorubicin/placebo arm. Based upon this FDA has revoked the approval of olaratumab leading to nihilism and disappointment amongst oncologists. In STRASS trial failed to meet the primary end point though there was a benefit in the liposarcoma subgroup in terms of abdominal recurrence free survival. There are several reasons that this trial might have failed. First, RPSs are not homogeneous population. RPSs might behave very differently as per the histopathology ranging from well differentiated LPS to leiomyosarcoma. Since the event rate in well-differentiated liposarcoma might happen late, the median follow-up of 43 months might not be sufficient. In SARC trial ORR in pleomorphic undifferentiated sarcoma (PUS) cohort was 9/40 (22.5%), while response rates in liposarcoma cohort were 4/39 (10.2%). There was poor correlation between the response and the tumor cells' PD-L1 positivity. Simultaneously, we must not take for granted the role of pembrolizumab in PUS as the previous study (PEMBROSARC) had also showed dismal outcomes with immunotherapy. CONCLUSION: In this paper we discuss the intricacies of these trials and how they affect the rapidly changing landscape in advanced soft tissue sarcoma.

A pilot study of first-line olaratumab, doxorubicin and ifosfamide in patients with metastatic soft tissue sarcoma.

INTRODUCTION: Olaratumab (O) is a monoclonal antibody that specifically binds PDGFRα. The addition of O to doxorubicin (D) has been approved by the regulatory authorities for metastatic soft tissue sarcoma (MSTS). Since the combination of D + ifosfamide (I) is commonly used in MSTS and is associated with a higher response rate than D alone, it seems reasonable to combine O with the combination of D + I (ODI). We report our preliminary experience with O + D+I in MSTS. METHODS: Between 01/01/2015 and 30/05/2018, 15 patients (pts) with MSTS were treated with ODI as first-line therapy. The treatment protocol consisted of IV D 50 mg/m2 and I 5000 mg/m2, day 1 (3 pts), or D 37.5 mg/m2 and I 3000 mg/m2 days 1-2 (12 pts). O (15 mg/kg) was given IV on days 1, 8, and cycles were repeated every 21 days. RESULTS: With a median follow up of 16 months, 63 cycles of ODI were given. Objective response was achieved in 4 pts (27%) (CR in 3, PR in 1); 5 pts (33%) remained with stable disease for ≥ 5 mo. Median overall survival was 22 months. Major hematological toxicities (grade 3-4) included: neutropenia-7 pts (47%), and neutropenic fever-3 pts (20%). Non-hematological toxicities included grade 3 diarrheas in 2 pts (13%) after the second cycle. There was no treatment-related mortality. CONCLUSION: According to our preliminary experience, adding olaratumab to doxorubicin and ifosfamide is active and its safety profile is comparable to that of doxorubicin and ifosfamide alone in MSTS.

Olaratumab administered in two cases of phyllodes tumour of the breast: end of the beginning?

Phyllodes tumours of the breast are rare mesenchymal tumours with differential malignant potential. Treatment of choice is radical excision with negative margins. Radiation therapy has shown controversial results in small series. Chemotherapy in the adjuvant setting still remains a matter of debate. Doxorubicin-based chemotherapy is recommended for breast sarcomas' first-line treatment. Herein we present two cases of breast phyllodes tumour treated with the recent combination of doxorubicin and olaratumab.

Assessment of the platelet-derived growth factor receptor alpha antibody olaratumab in a panel of patient-derived soft tissue sarcoma xenografts.

BACKGROUND: Soft tissue sarcoma (STS) comprises a family of rare, heterogeneous tumors of mesenchymal origin. Single-agent doxorubicin remains the first-line standard-of-care treatment for advanced and inoperable STS, but response rates are only around 15%. In 2016, phase Ib/II clinical trial results reported an overall survival benefit of 11.8 months when combining doxorubicin and the platelet-derived growth factor receptor alpha (PDGFRA)-directed antibody olaratumab compared to doxorubicin alone, without providing a scientific rationale for such unprecedented therapeutic effect. We decided to evaluate the efficacy of olaratumab in a panel of STS patient-derived xenografts (PDX). METHODS: NMRI nu/nu mice were bilaterally transplanted with tumor tissue of patient-derived xenograft models expressing PDGFRA, including models of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (UZLX-STS39), myxofibrosarcoma (UZLX-STS59) and undifferentiated pleomorphic sarcoma (UZLX-STS84). Mice were randomly divided into four different treatment groups: (1) control, (2) doxorubicin (3 mg/kg once weekly), (3) anti-PDGFRA [olaratumab (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of doxorubicin and anti-PDGFRA (same dose/schedule as in the single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy. RESULTS: Anti-PDGFRA treatment as a single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining doxorubicin and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in UZLX-STS39 and -STS59. A pro-apoptotic effect was observed in all models except UZLX-STS22. Antitumor effects on histology were not significantly different comparing doxorubicin and the combination treatment. Moreover, anti-PDGFRA treatment, both as a single agent as well as combined with doxorubicin, did not result in inhibition of the downstream MAPK and PI3K/AKT signaling pathways. CONCLUSIONS: We were not able to demonstrate significant antitumor effects of anti-PDGFRA treatment in selected STS PDX models, neither alone nor in combination with doxorubicin. This is in line with the very recent results of the phase III clinical trial NCT02451943 ANNOUNCE, which did not confirm the clinical benefit of olaratumab in combination with doxorubicin over single agent doxorubicin.

American Society of Clinical Oncology (ASCO) - 55th Annual Meeting (May 31-June 4, 2019 - Chicago, Illinois, USA).

The theme for this year's meeting of the American Association of Clinical Oncology (ASCO) was 'Caring for Every Patient, Learning from Every Patient'. The meeting consisted of oral, plenary and educational sessions, as well as poster presentations and discussions about important topics in the field of oncology, such as precision medicine, the latest in cancer research impacting patient care, new treatment options and insights for improving access to care. This 55th ASCO annual meeting was held from May 31 to June 4 in Chicago, Illinois, and was attended by over 40,000 cancer experts from around the world who followed a robust program providing opportunities to teach, engage and, most importantly, bring the oncology field together with the aim of improving care for patients with a cancer diagnosis. This report covers some of the later-stage developments and results presented at the meeting.

The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model.

PURPOSE: Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX). METHODS: Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment. RESULTS: Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis. CONCLUSIONS: The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

Olaratumab combined with doxorubicin and ifosfamide overcomes individual doxorubicin and olaratumab resistance of an undifferentiated soft-tissue sarcoma in a PDOX mouse model.

Olaratumab (OLA), a monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), with limited efficacy. The goal of the present study was to determine the efficacy of OLA in combination with DOX and ifosfamide (IFO) on STS. Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish USTS patient-derived orthotopic xenograft (PDOX) model. USTS PDOX tumors were treated with OLA alone, DOX alone, DOX combined with IFO, OLA combined with DOX or IFO, and OLA combined with DOX and IFO. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested by OLA combined with DOX and IFO. Tumors treated with OLA combined with DOX and IFO had the most necrosis. The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, DOX and IFO for soft-tissue sarcomas.

Current state of the art and emerging pharmacotherapy for uterine leiomyosarcomas.

INTRODUCTION: Uterine leiomyosarcomas (ULMS) account for 1% of all uterine malignancies and for 30% of all uterine sarcomas. The preoperative diagnosis of ULMS is challenging for the physicians, as the symptoms of these tumors are often vague and nonspecific. Moreover, as ULMS have an aggressive biologic behavior, affected women frequently have very poor prognosis. AREAS COVERED: The aim of this review is to describe the current pharmacotherapy for ULMS, including the ongoing clinical trials. EXPERT OPINION: Surgery is the standard treatment for patients with early-stage ULMS. In this setting, the role of adjuvant therapies is still unclear. In the case of advanced, persistent, or recurrent ULMS, chemotherapy is the standard care with the most frequently used drug being doxorubicin. As the outcomes for patients with the currently available conventional single or combined regimens are far from being satisfactory, new alternative and innovative medical compounds have or are being evaluated. Recently, pazopanib, and olaratumab, two innovative targeted drugs, have been approved by the Food and Drug Administration (FDA) for treating advanced soft-tissue sarcoma, including ULMS. However, further clinical investigations into new and innovation therapeutic options are warranted.

Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas.

BACKGROUND: Olaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS. METHODS: Primary STS were initiated in mice. When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm3, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype. FINDINGS: RT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09). INTERPRETATION: 1E10Fc did not act as a radiosensitizer in this primary STS model. FUNDING: This study was funded by a research agreement from Eli Lilly and Company.