Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study.

In monarchE, adjuvant abemaciclib significantly improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS), with sustained benefit beyond the 2-year treatment period. Abemaciclib dose reductions were allowed to proactively manage adverse events. Exploratory analyses to investigate the impact of dose reductions on efficacy were conducted. Across the three patient subgroups as defined by relative dose intensity (≤66%, 66-93%, ≥93%), the estimated 4-year IDFS rates were generally consistent (87.1%, 86.4%, and 83.7%, respectively). In the time-dependent Cox proportional hazard model, the effect of abemaciclib was consistent at the full dose compared to being reduced to a lower dose (IDFS hazard ratio: 0.905; 95% confidence interval: 0.727, 1.125; DRFS hazard ratio: 0.942; 95% confidence interval: 0.742, 1.195). These analyses showed that the efficacy of adjuvant abemaciclib was not compromised by protocol mandated dose reductions for patients with node positive, hormone receptor positive, human epidermal growth factor 2-negative, high-risk early breast cancer.

Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients. Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE. Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.

BACKGROUND: Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up. METHODS: In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing. FINDINGS: Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37-47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578-0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2-87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5-81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748-1·153; p=0·50). The most common grade 3-4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group. INTERPRETATION: Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients. FUNDING: Eli Lilly.

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial.

PURPOSE: Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943). PATIENTS AND METHODS: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m2. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%. RESULTS: A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m2 (range, 72.3-634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450-<600 mg/m2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m2, 82 of 159 patients (51.6%) who received 450-<600 mg/m2, and 50 of 89 patients (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m2, 3% at 450-<600 mg/m2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs was low across all dose ranges. CONCLUSIONS: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration.See related commentary by Benjamin and Minotti, p. 3809.

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.

Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial.

Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. Design, Setting, and Participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. Main Outcomes and Measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). Conclusions and Relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02451943.

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.

Incidence and Management of Olaratumab Infusion-Related Reactions.

PURPOSE: Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports. METHODS: Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies. RESULTS: In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials. CONCLUSION: Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

Randomised phase II study of second-line olaratumab with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer.

INTRODUCTION: Platelet-derived growth factor receptor-α (PDGFRα) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFRα and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel. METHODS: Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m2, Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts. RESULTS: A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87-1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72-1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade ≥3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043). CONCLUSIONS: Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered.

Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer.

BACKGROUND: Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. METHODS: Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. RESULTS: A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698-1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6-9.2) and 3.7 months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. CONCLUSIONS: The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.

Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer.

Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.

Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC.

BACKGROUND: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. MATERIALS AND METHODS: Patients received up to six 21-day cycles of P 200mg/m2 and C AUC 6 (day 1)±olaratumab 15mg/kg (days 1 and 8). Primary endpoint was PFS. Olaratumab was continued in the olaratumab+P/C arm until disease progression. RESULTS: 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. CONCLUSIONS: The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.

Mechanical bridge to recovery in pheochromocytoma myocarditis.

BACKGROUND: A 27-year-old male presented with exercise-related symptoms of chest tightness, palpitations, breathlessness and severe headache, with occasional nausea, dizziness, and blurred vision. Apart from a family history of coronary artery disease there was no other medical history of note. INVESTIGATIONS: Clinical examination, treadmill exercise test (Bruce protocol), electrocardiography, MRI of the abdomen, blood tests, chest radiography, coronary angiography, two-dimensional echocardiography, transesophageal echocardiography, microscopy of the tumor, (131)iodine metaiodobenzylguanidine scan. DIAGNOSIS: Pheochromocytoma myocarditis. MANAGEMENT: Intra-aortic balloon pump, levosimendan and dobutamine infusion, alpha-blockade with phentolamine, surgical removal of the pheochromocytoma, Levitronix (Levitronix LLC, Waltham, MA) left ventricular assist device implantation.