Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial.

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease. METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer. FUNDING: GTx.

Overcoming Barriers to Referral for Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma. Although outcomes to frontline therapy are encouraging, patients who are refractory to or in relapse after first-line therapy experience inferior outcomes. A significant proportion of patients treated with additional lines of cytotoxic chemotherapy ultimately succumb to their disease, as established in the SCHOLAR-1 study. Chimeric antigen receptor (CAR) T cell therapy is a novel approach to cancer management that reprograms a patient's own T cells to better target and eliminate cancer cells. It was initially approved by the US Food and Drug Administration for patients with relapsed/refractory (r/r) DLBCL as a third line of treatment. Based on recently published randomized data, CAR-T therapy (axicabtagene ciloleucel and lisocabtagene maraleucel) also has been approved as a second line of treatment for patients who are primary refractory or relapse within 12 months of first-line therapy. Despite the proven efficacy in treating r/r DLBCL with CD19-directed CAR-T therapy, several barriers may prevent eligible patients from receiving treatment. Barriers to CAR-T therapy include cost of therapy, patient hesitancy, required travel to academic treatment centers, nonreferrals, poor understanding of CAR-T therapy, lack of caregiver support, knowledge of available resources, and timely patient selection by referring oncologists. In this review, we provide an overview of the FDA-approved CD19-directed CAR-T cell therapies (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) from pivotal clinical trials and supporting real-world evidence from retrospective studies. In both clinical trials and real-world settings, CAR-T therapy has been shown to be safe and efficacious for treating patients with r/r DLBCL: however, several barriers prevent eligible patients from accessing these therapies. Barriers to referrals for CAR-T therapy are described, along with recommendations to improve collaboration between community oncologists and physicians from CAR-T therapy treatment centers and subsequent long-term care of patients in community treatment centers.

Impact of early detection on cancer curability: A modified Delphi panel study.

Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients.

A review of the totality of evidence in the development of ABP 798, a rituximab biosimilar.

ABP 798 (RIABNI™) is a biosimilar to rituximab reference product (RP), a monoclonal antibody that targets CD20. Approval of ABP 798 was based on the totality of evidence generated using a stepwise approach which began by showing that it is structurally and functionally similar to rituximab RP. This analytical assessment was followed by a demonstration of pharmacokinetic/pharmacodynamic similarity in patients with rheumatoid arthritis. Comparative clinical efficacy and safety of ABP 798 with rituximab RP was demonstrated as a final step in patients with non-Hodgkin lymphoma and in those with rheumatoid arthritis. Overall, the totality of evidence supported the conclusion that ABP 798 is highly similar to rituximab RP and provided scientific justification for extrapolation to other approved indications of rituximab RP.

Correction to: Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

Page 608, 4 Discussion, right column, second paragraph.

Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

INTRODUCTION: ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). METHODS: This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. RESULTS: Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (- 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (- 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. CONCLUSIONS: These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT NUMBER: NCT02747043; first posted April 21, 2016. EUDRACT NUMBER: 2013-005,542-11; submitted 14 October, 2014.

A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study.

Eflapegrastim (Rolontis® ) is a novel, long-acting hematopoietic growth factor consisting of a recombinant human granulocyte-colony stimulating factor (rhG-CSF) analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. We report results from a second pivotal, randomized, open-label, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. Patients with Stage I to IIIA early-stage breast cancer (ESBC) were randomized 1:1 to fixed-dose eflapegrastim 13.2 mg (3.6 mg G-CSF) or pegfilgrastim (6 mg G-CSF) administered one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary objective was to demonstrate noninferiority (NI) of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN; Grade 4) in Cycle 1. A total of 237 eligible patients were randomized 1:1 to receive either eflapegrastim (n = 118) or pegfilgrastim (n = 119). Cycle 1 severe neutropenia was observed in 20.3% (n = 24) of patients receiving eflapegrastim and 23.5% (n = 28) receiving pegfilgrastim. The DSN of eflapegrastim in Cycle 1 was noninferior to pegfilgrastim with a mean difference of -0.074 days (NI P-value < .0001). Noninferiority was maintained throughout the four treatment cycles (P < .0001 in all cycles). Other efficacy endpoints results were comparable between treatment arms, and adverse events, irrespective of causality and grade, were comparable between treatment arms. The results demonstrate noninferior efficacy and comparable safety for eflapegrastim, at a lower G-CSF dose, vs pegfilgrastim. The potential for the increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study.

Eflapegrastim, a Long-Acting Granulocyte-Colony Stimulating Factor for the Management of Chemotherapy-Induced Neutropenia: Results of a Phase III Trial.

BACKGROUND: Eflapegrastim, a novel, long-acting recombinant human granulocyte-colony stimulating factor (rhG-CSF), consists of a rhG-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Preclinical and phase I and II pharmacodynamic and pharmacokinetic data showed increased potency for neutrophil counts for eflapegrastim versus pegfilgrastim. This open-label phase III trial compared the efficacy and safety of eflapegrastim with pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. MATERIALS AND METHODS: Patients with early-stage breast cancer were randomized 1:1 to fixed-dose eflapegrastim 13.2 mg (3.6 mg G-CSF) or standard pegfilgrastim (6 mg G-CSF) following standard docetaxel plus cyclophosphamide chemotherapy for 4 cycles. The primary objective was to demonstrate the noninferiority of eflapegrastim compared with pegfilgrastim in mean duration of severe neutropenia (DSN; grade 4) in cycle 1. RESULTS: Eligible patients were randomized 1:1 to study arms (eflapegrastim, n = 196; pegfilgrastim, n = 210). The incidence of cycle 1 severe neutropenia was 16% (n = 31) for eflapegrastim versus 24% (n = 51) for pegfilgrastim, reducing the relative risk by 35% (p = .034). The difference in mean cycle 1 DSN (-0.148 day) met the primary endpoint of noninferiority (p < .0001) and also showed statistical superiority for eflapegrastim (p = .013). Noninferiority was maintained for the duration of treatment (all cycles, p < .0001), and secondary efficacy endpoints and safety results were also comparable for study arms. CONCLUSION: These results demonstrate noninferiority and comparable safety for eflapegrastim at a lower G-CSF dose versus pegfilgrastim. The potential for increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study in patients at higher risk for CIN. IMPLICATIONS FOR PRACTICE: Chemotherapy-induced neutropenia (CIN) remains a significant clinical dilemma for oncology patients who are striving to complete their prescribed chemotherapy regimen. In a randomized, phase III trial comparing eflapegrastim to pegfilgrastim in the prevention of CIN, the efficacy of eflapegrastim was noninferior to pegfilgrastim and had comparable safety. Nevertheless, the risk of CIN remains a great concern for patients undergoing chemotherapy, as the condition frequently results in chemotherapy delays, dose reductions, and treatment discontinuations.

Symptom trajectories during chemotherapy in outpatients with lung cancer colorectal cancer, or lymphoma.

PURPOSE: Pain, depression, distress, fatigue, and sleep disturbance are common symptoms in oncology patients, but little data are available that examine the trajectories of these symptoms during chemotherapy (CTX). The purposes of this study were to examine the trajectories of these symptoms during the first six cycles of CTX and to determine whether individual characteristics predicted the trajectories of these symptoms. METHODS: Oncology outpatients (n = 118) with newly diagnosed lung cancer, colorectal cancer, or lymphoma rated symptoms using an electronic patient care monitor system. Pain, fatigue, and sleep disturbance were rated on 0-10 numeric rating scales; depression and distress were evaluated using scales converted to normalized T scores. Latent growth curve analyses (LGCA) examined for intra- and inter-individual differences in the trajectories of these five symptoms during the six cycles of CTX. RESULTS: Symptoms were present at the initiation of CTX (p < 0.0001) for all symptoms (p < 0.05). Distress (p = 0.03) and pain (p = 0.02) intensity decreased significantly over the six cycles of CTX. Advanced disease and a higher number of comorbidities predicted higher fatigue at baseline (p = 0.02 and 0.01 respectively). A diagnosis of lung cancer predicted an increasing intensity of fatigue during CTX (p = 0.04). Concurrent radiation therapy predicted more intense pain over time (p = 0.03). CONCLUSIONS: While symptom trajectories were highly variable in patients undergoing initial CTX, the majority of the symptom intensity scores decreased over time. However, patients with lung cancer, those with a higher number of comorbidities, and those with advanced disease experienced more intense fatigue and sleep disturbance over time.

Symptom trajectories in posttreatment cancer survivors.

BACKGROUND: Cancer survivorship following cancer treatment is uncertain as physical and psychological sequelae related to the disease or its treatment may persist. However, little is known about the experience of symptoms after treatment. OBJECTIVES: The purposes of this study were to (1) examine postchemotherapy (post-CTX) symptom trajectories in cancer survivors and (2) determine whether demographic characteristics predicted symptom trajectories. METHODS: One hundred patients who recently completed CTX for lung cancer, colorectal cancer, or lymphoma rated symptoms on an electronic patient care monitor system prior to ambulatory care visits. Latent growth curve analyses were conducted to examine the trajectories of pain, fatigue, sleep disturbance, distress, and depression for 16 months after initial CTX. RESULTS: Symptoms were present at the first follow-up visit following CTX (P < .0001) and persisted over 16 months. The depression trajectory was predicted by sex: males showed a convex curvilinear growth trajectory, whereas females showed a concave trajectory (P < .05). Higher distress was predicted by younger age (P < .05). CONCLUSIONS: Psychological and physical symptoms persisted over the 16-month period following CTX for the entire sample. Sex differences in coping could partially explain the different trajectories of growth for depression, but further studies are warranted. Younger patients may be more vulnerable for distress during this posttreatment phase. IMPLICATIONS FOR PRACTICE: The posttreatment surveillance plan for cancer survivors should include a comprehensive assessment of psychological and physical symptoms. Persistence of symptoms can be expected in some patients, and supportive interventions should be tailored according to symptom reports.

Initial treatment and changes in adjuvant endocrine therapy for early stage breast cancer.

Clinical trials have shown that aromatase inhibitors (AIs) are an important advance in the treatment of early stage breast cancer (ESBC), but practice patterns and the impact of treatment side effects of endocrine therapy in the community setting have not been extensively explored. This retrospective chart review describes practice patterns among patients receiving adjuvant endocrine therapy for ESBC. Charts of 200 patients with confirmed stage I-IIIA breast cancer were reviewed. Patients received first-line treatment with tamoxifen (n=96) or AIs (n=104). Fifty-one patients completed a structured interview regarding symptom burden during therapy. Time to discontinuation or switching from first-line therapy did not vary by drug class (tamoxifen vs. AI). Musculoskeletal symptoms predicted time to switching among AI patients. Tamoxifen patients who switched to AIs tended to do so following clinical guidelines for use of AIs. Interview results showed that more anastrozole than tamoxifen patients cited side effects as the reason for switching.

Patient and practice impact of capecitabine compared to taxanes in first-/second-line chemotherapy for metastatic breast cancer.

BACKGROUND: Oral chemotherapy regimens have emerged as comparably effective to intravenous regimens with the potential for less resource utilization, fewer treatment side effects and a better quality-of-life outcome. The objective of this retrospective chart review was to examine these issues among patients who received single-agent taxane therapy vs. single-agent capecitabine for first- or second-line treatment of metastatic breast cancer (MBC) METHODS: Data from the medical charts of 61 patients who received single-agent capecitabine, docetaxel, or paclitaxel therapy were supplemented with data from the 38-item Patient Care Monitor (PCM) survey of symptom burden and quality of life, prospectively collected during chemotherapy. The endpoints were PCM index scores, hospitalization during treatment, and the number of clinic visits during treatment. RESULTS: The sample was 75% Caucasian, 16% African-American, with a mean age of 59.4 years. Taxane-treated patients had more clinic visits than capecitabine patients, were more likely to have been hospitalized during treatment, and had worse treatment side effects. Controlling for depression, infusion-treated patients reported greater acute distress at the start of therapy than those on oral medication. CONCLUSION: Capecitabine for MBC was associated with a more favorable outcome regarding treatment side effects and quality of life, with reduced resource burden to patients and providers. Physicians may have differentially selected patients with greater depressive symptoms for capecitabine therapy.

Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study.

From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session. Therapy was delivered for six weeks out of every 8-week treatment cycle. The gastrointestinal toxicity of this regimen was mild with 2 patients experiencing grade 3 stomatitis, and 6 patients having grade 3 diarrhea; and the hematologic toxicity was acceptable with 6 of 57 patients found to have had grade 3 or 4 leukopenia, and 14 of 57 patients experiencing grade 3 or 4 neutropenia. There were two deaths judged possibly related to treatment; one in a patient who experienced a variety of Grade 2 gastrointestinal toxicities and died at home with an unknown cause of death; and a second patient who also died at home, and for whom treatment-related sepsis could not be ruled out. The overall median survival was 7.2 months. The ability to safely deliver twice the usual dose of 5-FU with leucovorin on a weekly schedule suggests that oral uridine analog supplementation with PN401 may enhance the therapeutic index of the fluoropyrimidines.