Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer.

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors.

PURPOSE: Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label, phase II, registrational study. Cohort 1 includes patients with locally advanced or unresectable or mUC who had progressed after prior PLT and CPI. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary outcome was centrally reviewed ORR; secondary outcomes were progression-free survival, OS, duration of response, and safety. RESULTS: Cohort 1 included 113 patients (78% men; median age, 66 years; 66.4% visceral metastases; median of three [range, 1-8] prior therapies). At a median follow-up of 9.1 months, the ORR was 27% (31 of 113; 95% CI, 19.5 to 36.6); 77% had decrease in measurable disease. Median duration of response was 7.2 months (95% CI, 4.7 to 8.6 months), with median progression-free survival and OS of 5.4 months (95% CI, 3.5 to 7.2 months) and 10.9 months (95% CI, 9.0 to 13.8 months), respectively. Key grade ≥ 3 treatment-related adverse events included neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%), with 6% discontinuing treatment because of treatment-related adverse events. CONCLUSION: SG is an active drug with a manageable safety profile with most common toxicities of neutropenia and diarrhea. SG has notable efficacy compared with historical controls in pretreated mUC that has progressed on both prior PLT regimens and CPI. The results from this study supported accelerated approval of SG in this population.

High Body Mass Index and Use of Fentanyl Iontophoretic Transdermal System in Postoperative Pain Management: Results of a Pooled Analysis of Six Phase 3/3B Trials.

INTRODUCTION: Postoperative pain management can be challenging in patients with a high body mass index (BMI) especially as a result of poor venous access and delayed ambulation that can result in serious complications. Fentanyl iontophoretic transdermal system (ITS) is a needle-free, patient-controlled analgesic method available for use in acute postoperative pain. The primary objective of these analyses was to determine if there were any differences between patients with high BMI (>40 kg/m2) and lower BMIs (<30 kg/m2 and 35-40 kg/m2) in terms of efficacy or safety. METHODS: Data from three registration, placebo-controlled trials and three active-comparator trials using fentanyl ITS (IONSYS®, The Medicines Company, Parsippany, NJ) for the management of postoperative pain were analyzed using BMI categories of <35 kg/m2, 35-40 kg/m2, and >40 kg/m2. The majority of patients had lower abdominal or orthopedic surgery. For these analyses, the primary efficacy variables were assessed via patient global assessment of pain control (PGA) at 24 h and investigator global assessment (IGA) at study discharge. PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment "success" defined as either excellent or good. Safety was evaluated via treatment emergent adverse events (TEAEs). RESULTS: There were 1403 patients randomly assigned and treated with fentanyl ITS for at least 3 h (BMI <35 kg/m2: 1180; 35-40 kg/m2: 136, BMI >40 kg/m2: 85; and 2 missing). PGA treatment success, which evaluates the method of pain control, at 24 h was consistent in the high and low BMI groups in patients treated with fentanyl ITS (<35 kg/m2: 946/1180 [80.2%]; 35-40 kg/m2: 103/136 [75.7%]; and >40 kg/m2: 65/85 [76.5%]). The IGA results at study discharge were similar to the PGA. Safety appeared similar with fentanyl ITS across the BMI groups. CONCLUSION: In these analyses, fentanyl ITS was as efficacious, as assessed by the PGA ratings of treatment "success", in patients with high BMI (>40 kg/m2) as it was for those with lower BMIs (<35 kg/m2 or 35-40 kg/m2) and was generally well tolerated across all BMI categories.

Use of Fentanyl Iontophoretic Transdermal System (ITS) (IONSYS®) in the Management of Patients with Acute Postoperative Pain: A Case Series.

Fentanyl iontophoretic transdermal system (ITS) [IONSYS®, The Medicines Company, Parsippany, NJ, USA] is a needle-free, patient-controlled, postoperative opioid pain management treatment. It is indicated for the short-term management of acute postoperative pain in adults requiring opioid analgesia in the hospital. The safety and effectiveness of fentanyl ITS for acute postoperative pain management has been demonstrated in a range of surgery and patient types studied in seven phase 3 trials (three placebo-controlled trials and four active-comparator trials). The majority of the patients in the phase 3 trials had undergone either abdominal/pelvic, orthopedic, or thoracic surgery. Consistent with the prescribing information, physicians in clinical practice may treat patients with this system following any type of surgery including those that may not have been included in the phase 3 trials. The purpose of this case series is to illustrate how fentanyl ITS is being utilized for postoperative pain management in real-world clinical practice following a variety of surgeries and in current pain management protocols that may have evolved since the completion of the phase 3 program. There are seven cases from three clinical centers described within this case series, each using fentanyl ITS according to the prescribing information. The surgery types included are bariatric (N = 3), prostate (N = 2), colorectal (N = 1), and perirectal abscess drainage (N = 1). A systematic review of each patient chart was conducted via a standardized retrospective assessment by the clinicians who managed each patient. Additionally, each healthcare professional was interviewed regarding their overall experience and key learnings using fentanyl ITS. Overall, fentanyl ITS was effective and well tolerated in these case reports in current-day clinical practice settings. These case studies are informative about fentanyl ITS use shortly after product approval and set the stage for additional clinical research.

The Efficacy and Safety of the Fentanyl Iontophoretic Transdermal System (IONSYS®) in the Geriatric Population: Results of a Meta-Analysis of Phase III and IIIb Trials.

BACKGROUND AND OBJECTIVES: Acute postoperative pain management in the geriatric patient can be challenging, including their response to medications. The purpose of this analysis was to evaluate whether the efficacy and safety profile of fentanyl iontophoretic transdermal system (ITS) (IONSYS®) was similar in geriatric (≥65 years) and non-geriatric (<65 years) patients. METHODS: Efficacy and safety data from three randomized, double-blind, placebo-controlled trials and four randomized, open-label, active-comparator trials were utilized for this analysis. Efficacy was assessed via the patient global assessment (PGA) and the investigator global assessment (IGA) scales. The PGA and IGA are categorical 4-point scales (excellent, good, fair, or poor) with treatment success defined as excellent or good. Safety was evaluated via adverse events. RESULTS: A total of 1763 patients were assigned to the fentanyl ITS treatment group. Of the 1763 patients in the fentanyl ITS group, 499 patients were ≥65 years of age; 65.1% were 65-74 years of age, 31.7% were 75-84 years of age, and 3.2% were ≥85 years of age. In the fentanyl ITS treatment groups, there were no statistically significant differences between the non-geriatric and geriatric patients in terms of patients reporting success on the PGA at 24 h (80.0 vs. 83.0%, respectively; p = 0.3415). There were no statistically significant differences between the groups in success rates on the IGA at study discharge (82.8 vs. 87.5%, respectively; p = 0.1195). The safety profile was similar between the age groups. CONCLUSIONS: Overall, efficacy and safety of the fentanyl ITS were similar between the geriatric and non-geriatric patients.

Fentanyl Iontophoretic Transdermal System (IONSYS(®)) can be Safely used in the Hospital Environment with X-Rays, Computerized Tomography and Radiofrequency Identification Devices.

INTRODUCTION: Fentanyl iontophoretic transdermal system (fentanyl ITS, IONSYS(®)) is a patient-controlled analgesia system used for the management of acute postoperative pain, designed to be utilized in a hospital setting. The objective of the two studies was to determine if fentanyl ITS could be safely used with X-rays, computerized tomography (CT) scans and radiofrequency identification (RFID) devices. METHODS: The ITS system has two components: controller and drug unit; the studies utilized ITS systems without fentanyl, referred to as the ITS Placebo system. The first study evaluated the effect of X-radiation on the operation of an ITS Placebo system. Five ITS Placebo systems were exposed to X-rays (20 and 200 mSv total radiation dose-the 200 mSv radiation dose represents a tenfold higher exposure than in clinical practice) while operating in the Ready Mode and five were exposed while operating in the Dose Mode. The second study evaluated the effect of RFID (worst-case scenario of direct contact with an RFID transmitter) on the operation of an ITS Placebo system. During these tests, observations of the user interface and measurements of output voltage confirmed proper function throughout all operational modes (Ready Mode, Dose Mode, End-of-Use Mode, and End-of-Life Mode). RESULTS: The ITS Placebo system met all specifications and no functional anomalies were observed during and following X-ray exposure at two radiation dose levels or exposure at six different combinations of RFID frequencies and field strengths. CONCLUSION: The performance of the ITS system was unaffected by X-ray exposure levels well beyond those associated with diagnostic X-rays and CT scans, and by exposure to radiofrequency field strengths typically generated by RFID devices. These results provide added confidence to clinicians that the fentanyl ITS system does not need to be removed during diagnostic X-rays and CT scans and can also be utilized in close proximity to RFID devices. FUNDING: The studies and writing of this manuscript were supported financially by The Medicines Company.

5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.

PURPOSE: A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. METHODS: Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. RESULTS: Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). CONCLUSION: In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951).

PURPOSE: In a randomised study (GM301; dacarbazine with/without oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine-oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine-oblimersen in patients with normal baseline LDH [1.1xupper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH. EXPERIMENTAL DESIGN: Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1xULN. Baseline LDH in EORTC study 18951 (dacarbazine, cisplatin, interferon-alfa-2b with/without interleukin-2 in advanced melanoma) was independently analysed using the same approach. In Study GM301, the relation between treatment effect and LDH, treatment effect and tumour size, LDH and tumour size and LDH and disease site were determined. RESULTS: In Study GM301 (N=760) and Study 18951 (N=325), LDH was within the upper range of normal for a large number of patients. This was not exhibited in the general population, suggesting such values may be elevated rather than normal in melanoma. A highly ordered and monotonic relationship was apparent between LDH and survival: survival worsened as LDH became more elevated, even when LDH remained within normal range. LDH and tumour size were poorly correlated; elevated LDH was not associated with any one disease site. LDH was highly predictive of oblimersen effect. CONCLUSION: In designing studies, LDH should be considered, regardless of tumour size or disease site.

The use of epoetin alfa in chemotherapy patients: a consistent profile of efficacy and safety.

Epoetin alfa has been in use for over a decade to increase hemoglobin in patients with cancer who develop chemotherapy-associated anemia. Early placebo-controlled, randomized studies, as well as recent large, community-based trials in thousands of patients, have consistently shown recombinant human erythropoietin (rHuEPO, epoetin alfa) to be effective and safe in the treatment of chemotherapy-associated anemia. Patients experienced an improved quality of life (QOL) related to the magnitude of the hemoglobin increase. As measured by a Linear Analog Scale Assessment, mean energy level, ability to do daily activities, and overall QOL improved significantly in patients who received epoetin alfa. The improvement in QOL was similar when anemia-specific instruments (Functional Assessment of Cancer Therapy-Anemia) were used. A large community-based trial has demonstrated that the more convenient once-weekly dosing schedule resulted in good efficacy and safety profiles. A recent double-blind placebo-controlled study that compared the efficacy of epoetin alfa versus placebo in patients receiving nonplatinum-based chemotherapy has confirmed epoetin alfa's efficacy, safety, and beneficial QOL effects. These findings should challenge current anemia management practices and encourage aggressive treatment of anemia in cancer patients receiving chemotherapy.

Neuroprotective properties of epoetin alfa.

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Managing cancer-related anaemia with epoetin alfa.

Anaemia occurs in a significant number of patients with cancer, and is associated with symptoms of fatigue, dizziness, headache and decreased health-related quality of life. Clinical trials have demonstrated the ability of epoetin alfa to increase haemoglobin concentrations and reduce transfusion requirements in patients with cancer. Data from three large, open-label, community-based trials of >7000 patients, as well as a series of smaller, randomized, placebo-controlled studies, have confirmed the efficacy of treatment with epoetin alfa in patients undergoing chemotherapy. In two of the community-based studies (>2000 patients in each), patients undergoing chemotherapy received epoetin alfa, 150-300 IU/kg or 10,000-20,000 IU, three times weekly. Significant (P<0.01) increases in haemoglobin concentrations and reductions in transfusion rates were seen in both studies. Significant improvements in quality of life were also reported, as measured by the Linear Analogue Scale Assessment and the Functional Assessment of Cancer Therapy-Anaemia. Importantly, the increases in quality of life were independent of tumour response. These findings were also observed in randomized, placebo-controlled studies. The third study, in approximately 3000 patients, evaluated the efficacy of once-weekly dosing, which significantly (P<0.01) increased haemoglobin concentrations, reduced transfusion requirements and improved quality of life. Greater increases in haemoglobin concentration were associated with greater improvements in quality-of-life scores. The safety and efficacy profile of the once-weekly regimen was comparable with that of the three times weekly regimen. Maintaining optimal quality of life, while achieving tumour stabilization or regression, is essential to the successful management of patients with cancer. Epoetin alfa has been shown to increase haemoglobin concentration, decrease transfusion requirements and increase quality of life. Given the frequency of adverse sequelae associated with anaemia, its aggressive management should become an integral and routine part of cancer treatment.