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Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600 mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4–23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43–63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1–45·4) for the atezolizumab group versus 22·8 months (10·6–44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9–not estimable) in the atezolizumab group versus 25·8 months (22·0–34·6) in the control group (HR 0·84 [95% CI 0·66–1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3–4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAFV600 mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. F Hoffmann-La Roche.

PurposeTo update and expand on data related to treatment, resource utilization, and costs by cancer stage in Canadian patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC).MethodsWe analyzed data for adult women diagnosed with invasive HR+/HER2− BC between 2012 and 2016 utilizing the publicly funded health care system in Ontario. Baseline characteristics, treatment received, and health care use were descriptively compared by cancer stage (I–III vs. IV). Resource use was multiplied by unit costs for publicly funded health care services to calculate costs.ResultsOur study included 21,360 patients with stage I–III plus 813 with stage IV HR+/HER2− BC. Surgery was performed on 20,510 patients with stage I–III disease (96.0%), with the majority having a lumpectomy, and radiation was received by 15,934 (74.6%). Few (n = 1601, 7.8%) received neoadjuvant and most (n = 15,655, 76.3%) received adjuvant systemic treatment. Seven hundred and fifty eight patients with metastatic disease (93.2%) received systemic therapy; 542 (66.7%) received endocrine therapy. Annual per patient health care costs were three times higher in the stage IV vs. stage I–III cohort with inpatient hospital services representing nearly 40% of total costs.ConclusionThe costs associated with metastatic HR+/HER2− BC reflect a significant disease burden. Low endocrine treatment rates captured by the publicly funded system suggest guideline non-adherence or that a fair portion of Ontarian patients may be incurring out-of-pocket drug costs.

PurposeWe sought to expand the currently limited, Canadian, population-based data on the characteristics, treatment pathways, and health care costs according to stage in patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC).MethodsWe extracted data from the publicly funded health care system in Ontario. Baseline characteristics, treatment patterns, and health care costs were descriptively compared by cancer stage (I–III vs. IV) for adult women diagnosed with invasive HER2+ BC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health care services to calculate costs.ResultsOverall, 4535 patients with stage I–III and 354 with stage IV HER2+ BC were identified. Most patients with stage I–III disease were treated with surgery (4372, 96.4%), with the majority having a lumpectomy, and 3521 (77.6%) received radiation. Neoadjuvant (NAT) and adjuvant (AT) systemic treatment rates were 20.1% (n = 920) and 88.8% (n = 3065), respectively. Systemic treatment was received by 311 patients (87.9%) with metastatic HER2+ BC, 264 of whom (84.9%) received trastuzumab. Annual health care costs per patient were nearly 3 times higher for stage IV vs. stage I–III HER2+ BC.ConclusionPer-patient annual costs were substantially higher for women with metastatic HER2+ BC, despite less frequent exposure to surgery and radiation compared to those with early stage disease. Increasing NAT rates in early stage disease represent a critical opportunity to prevent recurrence and reduce the costs associated with treating metastatic HER2+ BC.

Background There have been few publications exploring the characteristics, treatment pathways, and health‐care costs by stage in patients with a triple‐negative breast cancer (TNBC) phenotype. Methods Data from a publicly funded health‐care system in Ontario were assessed. Baseline characteristics, treatment patterns, and health‐care costs were descriptively compared by cancer stage (I‐III vs IV) for adult women diagnosed with invasive TNBC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health‐care services to calculate health system‐related costs. Results A total of 3271 cases were identified, 3081 with stage I‐III and 190 with stage IV TNBC. Baseline characteristics were aligned with previous reports. Surgery was the most common treatment among patients with stage I‐III disease (n = 2979, 96.7%); 557 (18.7%) received neoadjuvant therapy (NAT) and 1974 (66.3%) received adjuvant therapy (AT), the latter at a median of 44 days postsurgery, and 2446 (79.4%) in the stage I‐III cohort received radiation. Treatment for metastatic TNBC included surgery in 48 (25.3%), systemic therapy in 138 (72.6%), and radiotherapy in 112 (58.9%) patients. Top drug regimens included anthracyclines/taxanes. Annual per‐patient health care costs were four times higher for stage IV vs. stage I‐III TNBC. Conclusion Per‐patient costs were higher in metastatic TNBC, despite a less frequent use of all treatment modalities compared to early TNBC. Treatment patterns were aligned with the options available at the time; however, neoadjuvant treatment rates were low. Characteristics and treatment patterns of Ontario patients diagnosed with TNBC are similar to that of other contemporary reports; however, it appears that uptake of neoadjuvant therapy could be improved. Cost of metastatic disease is high and novel treatments should be adopted and evaluated for their impact.

Introduction and Objective Serous retinopathy can be associated with MEK inhibitors, including cobimetinib. We present results of an integrated safety analysis to further characterize ocular functional and structural changes due to serous retinopathy. Methods Four studies evaluating cobimetinib at the approved dose and schedule in combination with other oncology drugs were included. Study CO39721 incorporated standardized ophthalmologic assessments to fully characterize serous retinopathy events over time and was the primary study for analysis. Supporting information was provided by studies GO28141, WO29479, and GO30182. Results In total, 655 patients received one or more doses of cobimetinib and comprised the safety-evaluable population. Overall, 117 patients (17.9%) had one or more serous retinopathy events, 24 (3.7%) had two or more events, and four (0.6%) had three or more events. Grade 3 events occurred in < 2.5% of patients. In CO39721, the median time to onset was 15 days (range 7–111); median time to resolution of first occurrence was 26 days (range 6–591 + days). Twelve of 25 patients (48.0%) recovered without a dose modification and 4/25 (16.0%) were recovered/recovering following a dose modification. The most frequent presentation of serous retinopathy was focal subretinal fluid on optical coherence tomography (62.8% of cases); in some instances (25.7% of cases), subretinal fluid was multifocal. There was no loss of visual function or visual acuity at serous retinopathy onset or resolution. Conclusions Results from this integrated safety analysis indicate that cobimetinib-associated serous retinopathy can be managed with or without a dose modification of cobimetinib at the discretion of the treating physician. No visual loss or permanent retinal damage was identified on comprehensive ophthalmologic assessments. Clinical Trial Registration ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279.

The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a–c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1–14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1–21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0–68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0–67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was –75% (95% CI –80 to –70) with giredestrant and –67% (–73 to –59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3–4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. F Hoffmann-La Roche.

Primary analysis of the phase 3 IMspire150 study showed improved investigator-assessed progression-free survival with first-line atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF mutation-positive melanoma. With a median follow-up of 18·9 months (IQR 10·4-23·8) at the primary analysis, overall survival data were immature. Here, we report the results from the second, prespecified, interim overall survival analysis. The multicentre, double-blind, placebo-controlled, randomised, phase 3 IMspire150 study was done at 108 academic and community hospitals in 20 countries. Patients aged 18 years or older with previously untreated unresectable stage IIIc or stage IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive either atezolizumab (840 mg intravenously on day 1 and 15) or placebo plus vemurafenib (960 mg or 720 mg twice daily orally) and cobimetinib (60 mg once daily orally; 21 days on and 7 days off) in 28-day cycles. Atezolizumab and placebo were added to treatment regimens from cycle two onwards. Randomisation was done centrally (Durham, NC, USA) based on a permuted block randomisation scheme (block size of 4) using an interactive web-based response system and was stratified by geographical region and baseline lactate dehydrogenase concentration. Overall survival was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug according to actual treatment received. The primary endpoint was investigator-assessed progression-free survival, which was previously reported. Here, we report the second, prespecified, interim overall survival analysis, which was planned after about 270 overall survival events had occurred. The trial is ongoing, but is no longer enrolling patients, and it is registered with ClinicalTrials.gov, NCT02908672. Between Jan 13, 2017, and April 26, 2018, 514 patients (median age 54 years [IQR 43-63]; 299 [58%] men and 215 [42%] women) were enrolled in the trial and randomly assigned to the atezolizumab group (256 [50%] patients) or the control group (258 [50%] patients). At the data cutoff (Sept 8, 2021), 273 patients had died (126 in the atezolizumab group and 147 in the control group). Median follow-up was 29·1 months (IQR 10·1-45·4) for the atezolizumab group versus 22·8 months (10·6-44·1) for the control group. Median overall survival was 39·0 months (95% CI 29·9-not estimable) in the atezolizumab group versus 25·8 months (22·0-34·6) in the control group (HR 0·84 [95% CI 0·66-1·06]; p=0·14). The most common adverse events of any grade in the atezolizumab group were blood creatine phosphokinase increased (123 [53%] of 231 patients), diarrhoea (116 [50%]), and pyrexia (115 [50%]). The most common adverse events of any grade in the control group were diarrhoea (157 [56%] of 280 patients), blood creatine phosphokinase increased (135 [48%]), and rash (119 [43%]). The most common grade 3-4 adverse events were increased lipase (54 [23%] of 231 patients in the atezolizumab group vs 62 [22%] of 280 patients in the control group), increased blood creatine phosphokinase (51 [22%] vs 50 [18%]), and increased alanine aminotransferase (32 [14%] vs 26 [9%]). Serious adverse events were reported in 112 (48%) patients in the atezolizumab group and 117 (42%) patients in the control group. Grade 5 adverse events were reported in eight (3%) patients in the atezolizumab group versus six (2%) patients in the control group. Two grade 5 adverse events (hepatitis fulminant and hepatic failure) in the atezolizumab group were considered to be associated with the triplet combination, and one event in the control group (pulmonary haemorrhage) was considered to be associated with cobimetinib. Additional follow-up of the IMspire150 trial showed that overall survival was not significantly improved with atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib in patients with BRAF mutation-positive advanced melanoma. Results of the final analysis are awaited to establish whether a significant improvement in overall survival can be achieved with long-term treatment with this triplet combination versus vemurafenib plus cobimetinib. F Hoffmann-La Roche.