Retrospective Assessment Of Treatment With T-Dm1 After Pertuzumab In Her2-Positive Metastatic Breast Cancer

T-DM1/ ado-trastuzumab emtansine, the most recent addition to the HER2-targeted therapies approved to treat HER2-positive metastatic breast cancer (MBC), is an antibody-drug conjugate with a favorable side effect profile. T-DM1 is currently approved for patients with HER2-positive MBC who previously received trastuzumab and a taxane. Since the trial resulting in T-DM1 approval was conducted, the standard first-line therapy for metastatic HER2-positive breast cancer has changed from trastuzumab and a taxane to a three-drug combination of trastuzumab and a taxane plus pertuzumab. Due to the timing of these approvals, there is no clinical trial or observational data on the activity of T-DM1 in patients who have received prior therapy that included pertuzumab. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. To address this goal, a retrospective chart review was performed for all patients with HER2-positive MBC who received T-DM1 after pertuzumab between March 1, 2013 and July 15, 2015 at three institutions (Smilow Cancer Hospital at Yale-New Haven, MD Anderson Cancer Center, and The James Cancer Hospital at the Ohio State University). We manually reviewed the medical records of each case to confirm treatment sequencing and outcome. Eighty-two patients were identified who had received single agent T-DM1 and had received pertuzumab at any time previously. Demographic characteristics and prior therapy were reported for these patients. Seventy-eight patients were available for analysis of response. The rate of prolonged duration on therapy (PDT), defined as duration on therapy \u3e 6 months, was 30.8% (95% CI, 20.6-41.1%) and the tumor response rate was 17.9% (95% CI, 9.4-26.4%). The rate of any benefit (AB), defined as PDT and/or TR, was 37.2% (95% CI, 26.5-47.9%). The median duration on therapy was 4.0 months (95% CI, 2.7-5.1, range 0-22.5). The reason for discontinuation of T-DM1 was progression of disease in 84% of patients. Only 7 patients (10%) discontinued T-DM1 due to toxicity or poor tolerance. Overall, this retrospective analysis provides the first data demonstrating the efficacy of T-DM1 in patients who have received pertuzumab previously. Response rates were lower than prior reports in trastuzumab-resistant HER2-positive MBC, but one third of patients received therapy with T-DM1 for at least 6 months, which suggests tumor control and clinically relevant benefit to T-DM1 in patients who received prior trastuzumab and pertuzumab

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: A retrospective international multicenter study

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations. Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months. Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%). Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study

BACKGROUND: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations. METHODS: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months. RESULTS: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%). CONCLUSIONS: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.status: publishe

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study

BACKGROUND: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. METHODS: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. FINDINGS: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. INTERPRETATION: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. FUNDING: None.status: publishe