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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.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.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.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.ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279.

Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations.Experimental Design: Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min+/− mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps.Results: Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients >40 years of age and treated for >2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min+/− mice (20.8 ± 9.2 vs 12.8 ± 0.1; P = 0.016). No polyps were observed in BRAFi-treated wild-type mice.Conclusions: BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi. Clin Cancer Res; 21(23); 5215–21. ©2015 AACR.

Supplemental Figure 1. Endoscopic and histological H&E images of colonic polyps in a Magnification: 10X (bottom left); 200X (bottom right) BRAF mutant melanoma patient treated with long-term vemurafenib.

Supplemental Methods from Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.

Background We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC–IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study. Patients and methods BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAFV600 mutation–positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively. Results Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with Conclusions The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. ClinicalTrials.gov identifier NCT01667419

Aim of study The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC–IIIC melanoma. Methods The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAFV600 mutation–positive resected stage IIC–IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 × 28-day cycles). Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period. Results Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function ( Conclusions The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time.

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAF

The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC-IIIC melanoma.The phase 3 BRIM8 study (NCT01667419) randomised patients with BRAFCompletion rates for the EORTC QLQ-C30 questionnaire were high (80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (±22.9) and 17.3 (±24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation.The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time.

Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations. Experimental Design: Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min+/− mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps. Results: Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients >40 years of age and treated for >2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min+/− mice (20.8 ± 9.2 vs 12.8 ± 0.1; P = 0.016). No polyps were observed in BRAFi-treated wild-type mice. Conclusions: BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi. Clin Cancer Res; 21(23); 5215–21. ©2015 AACR.

Summary Background Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma. Methods BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. Findings The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. Interpretation The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. Funding F Hoffman–La Roche Ltd.

Purpose: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the extended follow-up of HCL patients treated with cladribine. Patients and Methods: Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. Results: Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of cladribine (overall response rate, 100%). The median first-response duration for all responders was 98 months. Seventy-six patients (37%) experienced relapse after their first course of cladribine. The median time to first relapse for all responders was 42 months. Time to treatment failure of CRs compared with PRs was statistically significant (P < .0005). The overall survival rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies. The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71). Conclusion: These results confirm previous observations that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are CRs. Most patients enjoy long-lasting complete remissions, and those patients who experience relapse can be successfully re-treated with cladribine.

Cladribine, a purine nucleoside analogue, is a safe and effective treatment for patients with hairy-cell leukaemia. It is administered at a dose of 0.09 mg/kg daily as a continuous intravenous infusion over 7 days. This chapter discusses the history, rationale, chemical structure and mechanism of action of cladribine. The indications for therapy and guidelines for clinical usage are reviewed. The response of hairy-cell leukaemia to cladribine, the acute and chronic complications and the risk for second malignancies are summarized. The chapter concludes with a section on salvage therapy.

TPS9118^ Background: Approximately 50% of melanomas carry a mutation in the BRAF gene. The oral BRAF inhibitor vemurafenib (VEM) has demonstrated meaningful clinical benefit in BRAFV600 mutation-po...

Objective: Osteoporosis is a silent epidemic that afflicts millions of postmenopausal women around the world. Osteoporosis places an enormous economic burden on society, including significant morbidity and mortality. Because of the increasing numbers of patients with osteoporosis, primary care physicians have become the front line for the diagnosis and treatment of this condition. Thus, the primary care provider should be able to diagnose osteoporosis in both asymptomatic and symptomatic women, perform a thorough workup to exclude secondary causes of osteoporosis, and optimally prevent and treat osteoporosis using the various forms of pharmacologic and nonpharmacologic therapies. Design: Review of current literature and articles dealing with pathophysiology, diagnosis, and treatment of osteoporosis. Results: Diagnostic and therapeutic modalities can reduce the incidence of fractures. Conclusions: The diagnosis and treatment of osteoporosis has greatly improved but needs further efforts to prevent the disease. (Menopause 1999;6:242-250. © 1999. The North American Menopause Society.)

Hairy cell leukemia is an indolent, chronic B-cell lymphoproliferative disorder comprising approximately 2 to 3% of all adult leukemias in the United States. Hairy cells are clonal expansions of mature, activated B-cells. They co-express CD11c, CD19, CD20, CD22, CD25, and CD103. Hairy cells possess clonal immunoglobulin gene rearrangements and express monoclonal surface immunoglobulin of either IgG or multiple heavy-chain isotypes. Treatment of hairy cell leukemia should be considered for symptomatic patients. It is indicated in patients with significant neutropenia, anemia, thrombocytopenia, symptomatic splenomegaly, constitutional symptoms due to hairy cell leukemia, or recurrent serious infections. Many treatments exist, including cladribine, pentostatin, interferon-alpha, splenectomy, rituximab (mabthera), and BL-22 immunotoxin.

Publisher Summary Immunosuppressants are a group of drugs used in the treatment of immunologic disorders, such as psoriasis, rheumatoid arthritis, nephrotic syndrome, and inflammatory bowel disease. They are also used extensively, in various combinations, in the prevention of organ rejection in transplant patients and have significantly altered the outcome of these procedures. They have numerous side effects that vary from organ to organ. This chapter will concentrate on skeletal adverse effects, viz. osteoporosis with an increased risk of fractures. Immunosuppressants used in either clinical practice or clinical trials include glucocorticoids, cyclosporine, tacrolimus, methotrexate, azathioprine, rapamycin, mycophenolate mofetil, deoxyspergualin, brequinar sodium, mizoribine, leflunomide, and azasperane. Glucocorticoids have significant anti-inflammatory, immunosuppressive, and antineoplastic effects. They are used in organ transplantation and in the treatment of diseases, such as temporal arteritis, polymyalgia rheumatica, chronic obstructive pulmonary disease, rheumatoid arthritis, and multiple myeloma. Glucocorticoids are well known to cause osteoporosis that affects about 50% of patients receiving therapy. Cyclosporine A (CsA) is a cyclic endecapeptide, initially isolated from the fungus Tolypocladium inflatum Gams and is used in the treatment of rheumatoid arthritis, psoriasis, nephrotic syndrome, inflammatory bowl disease, and in the prevention of organ rejection in transplantation.