The medical letter on drugs and therapeutics june 8 2015

Drugs for Psoriasis Mild to moderate psoriasis is generally treated with topical corticosteroids. Vitamin D analogs and tazarotene are topical alternatives that can be used in combination with topical... Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC The FDA has approved nivolumab (Opdivo – BMS), an IV programmed death receptor-1 (PD-1) blocking antibody, for treatment of unresectable or metastatic melanoma that has progressed... Recombinant Human Parathyroid Hormone (Natpara) The FDA has approved a subcutaneously injected formulation of recombinant human parathyroid hormone (Natpara – NPS) as an adjunct to calcium and vitamin D to control hypocalcemia in... Drugs for Psoriatic Arthritis (online only) Psoriatic arthritis is a chronic inflammatory arthropathy that develops in up to 40% of patients with psoriasis. Several guidelines for treatment of psoriatic arthritis have been published.

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1470 Volume 56 June 8, 2015 IN THIS ISSUE Drugs for Psoriasis p 81 Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC .p 85 Recombinant Human Parathyroid Hormone (Natpara) .p 87 Drugs for Psoriatic Arthritis online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1470 Volume 56 ▶ June 8, 2015 Take CME Exams ALSO IN THIS ISSUE Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC .p 85 Recombinant Human Parathyroid Hormone (Natpara) .p 87 Drugs for Psoriatic Arthritis online only Drugs for Psoriasis Related article(s) since publication Mild to moderate psoriasis is generally treated with topical corticosteroids Vitamin D analogs and tazarotene are topical alternatives that can be used in combination with topical corticosteroids Phototherapy and systemic therapy, including biologic agents, are recommended for patients with moderate to severe disease Drugs for psoriatic arthritis are reviewed in a separate article available at http://medicalletter.org/TML-article1470d TOPICAL THERAPY — Corticosteroids – Topical corticosteroids are widely used for treatment of psoriasis both alone and in combination with phototherapy and systemic therapy Ointments are generally the most effective Foams and sprays can be applied to large areas, but the alcohol base used in many of them may cause burning in patients with sensitive skin Adverse Effects – Superpotent topical corticosteroids, such as clobetasol propionate 0.05%, can induce adrenal suppression when applied to large body surface areas, but clinically significant adrenal insufficiency is rare Local cutaneous adverse effects such as atrophy of the dermis and epidermis, telangiectasias, and irreversible striae can occur when these agents are used for prolonged periods of time or under occlusion, when too much is applied, or when corticosteroid-sensitive areas such as the face and intertriginous regions are treated, but usually not when they are applied to active psoriatic lesions Pregnancy – Topical corticosteroids with mild to moderate potency appear to be safe for use during pregnancy.1 Calcipotriene – The synthetic vitamin D3 analog calcipotriene (Dovonex, Sorilux, and generics) is about as effective as a mid-strength corticosteroid for topical treatment of plaque psoriasis.2 Adverse Effects – Calcipotriene is generally well tolerated, but burning and itching can occur Hypercalcemia has been reported rarely Pregnancy – Calcipotriene is classified as category C (fetotoxicity in animals; no adequate studies in women) for use during pregnancy Calcipotriene/Betamethasone Dipropionate – This oncedaily combination ointment (Taclonex, and generics) is more effective than either component alone for treating plaque psoriasis and has been well tolerated.3 A suspension formulation that can be used on the scalp (Taclonex Topical Suspension) is also applied once daily Calcitriol — A second vitamin D3 analog, calcitriol (Vectical) is indicated for topical treatment of mild to moderate plaque psoriasis in adults.4 Adverse Effects – Calcitriol causes less skin irritation than calcipotriene.5 Skin discomfort, pruritus, and erythema can occur, but are generally mild Pregnancy – Like calcipotriene, calcitriol is classified as category C (fetotoxicity in animals; no adequate studies in women) for use during pregnancy Tazarotene – An acetylenic retinoid, tazarotene (Tazorac) has been effective for topical treatment of psoriasis, and in some patients the therapeutic effect may persist after treatment is stopped.6 Use of tazarotene in combination with topical corticosteroids may have a synergistic effect.7 Adverse Effects – Erythema, burning, pruritus, peeling, and an increased risk of sunburn can occur with tazarotene gel The cream formulation is better tolerated, but peeling may be more frequent 81 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 57 (1470) ® June 8, 2015 Table Some Systemic Drugs for Psoriasis and/or Psoriatic Arthritis Drug Usual Adult Dosage Cost1 Acitretin – Soriatane (Stiefel)2 Apremilast – Otezla (Celgene)2,4 Cyclosporine2 – generic Neoral (Novartis) Leflunomide6 – generic Arava (Sanofi) Methotrexate2 – generic Sulfasalazine6 – generic Azulfidine (Pfizer) enteric coated – generic Azulfidine EN-tabs Biologics Adalimumab – Humira (Abbvie)2,4 Certolizumab pegol – Cimzia (UCB)4 Etanercept – Enbrel (Amgen)2,4 Golimumab – Simponi (Centocor)4 Infliximab – Remicade (Janssen)2,4 Secukinumab – Cosentyx (Novartis)2 Ustekinumab – Stelara (Janssen)2,4 10-50 mg PO once/day3 30 mg PO bid5 2.5-4 mg/kg/day PO in divided doses $2778.40 5662.10 957.60 1091.80 182.30 3284.70 75.60 62.70 299.10 87.00 390.70 10-20 mg PO once/day 7.5-25 mg/week PO in a single dose or in divided doses over 36 hours 2-3 g/day PO in divided doses 80 mg SC x 1,7 then 40 mg q2 weeks 400 mg SC at 0, 2, and weeks, then 200 mg q2 weeks or 400 mg q4 weeks 50 mg SC twice/week x 12 weeks,7 then once/week 50 mg SC once/month mg/kg IV at 0, 2, and weeks, then q8 weeks 300 mg8 SC at 0, 1, 2, 3, and weeks, then q4 weeks 45 mg10 SC at and weeks, then q12 weeks 9606.30 9129.90 9607.90 9821.50 5842.30 10,260.009 7661.20 Approximate WAC for 12 weeks’ treatment at the lowest usual adult maintenance dosage (cyclosporine and infliximab cost calculated for a patient weighing 80 kg) WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly May 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy FDA-approved for treatment of psoriasis Some expert clinicians recommend not exceeding 25 mg/day to avoid adverse effects FDA-approved for treatment of psoriatic arthritis The recommended starting dose is 10 mg, which should be titrated over days to 30 mg The maintenance dosage is 30 mg bid, which should be reduced to 30 mg once/day in patients with severe renal impairment (CrCl 100 kg Dose for psoriatic arthritis is 45 mg, except in patients weighing >100 kg with coexistent moderate to severe psoriasis, for whom it is 90 mg Pregnancy – Systemic absorption is minimal, but the drug is contraindicated during pregnancy PHOTOTHERAPY — UV phototherapy is used when psoriasis is widespread or unresponsive to topical agents Narrow-band UVB is safer and more effective than broad-band UVB and has largely replaced it Oral or topical psoralens combined with UVA radiation (PUVA) is also effective for treating psoriasis, but it increases the risk of skin cancer Studies comparing narrow-band UVB with oral or topical PUVA have not shown that either one is consistently more effective than the other for treatment of psoriasis.8 The excimer laser has been safe and effective for localized disease and is FDA-approved for this indication.9 Adverse Effects – Itching, burning, blistering, stinging, dryness, and erythema can occur Pregnancy – Narrow-band UVB and the excimer laser are safe for use during pregnancy.1 SYSTEMIC THERAPY — A variety of drugs, including immunosuppressive agents, retinoids, and biologics, are used for systemic treatment of psoriasis The biologics are the most expensive and appear to be the most effective, but direct comparisons are limited.10,11 82 Methotrexate – For control of moderate to severe psoriasis refractory to topical treatments, low doses of methotrexate (7.5-25 mg/week) are often used Adverse Effects – Nausea and vomiting are common with methotrexate Hepatotoxicity is the most frequent serious adverse effect Methotrexate is immunosuppressive and should not be used in patients with active infections Methotrexate-induced pneumonitis is rare, but can be fatal Macrocytic anemia, leukopenia, and thrombocytopenia can occur Liver function and blood counts should be monitored Decreased renal function and inadvertent overdosing (daily rather than weekly) are common causes of hematologic toxicity Pregnancy – Methotrexate is teratogenic and is contraindicated during pregnancy; after stopping it, men should wait at least months and women should wait one ovulatory cycle before attempting to conceive Cyclosporine – Cyclosporine has been at least as effective as methotrexate in treating moderate to severe psoriasis.12,13 Adverse Effects – The doses of cyclosporine used for psoriasis (2.5-4 mg/kg/day in divided doses) have generally been safe, but hypertension and The Medical Letter ® nephrotoxicity can occur Cyclosporine can also cause GI disturbances, infection, hirsutism, pruritus, headache, paresthesias, hypertriglyceridemia, and musculoskeletal or joint pain It increases the risk of skin malignancies in patients previously treated with PUVA and interacts with many other drugs Pregnancy – Cyclosporine appears to be relatively safe for use during pregnancy, but has been associated with low birth weight and prematurity.1 Acitretin – Use of acitretin, an oral retinoid, in doses of 25-50 mg/day can reduce the area and severity of psoriasis, but with significant hepatic and mucocutaneous toxicity.6 Some expert clinicians recommend using lower doses (10-25 mg/day) to avoid adverse effects Synergism has been reported when acitretin was combined with UVB radiation or with PUVA.8 Adverse Effects – Like other systemic retinoids, acitretin frequently causes cheilitis, hair loss, dry skin, and desquamation Increases in aminotransferase levels occur in about one-third of patients; levels usually return to normal even when treatment is continued, but symptomatic retinoid hepatitis can occur and rarely progresses to cirrhosis Decreased HDL cholesterol, hypertriglyceridemia, skeletal hyperostosis, conjunctivitis, corneal erosions and opacities, iritis, and decreased visual acuity can also occur Pregnancy – Acitretin is a long-lasting teratogen; patients should not become pregnant or donate blood while taking the drug and for at least years after stopping it Phosphodiesterase Type-4 Inhibitor – Apremilast is approved by the FDA for treatment of adults with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy In two unpublished, randomized, double-blind trials (summarized in the package insert) in a total of 1257 adults with moderate to severe plaque psoriasis, PASI 75 responses (≥75% improvement in Psoriasis Area and Severity Index scores) occurred after 16 weeks in 33% and 29% of patients taking apremilast versus 5% and 6% of those taking placebo Adverse Effects – The most common adverse effects of apremilast in clinical trials were diarrhea, nausea, and headache These effects occurred most frequently during the first two weeks of treatment and tended to resolve with continued use of the drug Apremilast can increase the risk of depression Loss of 5-10% of body weight has been reported Vol 57 (1470) June 8, 2015 Pregnancy – Apremilast is classified as category C (fetotoxicity in animals; no adequate studies in women) for use during pregnancy BIOLOGIC AGENTS — In patients who have an inadequate response to monotherapy, combining a biologic agent with traditional systemic therapy or phototherapy may improve outcomes, but data are limited and the long-term safety of such combinations is unknown.14 Switching from one biologic agent to another when the response to the first one is inadequate has been effective in some patients.15 All of the biologics are classified as category B (no evidence of toxicity in animals, no adequate studies in women) for use during pregnancy TNF Inhibitors – Three TNF inhibitors, etanercept, infliximab, and adalimumab are approved for treatment of psoriasis One review of randomized, double-blind, placebo-controlled trials compared their efficacy for treatment of moderate to severe psoriasis; the average percentages of patients achieving a PASI 75 response within a 12-week period with infliximab, adalimumab, and etanercept were 78.6%, 70.5%, and 48.1%, respectively.16 Adverse Effects – Serious infections, including bacterial infections (particularly pneumonitis and cellulitis), histoplasmosis, and reactivation of tuberculosis and hepatitis B virus, have been reported with all the TNF inhibitors, particularly in the first 2-7 months of treatment.17 These drugs should not be given to patients with active localized or chronic infections Screening for exposure to tuberculosis is recommended before starting anti-TNF therapy and annually thereafter Lymphoma and other malignancies have been reported in patients with rheumatoid arthritis receiving these drugs, but a cause-and-effect relationship has not been established They generally should not be used in patients with a recent malignancy Exacerbations and new onset of heart failure, pancytopenia, and demyelinating disorders such as multiple sclerosis have been reported.18 Anti-TNF drugs have been associated with development of autoantibodies and the induction of a lupus-like syndrome A review of clinical studies found that autoantibodies reduced the efficacy of infliximab and adalimumab, but not of etanercept.19 IL-12/23 Antagonist – Ustekinumab is a human monoclonal antibody against interleukins 12 and 23.20 In a randomized, double-blind trial in 1230 adults with moderate to severe psoriasis, PASI 75 responses occurred in 66.7% of patients receiving ustekinumab 45 mg, in 75.7% of those receiving ustekinumab 90 mg, and in 3.7% receiving placebo.21 A randomized 83 The Medical Letter ® trial comparing ustekinumab (45 or 90 mg at weeks and 4) with etanercept (50 mg twice weekly) in 903 patients with moderate to severe psoriasis found that more patients treated with ustekinumab achieved a PASI 75 response at week 12 (67.5% and 73.8% vs 56.8%).22 Ustekinumab has been effective in patients with an inadequate response to methotrexate.23 Adverse Effects – Ustekinumab has been associated with serious infections (especially tuberculosis), malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy Screening for tuberculosis is recommended before treatment Autoantibodies have developed; whether they reduce treatment response remains to be determined.19 IL-17A Inhibitor – Secukinumab, an injectable human interleukin-17A antagonist, is approved by the FDA for treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.24 In four double-blind trials in adults with moderate to severe plaque psoriasis, secukinumab 150 mg or 300 mg was significantly more effective than placebo after 12 weeks of treatment in achieving a PASI 75 response (67-87% vs 0-5%) Both doses of secukinumab were also superior to etanercept (44%), which was included in one study as an active control.25-27 Secukinumab was more effective than ustekinumab for treatment of moderate to severe psoriasis in an unpublished, randomized, double-blind trial (PASI 90 response at week 16: 79.0% vs 57.6%).28 Adverse Effects – The most common adverse effects of secukinumab in clinical trials were nasopharyngitis, diarrhea, and upper respiratory infection Serious infections occurred in 1.2% of patients treated with the drug Patients should be screened for tuberculosis before starting therapy Crohn’s disease exacerbations, urticaria, and anaphylaxis have been reported with secukinumab INVESTIGATIONAL DRUG — Tofacitinib (Xeljanz), an oral Janus kinase (JAK) inhibitor approved for use in rheumatoid arthritis,29 has also been effective in clinical trials in patients with psoriasis.30 ■ MB Hoffman et al Psoriasis during pregnancy: characteristics and important management recommendations Expert Rev Clin Immunol 2015; 11:709 Calcipotriene for psoriasis Med Lett Drugs Ther 1994; 36:70 A betamethasone-calcipotriene combination for psoriasis Med Lett Drugs Ther 2006; 48:55 Calcitriol (Vectical) for mild to moderate plaque psoriasis Med Lett Drugs Ther 2009; 51:70 W Abramovits Calcitriol microg/g ointment: an effective and safe addition to the armamentarium in topical psoriasis therapy J Drugs Dermatol 2009; 8(8 Suppl):s17 84 Vol 57 (1470) June 8, 2015 Two new retinoids for psoriasis Med Lett Drugs Ther 1997; 39:105 A Menter et al Guidelines of care for the management of psoriasis and psoriatic arthritis Section Guidelines of care for the management and treatment of psoriasis with topical therapies J Am Acad Dermatol 2009; 60:643 X Chen et al Narrow-band ultraviolet B phototherapy versus broadband ultraviolet B or psoralen-ultraviolet A photochemotherapy for psoriasis Cochrane Database Syst Rev 2013; 10:CD009481 MB Totonchy and MW Chiu UV-based therapy Dermatol Clin 2014; 32:399 10 S Lee et al Biologic and nonbiologic systemic agents and phototherapy for treatment of chronic plaque psoriasis [Internet] AHRQ Comparative Effectiveness Reviews 2012 Nov Report No.12(13)-EHC144-EF 11 J Schmitt et al Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials Br J Dermatol 2014; 170:274 12 VM Heydendael et al Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis N Engl J Med 2003; 349:658 13 I Flyström et al Methotrexate vs ciclosporin in psoriasis: effectiveness, quality of life and safety A randomized controlled trial Br J Dermatol 2008; 158;116 14 JC Cather and JJ Crowley Use of biologic agents in combination with other therapies for the treatment of psoriasis Am J Clin Dermatol 2014; 15:467 15 P Sator et al Adalimumab in the treatment of moderate-to-severe chronic plaque psoriasis in patients switching from other biologics J Eur Acad Dermatol Venereol 2015 February (epub) 16 IH Kim et al Comparative efficacy of biologics in psoriasis: a review Am J Clin Dermatol 2012; 13:365 17 RE Kalb et al Risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and regiatryy (PSOLAR) JAMA Dermatol 2015 May 13 (epub) 18 AL Semble et al Safety and tolerability of tumor necrosis factor- inhibitors in psoriasis: a narrative review Am J Clin Dermatol 2014; 15:37 19 L Hsu et al Antidrug antibodies in psoriasis: a systematic review Br J Dermatol 2014; 170:261 20 Ustekinumab (Stelara) for psoriasis Med Lett Drugs Ther 2010; 52:7 21 KA Papp et al Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 2) Lancet 2008; 371:1675 22 CE Griffiths et al Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis N Engl J Med 2010; 362:118 23 C Paul et al Transition to ustekinumab in patients with moderateto-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT) Br J Dermatol 2014; 170:425 24 Secukinumab (Cosentyx) for psoriasis Med Lett Drugs Ther 2015; 57:45 25 A Blauvelt et al Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE) Br J Dermatol 2015; 172:484 26 C Paul et al Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE) J Eur Acad Dermatol Venereol 2015; 29:1082 27 RG Langley et al Secukinumab in plaque psoriasis – results of two phase trials N Engl J Med 2014; 371:326 28 D Thaci et al Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: 16 week results from the CLEAR study Presented at American Academy of Dermatology 73rd Annual Meeting San Francisco, CA, March 20, 2015 29 Tofacitinib (Xeljanz) for rheumatoid arthritis Med Lett Drugs Ther 2013; 55:1 30 A Chiricozzi et al Tofacitinib for the treatment of moderate-tosevere psoriasis Expert Rev Clin Immunol 2015; 11:443 The Medical Letter ▶ Vol 57 (1470) ® Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC Note: An addendum to this article has been published The FDA has approved nivolumab (Opdivo – BMS), an IV programmed death receptor-1 (PD-1) blocking antibody, for treatment of unresectable or metastatic melanoma that has progressed following treatment with ipilimumab (and a BRAF inhibitor in patients who are BRAF V600 mutation positive) and for treatment of metastatic squamous non-small cell lung cancer (NSCLC) that has progressed on or after platinumbased chemotherapy It is the second PD-1 inhibitor to be marketed in the US after pembrolizumab (Keytruda),1 and the first to be approved for treatment of NSCLC Pronunciation Key Nivolumab: ni voe' loo mab" Opdivo: op dee' voe STANDARD TREATMENT — Metastatic melanoma – High-dose interleukin-2 (aldesleukin – Proleukin) has produced responses in 15-20% of patients with metastatic melanoma, but its use has been limited by severe toxicity and cumbersome administration requiring hospitalization for treatment The antiCTLA4 monoclonal antibody ipilimumab (Yervoy) June 8, 2015 has produced response rates similar to those with high-dose interleukin-2, with 20-26% of patients surviving beyond years.2,3 Recently, pembrolizumab has produced a higher response rate and longer progression-free and overall survival than ipilimumab.4 A panel of experts has recommended that pembrolizumab should be considered a first-line option for treatment of metastatic melanoma.5 Dabrafenib (Tafinlar), vemurafenib (Zelboraf), and trametinib (Mekinist) are kinase inhibitors used for treatment of metastatic melanoma with BRAF V600 mutations, which are found in about 50% of melanomas.6,7 Metastatic Squamous NSCLC – Patients with metastatic squamous NSCLC and a good performance status usually receive platinum doublet therapy (a twodrug regimen that includes a platinum derivative such as cisplatin or carboplatin) For those with refractory disease, erlotinib (Tarceva), docetaxel (Taxotere) with or without ramucirumab (Cyramza), or gemcitabine (Gemzar) may be used; median overall survival in these patients is less than year.8 MECHANISM OF ACTION — The programmed death receptor-1 (PD-1) is an inhibitory receptor expressed Table Some Drugs for Metastatic Melanoma Drug Nivolumab – Opdivo (BMS) Class Programmed death receptor-1 (PD-1) inhibitor Indication1 Disease progression after ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Pembrolizumab – Keytruda (Merck) Programmed death receptor-1 (PD-1) inhibitor Ipilimumab – Yervoy (BMS) Cytotoxic T-lymphocyteassociated antigen (CTLA4) blocker Dabrafenib – Tafinlar (GSK) BRAF kinase inhibitor Disease progression after ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Melanoma regardless of BRAF mutation status, before or after other therapies Melanoma with BRAF V600E mutation5,6 Vemurafenib – Zelboraf (Genentech) Trametinib – Mekinist (GSK) BRAF kinase inhibitor MEK kinase inhibitor Melanoma with BRAF V600E mutation Melanoma with BRAF V600E or V600K mutations6,10 Efficacy OS rate (1 yr estimated): 72.9% vs 42.1% with dacarbazine PFS: 5.1 mos vs 2.2 mos with dacarbazine3 OS rate (1 yr estimated): 68.4% PFS: 4.1 mos4 Usual Dosage mg/kg IV q2 wks Cost2 $20,143.20 mg/kg IV q3 wks 25,896.00 OS rate (1 yr estimated): 58.2% PFS: 2.8 mos4 mg/kg IV q3 wks x doses 131,213.20 PFS: 5.1 mos vs 2.7 mos with dacarbazine7 150 mg PO bid8 26,393.90 PFS: 5.3 mos vs 1.6 mos with dacarbazine9 PFS: 4.8 mos vs 1.5 mos with dacarbazine or paclitaxel11 960 mg (4 tabs) 32,552.40 PO bid mg PO once/d 30,214.00 OS = overall survival, PFS = progression-free survival FDA-approved for use in patients with unresectable or metastatic melanoma Approximate WAC for 12 weeks' treatment for IV drugs and for months' treatment for oral drugs for a patient weighing 70 kg Cost of administration not included WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly May 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Efficacy data in previously untreated patients (C Robert et al N Engl J Med 2015; 372:320) C Robert et al N Engl J Med 2015 April 19 (epub) Not indicated for treatment of patients with wild-type BRAF (BRAF-negative) melanoma The combination of dabrafenib and trametinib is FDA-approved for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma A Hauschild et al Lancet 2012; 380:358 Taken at least hour before or at least hours after a meal PB Chapman et al N Engl J Med 2011; 364:2507 10 Trametinib monotherapy is not recomended for patients who have previously been treated with a BRAF inhibitor 11 KT Flaherty et al N Engl J Med 2012; 367:107 85 The Medical Letter ® Vol 57 (1470) June 8, 2015 Table Some Drugs for Squamous NSCLC that Progressed on or after Platinum-Based Therapy1 Drug Class Usual Dosage Cost2 Nivolumab – Opdivo (BMS) Programmed death receptor-1 (PD-1) inhibitor mg/kg IV q2 wks $20,143.20 Taxane 75 mg/m2 IV q3 wks 13,814.20 Ramucirumab – Cyramza (Lilly) VEGF receptor antagonist 10 mg/kg IV before docetaxel infusion q3 wks 28,560.00 Erlotinib – Tarceva (OSI)4 EGFR inhibitor 150 mg PO once/d 20,127.005 Cytidine analog 1000 mg/m IV on days 1, 8, and 15 q4 wks OR 1250 mg/m2 IV on days and q3 wks 10,669.70 11,855.20 Docetaxel – Taxotere (Sanofi) Gemcitabine – Gemzar (Lilly) VEGF = vascular endothelial growth factor; EGFR = epidermal growth factor receptor National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Small Cell Lung Cancer Version 2015 Available at www.nccn.org Accessed May 28, 2015 Approximate WAC for 12 weeks’ treatment at the usual dosage for a patient with weight of 70 kg or body surface area of 1.6 m2 Cost of administration not included WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly May 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Used only in combination with docetaxel Proteomic testing is recommended in patients with NSCLC and wild-type EGFR or with unknown EGFR status Patients with “poor” classification should not receive erlotinib (V Gregorc et al Lancet Oncol 2014; 15:713) Cost of a 90-day supply Not FDA-approved for this indication by T-cells during long-term antigen exposure, such as occurs in chronic viral infections or cancer.9 Nivolumab binds to the receptor, blocking the interaction with its ligands and promoting antitumor immune responses In animal models, blockade of the PD-1 pathway has decreased tumor growth CLINICAL STUDIES — Melanoma – Approval of nivolumab was based on an open-label trial in 405 patients with unresectable stage IIIC or IV melanoma that had progressed after being previously treated with ipilimumab (and a BRAF inhibitor in those who were BRAF V600 mutation-positive) who were randomized to receive nivolumab or chemotherapy (either dacarbazine, or paclitaxel plus carboplatin) until disease progression or unacceptable toxicity occurred In a prespecified interim analysis that included 167 patients followed for at least months (120 of whom had received nivolumab), the objective response rate was 31.7% with nivolumab and 10.6% with chemotherapy.10 In a double-blind trial, 418 adults with unresectable, previously untreated stage III or IV melanoma without a BRAF mutation were randomized to receive nivolumab or dacarbazine until disease progression or unacceptable toxicity occurred Nivolumab improved overall survival, the primary endpoint, by 58% compared to dacarbazine; 1-year survival rates were 72.9% with nivolumab and 42.1% with dacarbazine Median progressionfree survival was 5.1 months with nivolumab and 2.2 months with dacarbazine Patients taking nivolumab were more likely to have an objective response (40.0% vs 13.9%) and a complete response (7.6% vs 1.0%).11 Another study compared dual therapy with nivolumab and ipilimumab to ipilimumab alone in 142 patients 86 with previously untreated stage III or IV melanoma Combination therapy was significantly more likely to induce an objective response than ipilimumab alone among patients with BRAF wild-type tumors (61% vs 11%) Patients with BRAF mutation-positive tumors were also more likely to have an objective response with combination therapy (52% vs 10%) A complete response occurred in 22% of patients receiving combination therapy and in no patients receiving monotherapy.12 NSCLC – In a single-arm trial, 117 patients with stage IIIB or IV squamous NSCLC previously treated with at least systemic regimens including platinum doubletbased chemotherapy received nivolumab until disease progression or unacceptable toxicity occurred An objective response occurred in 14.5% of patients Median overall survival was 8.2 months, and the 1-year survival rate was 40.8%.13 In an open-label study, 272 patients with metastatic squamous NSCLC previously treated with one platinum doublet-based regimen were randomized to receive nivolumab or docetaxel until disease progression or unacceptable toxicity occurred A prespecified interim analysis found that nivolumab significantly improved overall survival, the primary endpoint, by 41% compared to docetaxel (median 9.2 vs 6.0 months).14 ADVERSE EFFECTS – Immune-mediated adverse effects, including pneumonitis, colitis, hepatitis, nephritis, and thyroid dysfunction, have occurred in patients taking nivolumab Some reactions have been severe, and fatal pneumonitis has been reported Liver enzyme elevations, hyponatremia, and hyperkalemia are common and can be severe In the single-arm The Medical Letter ® NSCLC trial, severe (grade 3/4) dyspnea, fatigue, and musculoskeletal pain each occurred in ≥5% of patients Less serious adverse effects occurring in ≥20% of patients have included cough, decreased appetite, nausea, constipation, and rash In the study evaluating dual use of nivolumab and ipilimumab for metastatic melanoma, 54% of patients taking the two drugs experienced at least one grade 3/4 adverse effect, and 47% discontinued treatment because of an adverse effect Three treatment-related fatalities occurred.12 PREGNANCY – Nivolumab has caused fetal harm in animal studies Women who could become pregnant should use effective contraception while taking the drug and for at least months after stopping it DOSAGE AND ADMINISTRATION – Nivolumab solution is available in 40 mg/4 mL and 100 mg/10 mL singleuse vials The recommended dosage is mg/kg infused intravenously over 60 minutes every weeks until disease progression or unacceptable toxicity occurs CONCLUSION — Nivolumab (Opdivo), like pembrolizumab (Keytruda), appears to increase response rates and survival more than ipilimumab (Yervoy) and should be considered an option for first-line treatment of metastatic melanoma Nivolumab also improved survival rates in patients with metastatic squamous non-small cell lung cancer (NSCLC) refractory to platinum doublet-based chemotherapy ■ Pembrolizumab (Keytruda) for metastatic melanoma Med Lett Drugs Ther 2014; 56:e114 Ipilimumab (Yervoy) for metastatic melanoma Med Lett Drugs Ther 2011; 53:51 D Schadendorf et al Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J Clin Oncol 2015 February (epub) C Robert et al Pembrolizumab versus ipilimumab in advanced melanoma N Engl J Med 2015 April 19 (epub) National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Melanoma Version 2015 Available at www.nccn.org Accessed May 28, 2015 Vemurafenib (Zelboraf) for metastatic melanoma Med Lett Drugs Ther 2011; 53:77 Dabrafenib (Tafinlar) and trametinib (Mekinist) for metastatic melanoma Med Lett Drugs Ther 2013; 55:62 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Small Cell Lung Cancer Version 2015 Available at www.nccn.org Accessed May 28, 2015 DM Pardoll The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012; 12:252 10 JS Weber et al Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, openlabel, phase trial Lancet Oncol 2015; 16:375 11 C Robert et al Nivolumab in previously untreated melanoma without BRAF mutation N Engl J Med 2015; 372:320 Vol 57 (1470) June 8, 2015 12 MA Postow et al Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015; 372:2006 13 NA Rizvi et al Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial Lancet Oncol 2015; 16:257 14 J Brahmer et al Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 2015; 373: 123 ▶ Recombinant Human Parathyroid Hormone (Natpara) The FDA has approved a subcutaneously injected formulation of recombinant human parathyroid hormone (Natpara – NPS) as an adjunct to calcium and vitamin D to control hypocalcemia in adults with hypoparathyroidism Natpara is an 84-amino acid single-chain polypeptide identical to native parathyroid hormone It is the first parathyroid hormone formulation to be approved for this indication Pronunciation Key Natpara: nat pa' ruh PARATHYROID HORMONE — Secreted in response to low serum calcium, parathyroid hormone binds to PTH-1 receptors both in bone, causing release of calcium into blood, and in the kidneys, increasing tubular reabsorption of calcium and conversion of vitamin D to its most active form.1 TREATMENT OF HYPOPARATHYROIDISM — Hypocalcemia caused by hypoparathyroidism is usually managed with oral calcium and vitamin D Patients typically require at least 1-2 g/day of elemental calcium in ≥3 divided doses to maintain serum calcium levels in the low-normal range, which is the goal for patients with hypoparathyroidism Calcium carbonate is often used because it is inexpensive and can reduce hyperphosphatemia by binding phosphate in the gut, but it requires an acidic pH for absorption and must be taken with food Calcium citrate is an option for patients with achlorhydria, such as the elderly and those taking a proton pump inhibitor Calcitriol, a synthetic form of the active metabolite of vitamin D3, is preferred over other vitamin D formulations (vitamin D2 and D3) because it does not require parathyroid hormone for activation and has a rapid onset of action and a short half-life Low-sodium diets and thiazide diuretics can reduce the risk of nephrolithiasis caused by hypercalciuria, which often occurs when hypocalcemia is corrected in patients with hypoparathyroidism.2 CLINICAL STUDY — In a 24-week, double-blind trial (REPLACE), 134 patients with hypoparathyroidism were randomized to receive subcutaneous recombinant 87 The Medical Letter human parathyroid hormone or placebo once daily The primary composite endpoint (≥50% reduction in vitamin D and calcium doses and maintenance of serum calcium between the baseline value and the upper limit of normal) was achieved in 53% of patients receiving the active drug and in 2% of those receiving placebo.3 ADVERSE EFFECTS — Hypo- and hypercalcemia occur commonly with use of recombinant human parathyroid hormone Other adverse effects occurring in ≥10% of patients in the clinical trial and more frequently than with placebo included paresthesia, hypoesthesia, headache, nausea, diarrhea, vomiting, arthralgia, and extremity pain Osteosarcoma has occurred in rats with parathyroid hormone levels 3-71 times those occurring in humans receiving 100 mcg daily Because of this potential risk, the package insert states that Natpara should only be used in patients who cannot be well controlled with calcium and active forms of vitamin D alone As part of a risk evaluation and mitigation strategy (REMS) program, the FDA has required that prescribers and pharmacies be certified before prescribing or dispensing the drug, and that patients and prescribers sign a form before starting treatment acknowledging that the risk of osteosarcoma was discussed PREGNANCY — Natpara is classified as category C (developmental effects and fetal death in animals; no adequate studies in women) for use during pregnancy DRUG INTERACTIONS — Coadministration of the bisphosphonate alendronate can reduce the effectiveness of Natpara and is not recommended; other bisphosphonates may have a similar effect Hypocalcemia could reduce the efficacy of digoxin, and hypercalcemia caused by Natpara could increase the risk of digitalis toxicity DOSAGE, ADMINISTRATION, AND COST — The starting dosage of Natpara is 50 mcg injected subcutaneously in alternating thighs once daily Treatment should not be started unless serum calcium is >7.5 mg/dL and the 25(OH) vitamin D level is within normal limits Once therapy is started, the daily dose of active vitamin D should be reduced by half Serum calcium should be measured every 3-7 days after starting treatment, and daily doses of vitamin D and calcium should be adjusted according to the recommendations in Table If serum calcium cannot be maintained above mg/dL without vitamin D and/or calcium supplementation, the daily Natpara dose may be increased by 25 mcg every weeks to a maximum of 100 mcg If serum calcium is re88 Vol 57 (1470) ® June 8, 2015 Table Active Vitamin D and Calcium Dose Adjustments with Natpara Serum Calcium1 >10.6 mg/dL >9 and ≤10.6 mg/dL ≥8 and ≤9 mg/dL 100 kg with coexistent moderate to severe psoriasis, for whom it is 90 mg effects, but evidence from controlled clinical trials is limited.6 One randomized, double-blind, 6-month trial in 221 patients with active psoriatic arthritis found that physician and patient global assessment scores improved significantly with methotrexate (target dose 15 mg/week), but the drug did not have a significant effect on ACR20 response rates, psoriatic arthritis response criteria (PsARC), measures of joint inflammation, or pain compared to placebo.7 Adverse Effects – Nausea and vomiting are common with methotrexate Hepatotoxicity is the most frequent serious adverse effect Methotrexate is immunosuppressive and should not be used in patients with active infections Methotrexate-induced pneumonitis is rare, but can be fatal Macrocytic anemia, leukopenia, and thrombocytopenia can occur Liver function and blood counts should be monitored Decreased renal function and inadvertent overdosing (daily rather than weekly) are common causes of hematologic toxicity Pregnancy – Methotrexate is teratogenic and is contraindicated during pregnancy; after stopping it, men should wait a minimum of months and women should wait at least one ovulatory cycle before attempting to conceive e89 LEFLUNOMIDE – An oral inhibitor of pyrimidine synthesis, leflunomide is often used for treatment of psoriatic arthritis in patients who have not responded to methotrexate or cannot tolerate it In a randomized, double-blind, 24-week trial in 190 patients with active psoriatic arthritis, the PsARC response rate was 59% with leflunomide (100 mg/day loading dose for days followed by 20 mg/day) compared to 30% with placebo.8 An observational study in 514 patients with active psoriatic arthritis treated with leflunomide found that 86% achieved a PsARC response after 24 weeks of treatment.9 Adverse Effects – Diarrhea occurs frequently with leflunomide Reversible alopecia, rash, hypertension, myelosuppression, and aminotransferase elevations have also been reported Anaphylaxis, StevensJohnson syndrome, weight loss, interstitial lung disease, peripheral neuropathy, and leukocytoclastic vasculitis have occurred rarely Pregnancy – Leflunomide is contraindicated for use during pregnancy SULFASALAZINE – In clinical studies in patients with psoriatic arthritis, sulfasalazine has produced modest improvements in symptoms.10 The beneficial effects may not become apparent for 2-3 months after starting treatment The Medical Letter ® Adverse Effects – Sulfasalazine frequently causes GI disturbances Leukopenia, agranulocytosis, reversible oligospermia, a lupus-like syndrome, and hepatotoxicity have been reported Pregnancy – Sulfasalazine is classified as category B (no evidence of toxicity in animals; no adequate studies in women) for use during pregnancy CYCLOSPORINE — Use of cyclosporine has resulted in modest improvements in pain and other symptoms in small, open-label studies in patients with psoriatic arthritis.10 In a 12-month, randomized, double-blind, placebo-controlled trial in psoriatic arthritis patients with an incomplete response to methotrexate, addition of cyclosporine (2.5-4 mg/kg/day) significantly reduced signs of joint inflammation.11 It is recommended only for short-term use (up to 12 months) Adverse Effects – The doses of cyclosporine used for psoriatic arthritis (2.5-4 mg/kg/day in divided doses) have generally been safe, but hypertension and nephrotoxicity can occur Cyclosporine can also cause diarrhea, nausea, vomiting, infection, hirsutism, gingival hyperplasia, pruritus, headache, paresthesias, and hypertriglyceridemia It increases the risk of skin malignancies in patients previously treated with psoralens combined with UVA radiation (PUVA) and interacts with many other drugs Pregnancy – Cyclosporine appears to be relatively safe for use during pregnancy, but has been associated with low birth weight and prematurity.12 PDE4 INHIBITOR APREMILAST — The oral phosphodiesterase type-4 (PDE4) inhibitor apremilast is approved by the FDA for treatment of active psoriatic arthritis in adults In randomized, double-blind, placebo-controlled trials in a total of 1493 adults with active psoriatic arthritis refractory to DMARDs, 32-41% of patients taking apremilast 30 mg twice daily achieved an ACR20 response after 16 weeks compared to 18-19% of those taking placebo.13,14 Among patients in one of the studies who continued taking apremilast, the ACR20 response at week 52 was 54.6% with 30 mg twice daily.15 No studies directly comparing apremilast with a TNF inhibitor are available; in cross-study comparisons, response rates appear to be lower with apremilast, and there is no evidence that apremilast retards joint damage Adverse Effects – The most common adverse effects of apremilast in clinical trials were diarrhea, nausea, Vol 57 (1470) June 8, 2015 and headache These effects occurred most frequently during the first two weeks of treatment and tended to resolve with continued use of the drug No increased risk of malignancy or serious infection, including reactivation of tuberculosis, has been reported to date Apremilast can increase the risk of depression Loss of 5-10% of body weight has been reported Pregnancy – Apremilast is classified as category C (fetotoxicity in animals; no adequate studies in women) for use during pregnancy BIOLOGIC AGENTS TNF INHIBITORS – The five tumor necrosis factor (TNF) inhibitors available in the US, adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab, are approved by the FDA for treatment of active psoriatic arthritis and they appear to be the most effective treatment available to date for this disease They have been shown to reduce joint disease activity, prevent structural damage, and improve function Some patients who have not responded to one TNF inhibitor have responded to another.16,17 A cohort analysis of patients with bone erosions treated in a psoriatic arthritis clinic found that progression of radiographic joint damage occurred less frequently in patients being treated with a TNF inhibitor than in those receiving methotrexate after 1-2 years (59% vs 80%) and after 3-4 years (61% vs 88%).18 In clinical trials with adalimumab, etanercept, infliximab and golimumab, ACR 20 response rates in patients with psoriatic arthritis were 58%, 59%, 58%, and 51%, respectively after 12-14 weeks of treatment.1 No headto-head comparisons of TNF inhibitors for treatment of psoriatic arthritis are available, but an indirect comparison meta-analysis of adalimumab, etanercept, golimumab, and infliximab found no statistically significant differences in efficacy between the drugs.19 Certolizumab pegol, the most recently approved TNF inhibitor, appears to be similar in efficacy to the others.20 A randomized, double-blind trial in 409 patients with active psoriatic arthritis found that significantly more patients receiving certolizumab pegol 200 mg SC every other week or 400 mg SC every weeks had an ACR20 response at week 12 compared to those treated with placebo (58% and 52% vs 24%).21 Adverse Effects – Serious infections, including bacterial infections (particularly pneumonitis and cellulitis), histoplasmosis, and reactivation of tuberculosis and hepatitis B virus have been reported with all the TNF e90 The Medical Letter ® inhibitors, particularly in the first 2-7 months of treatment.22 These drugs should not be given to patients with active localized or chronic infections Screening for exposure to tuberculosis is recommended before starting anti-TNF therapy and annually thereafter Lymphoma and other malignancies have been reported in patients with rheumatoid arthritis receiving these drugs, but a cause-and-effect relationship has not been established They generally should not be used in patients with a recent malignancy Exacerbations and new onset of heart failure, pancytopenia, and demyelinating disorders such as multiple sclerosis have been reported.23 Anti-TNF drugs have been associated with development of autoantibodies and the induction of a lupus-like syndrome A review of clinical studies found that autoantibodies reduced the efficacy of infliximab and adalimumab, but not of etanercept.24 Pregnancy – TNF inhibitors are classified as category B (no evidence of toxicity in animals; no adequate studies in women) for use during pregnancy IL-12/23 ANTAGONIST – The human interleukin-12 and -23 antagonist ustekinumab is FDA-approved for treatment of psoriatic arthritis.20 A randomized, double-blind trial in 615 patients with active psoriatic arthritis found that 42% and 50% of patients treated with ustekinumab 45 mg and 90 mg, respectively, achieved an ACR20 response at week 24 compared to 23% of those receiving placebo; responses were maintained at week 52.25 Ustekinumab also slowed radiographic progression, compared to placebo, for up to 52 weeks.26 Response rates with ustekinumab have been somewhat lower than with TNF inhibitors, but direct compartisons are lacking Adverse Effects – Ustekinumab has been associated with serious infections (especially tuberculosis), malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy Screening for tuberculosis is recommended before treatment Autoantibodies have developed; whether they reduce treatment response remains to be determined.24 Pregnancy – Ustekinumab is classified as category B (no evidence of toxicity in animals; no adequate studies in women) for use during pregnancy INVESTIGATIONAL DRUG SECUKINUMAB — The IL-17A inhibitor secukinumab is under investigation for treatment of psoriatic arthritis In a small randomized, double-blind, 24week trial in 42 patients with psoriatic arthritis, ACR20 e91 Vol 57 (1470) June 8, 2015 responses following doses of IV secukinumab (10 mg/kg) given weeks apart were greater than those with placebo, but the differences were not statistically significant There were significant reductions in C-reactive protein, erythrocyte sedimentation rate, and quality of life assessment scores in patients receiving secukinumab.27 COMBINATION THERAPY In patients with moderate to severe psoriatic arthritis who have an inadequate response to a DMARD, guidelines recommend addition of a TNF inhibitor.1,3,4 This combination may also be considered for initial treatment Whether combining a DMARD with a TNF inhibitor improves response rates in patients with psoriatic arthritis beyond those achieved by treatment with a TNF inhibitor alone is controversial In clinical trials of TNF inhibitors that allowed concomitant use of methotrexate, the combination did not appear to have additive or synergistic effects.28,29 In a nonrandomized, unblinded study in patients with severe psoriatic arthritis that had responded inadequately to methotrexate, the combination of cyclosporine and adalimumab was more effective than either drug alone.30 ■ A Gottlieb et al Guidelines of care for the management of psoriasis and psoriatic arthritis: Section Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics J Am Acad Dermatol 2008; 58:851 A Menter et al Guidelines of care for the management of psoriasis and psoriatic arthritis: section Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions J Am Acad Dermatol 2011; 65:137 CT Ritchlin et al Treatment recommendations for psoriatic arthritis Ann Rheum Dis 2009; 68:1387 L Gossec et al European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies Ann Rheum Dis 2012; 71:4 AJ Kivitz et al A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating the signs and symptoms of psoriatic arthritis Semin Arthritis Rheum 2007; 37:164 P Mease Methotrexate in psoriatic arthritis Bull Hosp Jt Dis (2013) 2013; 71 suppl 1:S41 GH Kingsley et al A randomized placebo-controlled trial of methotrexate in psoriatic arthritis Rheumatology (Oxford) 2012; 51:1368 JP Kaltwasser et al Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial Arthritis Rheum 2004; 50:1939 F Behrens et al Leflunomide in psoriatic arthritis: results from a large European prospective observational study Arthritis Care Res (Hoboken) 2013; 65:464 10 ER Soriano and NJ McHugh Therapies for peripheral joint disease in psoriatic arthritis A systematic review J Rheumatol 2006; 33:1422 11 AD Fraser et al A randomised, double-blind, placebo controlled, The Medical Letter Vol 57 (1470) ® multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis Ann Rheum Dis 2005; 64:859 12 MB Hoffman et al Psoriasis during pregnancy: characteristics and important management recommendations Expert Rev Clin Immunol 2015; 11:709 13 Apremilast (Otezla) for psoriatic arthritis Med Lett Drugs Ther 2014; 56:41 14 A Kavanaugh et al Treatment of psoriatic arthritis in a phase randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase inhibitor Ann Rheum Dis 2014; 73:1020 15 A Kavanaugh et al Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis J Rheumatol 2015; 42:479 16 R Goulabchand et al Effect of tumor necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials Ann Rheum Dis 2014; 73:414 17 AS Soubrier et al Treatment response, drug survival and safety of anti-tumour necrosis factor  therapy in 193 patients with psoriatic arthritis: a twelve-year “real life” experience Joint Bone Spine 2015; 82:31 18 L Eder et al Tumour necrosis factor  blockers are more effective than methotrexate in the inhibition of radiographic joint damage progression among patients with psoriatic arthritis Ann Rheum Dis 2014; 73:1007 19 K Thorlund et al Anti-tumor necrosis factor (TNF) drugs for the treatment of psoriatic arthritis: an indirect comparison metaanalysis Biologics 2012; 6:417 20 Certolizumab pegol (Cimzia) and ustekinumab (Stelara) for psoriatic arthritis Med Lett Drugs Ther 2014; 56:9 21 PJ Mease et al Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase double-blind randomised placebo-controlled June 8, 2015 study (RAPID-PsA) Ann Rheum Dis 2014; 73:48 22 RE Kalb et al Risk of serious infection with biologic and systemic treatment of psoriasis: results from the psoriasis longitudinal assessment and regiatryy (PSOLAR) JAMA Dermatol 2015 May 13 (epub) 23 AL Semble et al Safety and tolerability of tumor necrosis factor- inhibitors in psoriasis: a narrative review Am J Clin Dermatol 2014; 15:37 24 L Hsu et al Antidrug antibodies in psoriasis: a systematic review Br J Dermatol 2014; 170:261 25 IB McInnes et al Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT trial Lancet 2013; 382:780 26 A Kavanaugh et al Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials Ann Rheum Dis 2014; 73:1000 27 IB McInnes et al Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomized, double-blind, placebo-controlled, phase II proof-of-concept trial Ann Rheum Dis 2014; 73:349 28 M Daly et al Combination systemic therapies in psoriatic arthritis J Dermatolog Treat 2011; 22:276 29 ML Felquer and ER Soriano New treatment paradigms in psoriatic arthritis: an update on new therapeutics approved by the U.S Food and Drug Administration Curr Opin Rheumatol 2015; 27:99 30 GN Karanikolas et al Adalimumab or cyclosporine as monotherapy and in combination in severe psoriatic arthritis: results from a prospective 12-month nonrandomized unblinded clinical trial J Rheumatol 2011; 38:2466 EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Subscriptions (US): year - $98; years - $189; years - $279 $49 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: info@medicalletter.org Call: 800-211-2769 ext 315 Special rates available for bulk subscriptions Copyright 2015 ISSN 1523-2859 e92 The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 (Issue 1471) June 22, 2015 Take CME Exams Addendum: Nivolumab (Opdivo) for Metastatic Melanoma and Metastatic NSCLC After our article on nivolumab (Opdivo – BMS) for treatment of metastatic melanoma and metastatic squamous nonsmall cell lung cancer (NSCLC) was published in the most recent issue of The Medical Letter (June 8, 2015),1 some new data became available supporting the efficacy of the drug in previously untreated melanoma and previously treated nonsquamous NSCLC MELANOMA – In a double-blind trial, 945 patients with previously untreated, unresectable stage III or IV melanoma were randomized to receive ipilimumab, nivolumab, or combination therapy with ipilimumab and nivolumab Progression-free survival, a primary endpoint, improved by 43% with nivolumab (median 6.9 months) and by 58% with combination therapy (median 11.5 months), compared to ipilimumab (median 2.9 months) In patients with tumors that expressed the programmed death ligand (PD-L1) on ≥5% of cells, median progression-free survival was similar in the nivolumab and combination groups (both 14.0 months); in those with tumors that expressed PD-L1 on