PracticeUpdate Oncology May 2019

In patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy GIVE YOUR PATIENTS A KEY TO OVERALL SURVIVAL 1 *

NOW PBS LISTED 2

* KN-045: Median overall survival at 1 year was 10.3 months with KEYTRUDA [n=270] vs 7.4 months with chemotherapy (paclitaxel, docetaxel, or vinflunine) [n=272]; HR 0.73 (95% CI: 0.59–0.91), p=0.002 (Kaplan-Meier estimate). The co-primary endpoint of PFS was not met. 1

• In urothelial cancer, a higher number of deaths within 2 months was observed with KEYTRUDA vs chemotherapy. Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases. 1 • In KN-045, the most common adverse reactions (occurring in ≥20% of patients who received KEYTRUDA) were fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea and rash. 1

PBS Information: Authority required (STREAMLINED). Refer to PBS Schedule for full authority information. This product is not listed on the PBS for the first-line treatment of patients with urothelial carcinoma who are not eligible for cisplatin- or platinum-containing therapy.

Before prescribing, please review the Product Information. Product Information is available at http://msdinfo.com.au/keytrudapi

KEYTRUDA ® MinimumProductInformation(v22.4)Indications: Asmonotherapyforpatientswith locallyadvancedormetastaticurothelialcarcinoma(UC)whoarenoteligibleforcisplatin-containingtherapyandwhose tumours express PD-L1 [Combined Positive Score (CPS) ≥10], or in patients who are not eligible for, or have received prior platinum-containing chemotherapy regardless of PD-L1 status. See full PI. Contraindications: None. Precautions: Immune-mediated adverse reactions, including pneumonitis,colitis (including gastrointestinal perforation),hepatitis,nephritis,hypophysitis, type 1 diabetes mellitus,hyperthyroidism,hypothyroidism, thyroiditis, uveitis, myositis, Guillain-Barre syndrome, myasthenic syndrome/ myasthenia gravis (incl. exacerbation), pancreatitis, sarcoidosis, encephalitis, myocarditis, pericarditis and pericardial effusion, peripheral neuropathy, solid organ transplant rejection, severe skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and bullous pemphigoid), severe infusion reactions (hypersensitivity, anaphylaxis), and complications of allogeneic HSCT including fatal graft-versus-host-disease and hepatic veno-occlusive disease. Severe and fatal cases of immune-mediated adverse reactions have occurred. Increased mortality when in combination with dexamethasone and a thalidomide analogue in multiple myeloma (not indicated). Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.For management of immune-mediatedadverseevents,see fullPI.Limited information inpatientswithactive infectionandpatientswithon-goingadversereaction to ipilimumab–usecaution.Increaseddeathsobserved inpreviously-treatedUC patients infirsttwomonthsoftreatmentcomparedtochemotherapy.SeefullPIforfurther information. Pregnancy: CategoryD. Interactions: Noneexpected.Avoidcorticosteroidsor immunosuppressantspriortotreatment. Adverse events: hypothyroidism, nausea, asthenia, fatigue, hyperthyroidism, pneumonitis, colitis, hepatitis, hypophysitis, nephritis, type 1 diabetes mellitus, arthralgia, cough, back pain, vitiligo, abdominal pain, pruritus, rash, hyponatremia, anaemia, diarrhoea, pyrexia, adrenal insufficiency, autoimmune hepatitis, upper respiratory tract infection, constipation, vomiting, urinary tract infection, decreased appetite, musculoskeletal pain, haematuria,dyspnoea,diarrhoea,alopecia,headache,neutropenia.Post-marketing:arthritis,Vogt-Koyanagi-Harada syndrome. Dosage: 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. Treat with KEYTRUDA until disease progression or unacceptable toxicity, or up to two years or 35 cycles. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions followed by shrinkage) have been observed. Clinically stable patients (i.e. asymptomatic and not requiring urgent intervention) with initial evidence of progression can remain on treatment until confirmed. See full PI for further information. KN-045 study design: An international, open-label, randomised, phase III trial in patients aged 18 years or older with advanced urothelial cancer that had progressed during or after receipt of platinum- based chemotherapy. Patients with creatinine clearance ≥30 mL/min were eligible for treatment. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Patients with ECOG PS score of 0–2 were eligible, however those with ECOG PS 2 and ≥1 of the established poor prognostic factors for second-line therapy were excluded. Patients were randomised to either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator’s choice of chemotherapy (paclitaxel 175 mg/m 2 every 3 weeks, docetaxel 75 mg/m 2 every 3 weeks or vinflunine 320 mg/m 2 every 3 weeks; n=272). Assessment of tumour status was performed at 9 weeks after randomisation, then every 6 weeks through the first year, followed by every 12 weeks thereafter. PFS and ORR were assessed by BICR per RECIST v1.1. Treatment continued until RECIST-defined disease progression, unacceptable toxicity, or the completion of 2 years of KEYTRUDA therapy. Patients in the KEYTRUDA group who had a complete response could discontinue treatment if they had received KEYTRUDA for at least 24 weeks and for at least 2 doses beyond the time of initial complete response. Patients who were allocated to the chemotherapy arm who experienced disease progression were able to receive another immunotherapeutic agent or crossover to the KEYTRUDA arm of the study. Co-primary endpoints were overall survival and progression-free survival in the total population and in patients who had a tumour PD-L1 combined positive score of ≥10. 1,3,4 References: 1. KEYTRUDA Australian Approved Product Information, http://msdinfo.com.au/keytrudapi. 2. Australian Government Department of Health. Pharmaceutical Benefits Scheme (PBS). Available at: www.pbs.gov.au Accessed 16 April 2019. 3. Bellmunt J et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015–26. 4. Bellmunt J et al . Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab versus investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer. Oral presentation at ASCO GU, 8–10 Feb 2018, San Francisco, USA. BICR: blinded independent central review. CI: confidence interval. ECOG PS: Eastern Cooperative Oncology Group Performance Status. HR: hazard ratio. ORR: overall response rate. PBS: Pharmaceutical Benefits Scheme. PD-1: programmed death 1. PD-L1: programmed death ligand 1. PFS: progression-free survival. RECIST: Response Evaluation Criteria In Solid Tumors. UC: urothelial carcinoma, WHO: World Health Organization. Copyright © (2019) Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All rights reserved. Merck Sharp & Dohme (Australia) Pty Limited. Level 1 – Building A, 26 Talavera Road, Macquarie Park NSW 2113. AU-OBD-00029. First issued April 2019. ONC1377.