Practice Update: Haematology & Oncology

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EXPERT OPINION Combating “financial toxicity”: HER2 biosimilars and combinations with chemotherapy By Dr Lee Schwartzberg Dr Lee Schwartzberg comments on a couple of trials presented at this year’s ASCO meeting in the context of combination treatment in metastatic HER2 breast cancer and, extrapolating on that, on the cost of cancer drugs and the emergence of biosimilars. P HEREXA was a randomised trial looking at the addition of a drug called pertuzumab. 1

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

with regard to response rates, with regard to safety. 2 We really haven’t seen any difference in this study so far. References 1. Urruticoechea A, Rizwanullah M, Im S-A, et al. Paper presented at 2016 annual meeting of the American Society of Clinical Oncology; Abstract 504. 2. Rugo HS, Barve A, Waller CF, et al. Paper presented at 2016 annual meeting of the American Society of Clinical Oncol- ogy; Abstract LBA503.

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com Account Manager Stephen Yue s.yue@elsevier.com

biosimilar is a drug. Unlike a small molecule, a biological is manufac- tured usually in a living system, be it cells or bacteria, and it’s not easy to make the same type of drug. So, biosimilars, which are biologicals that are made and look similar to the parent compound, although they may differ a little in manufacturing, comprise a new class of agents. The FDA has just put out the guidance and approved the first biosimilars in oncology; before this, we had a com- plicated problem. Now, we’re going to see a lot of biosimilars for all of the biologicals that we use, and, of course, in oncology, there are many biologicals that are used across many different disciplines. In breast cancer, trastuzumab is commonly used. It is the standard drug used in HER2-positive breast cancer, whether in the early-disease setting or the late-disease setting. It’s the go-to drug. Now we have biosimilars, and a phase III study presented at ASCO showed that the first biosimilar seemed to perform virtually identically to trastuzumab age range, 25–69 years) and 103 in the placebo group (mean age, 50 years; age range, 30–67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, −7% to 15%; P=0.58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13–0.40) in the candesartan group and 0.16 (95% CI, 0.08–0.22) in the placebo group (P = 0.56). Candesartan did not affect changes in NT-proBNP and hs-TnT val- ues, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/ Pro + Ala/Pro genotypes in multivari- ate analysis (odds ratio, 0.09; 95% CI, 0.02–0.45; P=0.003). CONCLUSIONS AND RELEVANCE The find- ings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. Angiotensin II-receptor inhibition with candesartan to prevent trastu- zumab-related cardiotoxic effects in patients with early breast cancer

However, numerically, there was an improvement of a couple of months in progression-free survival. There was improvement of several months in overall survival with the addition of pertuzumab, although, again, based on the way the statistics were designed for this trial, it didn’t meet the endpoint. So, from a statistical perspective and a regulatory per- spective, the study didn’t meet its endpoint. From a clinical perspec- tive, I think it gives some weight to the possibility that, if we don’t use pertuzumab in the first-line setting, there could be benefit in the second- line setting for sure – it makes sense that, as a drug which adds to the anti-HER2 effect, it might have benefit there. Then, we have, as everyone is aware, an issue of financial toxicity in oncology. Drugs are very expensive, and they are getting more expensive. Combinations are coming. We have many wonderful innovations in on- cology, but the problem is that they cost a lot. One way to do something about it, is to make a biosimilar. A

Pertuzumab is an anti-HER2 an- tibody, and it has been shown to have great benefit in the first-line setting of metastatic breast cancer. When used in the first line-setting, it extends survival substantially when added to trastuzumab, the standard drug, plus a taxane. So, the stand- ard now in first-line setting is for patients to get a taxane, pertuzumab, and trastuzumab. However, not all patients get pertuzumab in the first-line setting, and so PHEREXA looked at how well will it perform in the second-line setting with trastu- zumab and another chemotherapy agent, capecitabine. These were all patients who received trastuzumab and a taxane first-line, and who were then randomised to get capecitabine, pertuzumab, and trastuzumab or just the trastuzumab and capecitabine without the pertuzumab. The study did not meet its primary endpoint, which was an improve- ment in progression-free survival.

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Dr Schwartzberg is Medical Director of the

West Clinic in Memphis, Tennessee, and Editor-in-Chief of PracticeUpdate Oncology.

New drugs and devices listing THERAPEUTIC GOODS ADMINISTRATION (TGA) www.tga.gov.au Emtricitabine/tenofovir alafenamide (Descovy) , Gilead Sciences – HIV-1 infection Progesterone (Prometrium) , Besins Healthcare – Menstrual abnormalities or secondary amenorrhoea, hormone replacement therapy Bimatoprost (Latisse) , Allergan – HER2-positive breast cancer Ulipristal acetate (Esmya) , ERA Consulting – Symptoms of uterine fibroids Perampanel (Fycompa) , Eisai – Primary generalised tonic-clonic seizures Secukinumab (Cosentyx) , Novartis – Psoriatic arthritis, ankylosing spondylitis PHARMACEUTICAL BENEFITS SCHEME www.pbs.gov.au Trastuzumab (Herceptin SC) , Roche – Breast cancer Enhancing eyelash growth Terlipressin (Glypressin) , Ferring Pharmaceuticals – Hepatorenal syndrome type 1 Pertuzumab (Perjeta) , Roche –

Editor’s pick JOURNAL SCAN Angiotensin II antagonist treatment with candesartan in patients with early breast cancer JAMA Oncology Take-home message • This was a randomised, placebo-controlled trial designed to assess whether treatment with the angiotensin II antagonist candesartan would decrease the risk of trastuzumab-related cardiotoxicity in 210 women with early-stage, HER2-positive breast cancer. Treatment with candesartan did not result in decreased rates of cardiotoxicity (20 events in candesartan group vs 16 events in placebo group). • The results of the study suggest that the use of candesartan does not protect against trastuzumab-related cardiotoxic effects; however, this study was limited in size, indicating the need for larger studies in the future. Dr Jeremy Jones

INTERVENTIONS A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES The primary outcome was LVEF. Second- ary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2(formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS A total of 206 participants were evaluable (mean age, 49 years; age range, 25–69 years) 103 in the can- desartan group (mean age, 50 years;

IMPORTANCE This is the first randomised placebo-controlled evaluation of a medi- cal intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE To determine as the primary end point whether angiotensin II an- tagonist treatment with candesartan can prevent or ameliorate trastuzumab- related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a de- crease below the absolute value 45%. DESIGN This randomised, placebo-con- trolled clinical study was conducted be- tweenOctober 2007 andOctober 2011 in 19 hospitals in the Netherlands, enrolling 210women with early breast cancer test- ing positive for human epidermal growth factor receptor 2 (HER2) who were be- ing considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.

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