Practice Update: Haematology & Oncology

ASCO 2016

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EXPERT OPINION Evidence-based integration of CDK inhibitor therapy By Dr Lee S. Schwartzberg Dr Lee Schwartzberg, Senior Partner and Medical Director of the West Clinic in Memphis, Tennessee and Clinical Professor of Medicine at the University of Tennessee College of Medicine, talks about two trials of CDK4/6 inhibitors presented last month at ASCO 2016. PALOMA-2

receptor-positive metastatic breast cancer. It did come at a price of more toxicity, though – significant fatigue and diarrhoea – and many patients did require a dose reduction. The CDK4/6 drugs comprise an exciting new class. Abemaciclib may be able to be used as a single agent in this particular setting, and we await the results from the combination studies in the next year or two to see if we have another agent that can be combined with anti-endocrine therapy. References 1. Finn RS, Martin M, Rugo HS, et al. Paper presented at 2016 Annual Meeting of the American Society of Clinical Oncology; June 3–7, 2016; Chicago, IL. Abstract 507. 2. Dickler MN, Tolaney SM, Rugo HS, et al. Paper presented at 2016 Annual Meeting of the Ameri- can Society of Clinical Oncology; June 3–7, 2016; Chicago, IL. Abstract 510.

of hormone receptor-positive breast cancer. That’s a big advance, and now we have solid data here. It has a similar ratio of about 0.6. It’s really a very important trial, I think, and will reinforce and expand how we use these drugs. MONARCH1 As a class, the CDK4/6 drugs are very in- teresting. They interfere with the cell cycle, and so they may have application even beyond breast cancer; however, most of the work to date has been in breast cancer. Abemaciclib is another CDK4/6 inhibitor, an oral drug, and it has been tested both as a monotherapy and in combination. At ASCO 2016, we heard the results of the monotherapy. 2 The monotherapy with abemaciclib was given at a little higher dose than is being used in the combination therapy with endocrine

treatment, results of which will be reported in the next year or two. In this study, MON- ARCH1, patients received abemaciclib. These were patients, though, who had hormone receptor-positive breast cancer and who had already had several lines of chemotherapy both in the adjuvant and the metastatic set- ting, and they had also had several lines of endocrine therapy. The study showed that the response rate was around 19%, which is a very respectable response rate in patients with metastatic breast cancer who have been heavily pretreated, whether it’s chemotherapy as a comparator, or certainly better than other single endocrine therapies we’ve seen in a late- line setting. I think we can interpret these data to sug- gest that, unlike palbociclib, abemaciclib does have single-agent activity in hormone

PALOMA-2 is a randomised phase III trial that is looking at the combination of palboci- clib, a CDK 4/6 inhibitor added to letrozole, an aromatase inhibitor, in the first-line set- ting of metastatic hormone receptor-positive/ HER2-negative breast cancer. 1 We already know, based on a small randomised phase II trial called PALOMA-1, that the combina- tion works. In fact, the US Food and Drug Administration approved the drug last year, and it’s available for use, and we’re using it quite successfully. However, we didn’t have the data on the combination in a larger group of patients. So, PALOMA-2 is that phase III trial, and it is a positive trial with an improvement of about 10 months for progression-free survival in women who get the combination compared with letrozole alone in the first-line setting

Image-guided thermal ablation is proven safe and effective in T1a renal cell carcinoma Minimally invasive therapy with image-guided thermal ablation has been shown to provide safe and effective treatment for T1a renal cell carcinoma in patients with other non-renal malignancies, reports a retrospective registry review presented at this year’s ASCO meeting. D r Mohamed E. Abdelsalam, of the Uni- versity of Texas MD Anderson Cancer Center, Houston, explained that, though

High-dose interleukin-2 continues to be a valuable treatment option for eligible patients with metastatic renal cell carcinoma An analysis of the national interleukin-2 registry has re- vealed that high-dose interleukin-2 therapy followed by targeted therapy and/or immune checkpoint blockade is potentially associated with survival benefit. T his conclusion, based on results of a registry study of high-dose interleukin-2 + targeted therapy ± immunotherapy, was presented at the 2016 ASCO meeting. Dr Joseph Clark of Loyola University Medical Center, Maywood, Illinois, explained that high dose interleukin-2 can provide durable re- sponses in patients with metastatic renal cell carcinoma. The PRoleukin Observational study to evaluate the treatment patterns and CLinicAl response in Malignancy (PROCLAIM) is an interluekin-2 registry with over 44 participating sites that captures real-world patient population survival and outcomes. Dr Clark and colleagues reported on contemporary patient experience sequencing high-dose interleukin-2 with targeted therapy and immune checkpoint blockade in metastatic renal cell carcinoma. Patients were prospectively enrolled into the registry as of 2011 and must have received at least one dose of high-dose interleukin-2 for the analysis. Statistical and survival analyses were performed. The median overall survival for all 411 patients with metastatic renal cell carcinoma was not reached after a median follow-up of 21 months. The overall response rate for the 382 patients with available data was 17.8%. The median overall survival for the 15 patients who experienced com- plete response, 53 who achieved partial response, or 145 who achieved stable disease was not reached, while in the 169 patients with progressive disease, median overall survival was 17 months. Treatments prior to high- dose interleukin-2 therapy included chemotherapy (n = 12), targeted therapy (n = 74), immunotherapy (n = 8), radiotherapy (n = 64), and surgery (n = 389). Dr Clark concluded that this analysis of the national interleukin-2 reg- istry revealed that high-dose interleukin-2 therapy followed by targeted therapy and/or immune checkpoint blockade is potentially associated with a survival benefit. High-dose interleukin-2 continues to be a valu- able treatment option for eligible patients with metastatic renal cell carcinoma.

surgical excision remains the gold standard treatment for renal cell carcinoma, active sur- veillance and thermal ablation provide alterna- tive options for patients at higher surgical risk. Dr Abdelsalam and colleagues set out to evaluate image-guided thermal ablation for pathologically proven T1a renal cell carci- noma in patients with other non-renal primary malignancies. The investigators reviewed their renal tu- mour ablation registry retrospectively for 2005 through 2013. They included patients with T1a renal tumours (<4 cm). They excluded patients without histologically proven renal cell carcinoma, those with Von Hippel Lindau syndrome, and those with a prior history of renal cell carcinoma. Two groups were created: 1. Patients with renal cell carcinoma and a history of other nonrenal primary malig- nancy (in remission or active) 2. Patients with renal cell carcinoma only Statistical analysis was performed to compare the two groups using Fisher’s exact and Kruskal- Wallis test for demographics (age, sex) and clinical characteristics (prior or current cancer history, renal tumour size, and complications). Overall survival was estimated using the Kaplan-Meier product-limit estimator and a log- rank test was used to compare the two groups. Overall survival was measured from the procedure date to the date of last contact or death. Seventy-four patients were included in the study, and 37 patients (50%) had other nonrenal primary disease. The average age at procedure was 68.8 years. Age (68.6 vs 68.9 years), sex (15 women and 22 men vs 13 men and 24 women), tumour size (2.3 vs 2.5), and complication rates (2.9 vs 5.9) did not differ significantly between the two groups. Median survival time for the entire population was

8.39 years. The probability of 5-year (10-year) survival was 0.74 (0.48). Survival did not differ between the two groups. Dr Abdelsalam concluded that minimally invasive therapy with image-guided thermal ablation was shown to provide safe and effective treatment for T1a renal cell carcinoma in patients with other nonrenal malignancies. Primary malignancies and therapy for them did not impact effectiveness, complications, or overall survival rates of thermal ablation discernibly.

VOL. 1 • No. 2 • 2016