PracticeUpdate: Haematology & Oncology

ESMO 2016

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Circulating tumour cells are an early predictor of disease progression in metastatic breast cancer Circulating tumour cells have been shown to be an early predictive biomarker of disease progression in metastatic breast cancer, conclude results of a 5-year, single-centre study of patients with stage 4 breast cancer. D ouaa M. Sayed, MD of South Egypt Cancer Institute SECI Assiut University, Assiut, Egypt, explained that circulating tumour cells are a prognostic marker in metastatic breast cancer, but their predictive value to monitor treatment efficacy needs further exploration. Eighty-five patients with stage 4 breast cancer met eligibility criteria. Before starting a new treatment, all patients underwent full imaging stud- ies and blood sampling for circulating tumour cell enumeration. Patients with fewer than five circulating tumour cells per 7.5 mL blood detected at baseline underwent no further count of circulating tumour cells. Patients with at least five circulating tumour cells per 7.5 mL blood underwent another blood sampling for estimation of circulating tumour cells before cycle 2. Disease status was assessed radiologically every 9 to 12 weeks. Disease response was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST). At baseline, 44 (51.8%) of the 85 eligible patients did not exhibit increased circulating tumour cell levels. Of the other 41 patients with at least five circulating tumour cells per 7.5 mL blood, only 38 underwent circulating tumour cell evaluation at first follow-up before cycle 2 that showed 25 (65.8 %) patients had fewer than five circulating tumour cells per 7.5 mL blood and 13 (34.2%) patients harboured at least five circulat- ing tumour cells per 7.5 mL blood. Seventy-five patients (75/85, 88.2 %) underwent radiological restaging. According to RECIST, 36 (48%) patients were scored as having expe- rienced a partial response, 19 (25.3%) stable disease, and 20 (26.7%) progressive disease. Radiologic response was concordant with follow-up circulating tumour cell levels in 76.5% of cases. Survival depended significantly results of both circulating tumour cell evaluation and radiological response. Median follow-up was 18.0 (1–60) months. Dr Sayed concluded that elevated circulating tumour cells before cycle 2 in patients with metastatic breast cancer starting a new line of chemotherapy can be considered an early predictive marker of disease progression, and of the benefit of treatment. The study confirmed that circulating tumour cells are an independent prognostic marker.

EXPERT OPINION ALISONK CONLIN HER2+ and ER+ breast cancer trials Interview by Sumanta Kumar Pal MD

Dr Sumanta Pal and Alison Conlin, MD, discuss HER2-positive and ER-positive breast cancer at ESMO 2016.

hormonal therapy for breast cancer, based on the data presented here, is it letrozole, is it fulvestrant? What’s your opinion there? Dr Conlin: I think that in the US we have a CDK4/6 inhibitor approved and available. It’s not ribociclib. It’s palbociclib. That’s an exciting first-line choice. It makes it a difficult decision because there is data, of course, com- bining it with fulvestrant. So if you’re going to not use a CDK4/6 inhibitor, then perhaps you want to start with fulvestrant, but if you are, the current data supports using letrozole and per- haps the combination, so I think we’re working it out. It’s not the same path for every wom- an depending on what her current pretreatment was, is she currently on an oestrogen-blocking therapy or is she oestrogen-naive.

Dr Pal: You have some really interest- ing data looking at a combination of HER2-directed therapy with a novel agent. Can you tell us a little bit about that? Dr Conlin: My presentation at this meeting is really a case series of eight women, who had cutaneous metastases or skin metastases with HER2-positive breast cancer. We find this to be a very morbid disease process for women with a lot of pain management, wound care. In my abstract, I’m looking at the results of a highly selective oral HER2 agent called tucatinib or ONT-380. We combined that with either Herceptin, Herceptin and capecitabine or T-DM1, and I found the eight women in the study in the phase I data who’d had skin disease and looked at their responses. We saw incredible responses. A woman with a complete response, partial responses, stable disease. And so clearly, this is an effective therapy in an area that’s another unmet need for women with HER2-positive metastatic breast cancer. Dr Pal: That’s fantastic. I mean skin metastases can be so cosmetically devastating. Dr Conlin: It’s really difficult for patients to manage, and so, we saw patients come down on their nar- cotics and have a better quality of life while being treated effectively for their HER2-positive disease. There is an abstract of a clinical

trial in progress of the phase 2 of this drug, so we’ll be looking at that with capecitabine and trastuzumab versus placebo, so more to come on this exciting tucatinib. Dr Pal: Now, I’m going to shift gears for just a second and ask you about another huge domain in breast cancer, which is ER-positive disease. There have been some really great abstracts highlighting that dataset here. Can you tell us a little bit about those? Dr Conlin: I think the two largest studies that were published at this meeting are the Mona Lisa study looking at a new oral CDK4/6 inhibitor ribociclib in combination with letrozole for women with first line metastatic disease that showed a great PFS benefit to that combination. That was published the same day as it was presented, so that’s always exciting to see it in print, as well as the FALCON study, which looked at whether first-line therapy for oestrogen- positive disease should be either fulvestrant or anastrozole showing, again, superiority with fulvestrant for those women. So I think we’re getting better at picking our first-line therapy for these women. Again, more to come when we look at later- line therapies. I think that will be exciting to see, as women need more therapies further down the line. Dr Pal: For the practicing oncologists out there, as you’re approaching

Dr Pal is an internationally recognised leader

in the area of genitourinary cancers. He is

the Co-Director of the City of Hope Kidney Cancer Program in California and is the head of the kidney and bladder cancer disease team at the institution.

Dr Conlin is a medical oncologist

at Providence Medical Group in Oregon.

Watch the full interview at PracticeUpdate.com

Sunitinib 2 weeks on/1 week off is superior to 4weeks on/2 weeks off in metastatic renal cell carcinoma Changing the sunitinib 4 weeks on/2 weeks off to 2 weeks on/1 week off schedule, rather than reducing the dose, was safe and resulted in a longer median progression-free and overall survival in patients with metastatic renal cell carcinoma, finds a comparative, single-centre trial. F ruzsina Gyergyay, MD, PhD, of the National Institute of Oncology, Budapest, Hungary, explained that the recom- mended schedule of sunitinib for metastatic renal cell carcinoma is 50 mg daily, orally for 4 weeks followed by 2 weeks of rest. Thirty-four (26%) had taken interferon and 21 (16%) patients had received interleukin-2 treatment. Patients received a total of 1617 cycles of sunitinib (median, eight cycles, range 1–68 cycles) were administered. • Diarrhoea 37% • Hand-foot syndrome 35% • Hypertension 30%. Though adverse events were frequent they were shorter. Dose reduction had to be performed in only 12% (n=16) during the 2/1 schedule.

A total of 344 (range 1–56) cycles were given according to the 4/2, and 1273 (1–18) according to the 2/1 schedule, respectively. On progression with sunitinib, the following therapies were given: • Sorafenib (n=10) • Axitinib (n=7) • Pazopanib (n=1) Median progression-free survival was 13.5 (95% CI 12–16.5) months. Median overall survival was 30 (24– 36) months. When the 2/1 schedule was given in more than 2/3 of total cycles (n=83), median progression-free survival was 18 (13.5–28.5) months and median overall survival was 38 (30–44) months. In those who received the 2/1 schedule for less than 2/3 of total cycles (n=47), median progression-free survival was 6 (4.5–9; P = 0.0002) months and median overall survival was 11 (7–21); P = 0.0001) months. Short-term adverse events were: • Cabozantinib (n=1) • Everolimus (n=16).

The half-life of sunitinib and its active metabolite is very long: 40–60 and 80–110 h, respectively. When given on several consecutive days, accumulations are 3–4-fold and 7–10-fold, respectively. Steady state concentration is achieved on days 7–10 and 10–14, respectively. Fifty milligrams daily is a high enough dose to achieve the target concentration ≥ 50 ng/mL. During the 14 days’ rest, the concentration decreases to the starting level. The correlation between the sunitinib area under the curve and time to progres- sion is well known. Based on the pharmacokinetics above, the 2 weeks on/1 week off schedule was applied rather than dose reduction, to reduce short-term adverse events. One hundred thirty patients with metastatic renal cell carcinoma (median age 61 years, male to female ratio 91/39) were enrolled. One hundred twenty-one (93%) patients were nephrectomised, 95% (n=123) had available renal cell carcinoma histology. Sixty-seven (30%); 49 (38%), and 42 (32%) patients were characterized as good, intermediate, and poor Memorial Sloan Kettering Cancer Center prognostic groups, respectively. Sunitinib was the first-line treatment in 75 cases (58%).

Dr Gyergyay concluded that changing the sunitinib schedule from 4/2 to 2/1, rather than reducing the dose, was safe and resulted in a longer median progression-free and overall survival in patients with metastatic renal cell carcinoma.

• Fatigue 41% • Anorexia 25% • Mucositis 35%

© ESMO 2016

VOL. 1 • No. 5 • 2016