This year’s ISMO Fellowship and Bursary Awards, which took place in the Catherine McAuley Centre, the Mater Misericordiae University Hospital, Dublin, from Friday 2-Saturday 3 February, featured a wide range of the best cancer research taking place in Ireland.
The keynote address was delivered by Dr Dean Bajorin, Medical Oncologist in Memorial Sloan Kettering Cancer Centre (MSKCC), New York, US, whose expertise is in the treatment of genitourinary tumours — particularly bladder and testicular cancers.
Dr Bajorin has received a number of honours and awards for his work, including, in 2011, the Statesman Award from the American Society of Clinical Oncology (ASCO), which recognises certain members for more than 20 years of extraordinary volunteer service, dedication and commitment. He is also a Professor of Medicine at Weill Cornell Medical College.
Much of Dr Bajorin’s research is focused on new drugs and new drug combinations for people who have developed advanced bladder cancer and other genitourinary malignancies. His research on testicular cancer has been directed toward decreasing the side-effects of chemotherapy drugs and evaluating biological characteristics of tumours to predict treatment response.
In his talk, Dr Bajorin presented a timeline of approved urothelial cancer treatments in both the US and EU. The year 2007 was a banner year in this regard, with five new drugs approved. These were atezolizumab (US and EU first-line cisplatin-ineligible and second-line prior platinum); pembrolizumab (US and EU first-line cisplatin-ineligible and second-line prior-platinum); nivolumab (US and EU second-line prior-platinum); avelumab (US second-line prior platinum); and durvalumab (US second-line prior-platinum).
Dr Bajorin referred to recent data from a phase 2 trial (Dreicer et al, ASCO 2016) examining the use of atezolizumab for previously-treated metastatic urothelial cancer patients.
“There was activity across the board,” Dr Bajorin told the meeting.
“They did it by PDL1 expression, there are a number of assays with PDL1 expression… For this disease, none of them are worthy of a biomarker in terms of clinical decision-making… So if you take a look at the response rate of 68 per cent, in this database it is better in terms of patients who are high expressors, but the most important thing is the CR [complete response] rate. If you look at the CR rate across the board, it still exists, so even if you have no cells that are positive, you can have CR with these patients whose disease has progressed despite chemotherapy. That is really important — that is a seminal finding in this area.”
So although the median survival is only eight months, Dr Bajorin said the durable CR rate is a really important finding. He said the same observations were made in trials of nivolumab, which he described as “highly encouraging”.
Dr Bajorin also pointed out that progression-free survival was not a useful measurement for urothelial cancer and that better endpoints were needed.
At ASCO’s annual meeting last year, Dr Bajorin presented new data showing the PD-L1 inhibitor pembrolizumab continued to demonstrate an overall survival (OS) benefit compared with chemotherapy among patients with advanced urothelial cancer, with no new safety signals.
KEYNOTE-045 was an open-label phase 3 trial in which 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy were randomly assigned 1:1 to receive pembrolizumab (200mg every three weeks) or the investigator’s choice of chemotherapy (paclitaxel, docetaxel or vinflunine). It is now a mature trial, with patients continuing to receive the study drug compared with no patients in the chemotherapy arm.
<h3><strong>Longer median OS </strong></h3>
Earlier data from the trial presented after a median follow-up of 14.1 months and published in the <em>New England Journal of Medicine </em>in March 2017 showed significantly longer median OS with pembrolizumab (10.3 months) compared with chemotherapy (7.4 months; hazard ratio [HR] for death 0.73, 95 per cent CI [0.59, 0.91]; p = 0.002).
That survival benefit was maintained at 18.5 months, with a HR for death of 0.70 (95 per cent CI [0.57, 0.86]; p = 0.0004). The benefit was maintained across all subgroups, regardless of age, ECOG performance status, prior therapy, liver metastases, histology or investigator choice of chemotherapy.
The median survival in the pembrolizumab arm was the same as previously reported: 10.3 months (95 per cent CI [8.0, 12.3]), compared with 7.4 months in the chemotherapy arm (95 per cent CI [6.1, 8.1]), with significance remaining, regardless of PD-L1 expression. At 18 months, 36.1 per cent of patients receiving pembrolizumab were alive, compared with 20.5 per cent of patients receiving chemotherapy.
Dr Bajorin also referred to data from IMvigor 210 examining atezolizumab as first-line treatment in cisplatin-ineligible patients with locally-advanced and metastatic urothelial carcinoma.
Between June 9, 2014, and March 30, 2015, 123 patients were enrolled, of whom 119 received one or more doses of atezolizumab. At 17·2 months’ median follow-up, the objective response rate was 23 per cent (95 per cent CI 16 to 31), the CR rate was nine per cent (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached.
Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median OS was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response.
Treatment-related adverse events that occurred in 10 per cent or more of patients were fatigue (36 [30 per cent] patients), diarrhoea (14 [12 per cent] patients), and pruritus (13 [11 per cent] patients). One treatment-related death (sepsis) occurred. A total of nine patients (8 per cent) had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12 per cent) of patients.
“In terms of first-line therapy, we have got interesting data showing there is a 24 per cent response rate, but this is what is even more important, that for some patients, responding belies the survival rate, at least in this study,” Dr Bajorin said.
“But look at the median survival here, it is now 16 months; these are patients that were ineligible for cisplatin therapy, so they do quite poorly as a group in terms of their prognostic features, but specifically in terms of their median and long-term survival.”
Dr Bajorin also spoke about the Genotype-Phenotype Urothelial Cancer Registry he oversees.
This study is being done to create a registry to learn more about these cancers, enabling researchers to look at large groups of people with and without this kind of cancer.
Researchers will look at risk factors to learn more about their relationship to cancer. They will also look at genetic markers in saliva, which may be associated with a particular trait. It is hoped that certain genes identified in patients may predict cancer risk or response to treatment, and the registry may lead to better methods of preventing, diagnosing and treating urothelial cancers.
<h3><strong>Irish research </strong></h3>
As usual, the ISMO meeting featured some of the most original cancer research taking place in Ireland. Dr Ahmed Nabil, Our Lady of Lourdes Hospital, Drogheda (OLOLH); Dr Fergus Keane, Galway University Hospital; Dr Oana Deac, St James’s Hospital, Dublin; and Dr Rozana Rahman, the Mater Misericordiae University Hospital, Dublin, were four of the award winners. Dr Nabil’s research consisted of a review of the national guidelines of paclitaxel administration in early breast cancer. Weekly paclitaxel 80mg/ m2 is a widely-used regimen in the neoadjuvant/adjuvant treatment of breast cancer. National and local guidelines suggest that treatment can be given if neutrophils are ≥1.5 X 103/mm3.
In addition, it is recommended for grade II neutropaenia (neutrophils 1.0 x 103/mm3 <1.5 x 103/ mm3), that the dose of paclitaxel to be reduced to 65mg/m2. To examine the local practice and the effect of changes in the dose, a retrospective review was conducted. The study retrospectively examined patients with breast cancer who received paclitaxel in 2016 in OLOLH. Patients who received adjuvant or neoadjuvant paclitaxel were included. Patients with metastatic disease or receiving other forms of treatment were excluded.
In 2016, 72 patients with newly-diagnosed breast cancer were seen in OLOLH. Twenty-one patients received weekly paclitaxel as adjuvant or neoadjuvant therapy; those were included as the study sample. The study found that the use of neutrophils 1.5 X 103/mm3 is associated with a higher rate of treatment modifications.
Dr Keane’s research was based on a survey of colorectal cancer (CRC) survivorship practices in Ireland and implementation of a survivorship care plan (SCP) pilot programme. The online survey was completed by 13 medical oncologists, comprising the lead treating physicians for the Irish regional cancer centres and their satellite centres.
“Surveillance practices in Ireland are heterogeneous,” according to the results.
“Which guidelines are used to follow patients is physician- and hospital-dependent. The SCP is a useful tool for streamlining follow-up practices so that they are more uniform. Physicians and patients both feel that SCPs are beneficial. Widespread use of SCPs may provide a mechanism to move CRC surveillance out of busy oncology clinics to a more appropriate setting, such as nurse-led clinics and primary care.”
Dr Deac’s research looked at real-world palbociclib dosing and safety monitoring in women with HR-positive/HER2-negative metastatic breast cancer. Endocrine therapy is the mainstay for hormone receptor-positive breast cancer.
Palbociclib is a novel small-molecule inhibitor of cyclin-dependant kinases 4 and 6, resulting in loss of retinoblastoma protein phosphorylation, which is responsible for breast cancer proliferation.
For the study, a retrospective, single-centre audit of all hormone-positive HER2-negative metastatic breast cancer patients who were treated with palbociclib over a six-month period in an Irish tertiary hospital was conducted. A total 64 patients were included in the analysis.
“To our knowledge, this is the largest real-world analysis of CBC monitoring in patients receiving palbociclib,” according to the results.
“This analysis demonstrates good compliance with CBC monitoring and dose adjustment guidelines. Palbociclib is a safe and effective therapy. Patients with ANC <4.0 prior to starting treatment are more likely to be dose-reduced. Increased awareness of significant side-effects such as thromboembolic events is important.”
Research by Dr Rahman examined outcomes following centralisation of pancreatic cancer care in Ireland. It found that centralisation of PDAC surgery in Ireland has resulted in a significant improvement in utilisation rates of surgery, chemotherapy and radiotherapy, leading to improved overall survival for patients.
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