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Impressive improvements in clinical outcomes are continuing across several cancer types due to immunotherapy advances – ESMO
Since the first immune checkpoint inhibitor was approved to treat advanced melanoma in 2011, impressive improvements in clinical outcomes have continued to be demonstrated across several cancer types, the ESMO 2016 Congress heard.
However, not all patients benefit from these agents and many studies have focused on identifying predictive and prognostic biomarkers in an attempt to better inform and guide treatment decisions.
Several studies investigating established and novel biomarkers of response to immunotherapy were presented at this year’s Congress.
Programmed death ligand-1 (PD-L1) expression has been one of the most hotly-debated biomarkers in immuno-oncology since the introduction of PD-1/PD-L1 immune checkpoint inhibitors, the ESMO Daily Reporter noted.
There are currently multiple assays under investigation or approved as companion or complementary diagnostic tests for PD-L1 expression.
It is a concern that the US FDA approval of an assay on the basis of its performance appears to have become more important than the accurate and reproducible measurement of the target, according to ESMO. As a result, at least four separate antibodies have been included in assays that are part of separate FDA submissions, creating a challenge for pathologists who may need to perform four different assays rather than simply assess PD-L1 expression.
A recent comparative study found that differences reported in PD-L1 expression in lung cancer tissue arose from tumour heterogeneity or the assay or platform used, rather than the choice of antibody. This could lead to a situation where a pathologist was required to use separate assays to assess the dozen or so drugs that target the oestrogen receptor in breast cancer.
Two late-breaking abstract presentations at the Congress described efficacy data in advanced non-small-cell lung cancer (NSCLC) by PD-L1 expression status.
The value of PD-L1 expression as a biomarker of response in melanoma was also considered in a pooled analysis of phase 2 (CheckMate 069) and phase 3 (CheckMate 066 and 067) trials comparing nivolumab plus ipilimumab versus nivolumab alone.
Data in advanced melanoma appear to be far from clear-cut and PD-L1 expression does not seem to predict response to immune-targeting drugs (abstract 1,112PD).
Multiple diagnostic assays are available for determining PD-L1 expression status and have been used in clinical trials of different immunotherapies. Data from a study comparing three PD-L1 diagnostic assays from biopsies of squamous cell carcinoma of the head and neck (SCCHN) show a strong correlation between the assays, suggesting that it may be feasible to compare data derived from different PD-L1 diagnostic tests (abstract 955PD).
To date, a number of regulatory approvals for PD-L1-targeting agents are linked to companion diagnostic assays and there are potential risks associated with cross-matching agents to assays in the absence of established clinical and analytical concordance, according to Dr Jorge Martinalbo from the European Medicines Agency (EMA), London, UK.
Further confusion comes from different scoring criteria and thresholds for defining PD-L1 positivity, which vary by agent and tumour type. Acknowledging that harmonisation of assays is probably unrealistic, a blueprint proposal initiative was started in 2015 with the remit to “agree and deliver, via cross-industry collaboration, a package of information/data upon which analytic comparison of the various diagnostic assays may be conducted, potentially paving the way for post-market standardisation and/or practice guideline development, as appropriate”.
In patients with advanced cancer, the relationship between tumour mutational burden and microsatellite instability both appear to be of value in identifying patients most likely to derive benefit from immunotherapy (abstract 52O). However, so far, there is no single, reliable, validated biomarker for selecting patients who are likely to benefit from immunotherapies.
Establishing predictive biomarkers is also becoming increasingly important from a health economic perspective, ESMO noted. The cost of immunotherapies is such that it impacts ever more on the total healthcare budget, which in turn affects the availability of these drugs in different European countries. The Netherlands Cancer Institute has developed the ‘cancer immunogram’, an initial framework of seven parameter classes describing cancer-immune interactions for individual patients. This may become a tool to help oncologists assess the likelihood of benefit from immunotherapy in the future.
Higher rates of end-of-life chemotherapy administration for solid cancer patients reported in hospitals without palliative care units
The rates of administering chemotherapy to patients with solid cancers within a month of succumbing to their disease remain high, which calls for a paradigm shift to consider initiating palliative care at an earlier stage and formulating clear guidelines for end-of-life care, according to the findings of a large audit presented at the ESMO 2016 Congress in Copenhagen, Denmark.
Chemotherapy is often administered near the end-of-life for solid cancer patients with the intent to ease symptoms but is usually ineffective and toxic, according to the study’s lead author Dr Phillipe Rochigneux, Medical Oncology, Institute Paoli-Calmettes, Marseille, France.
Dr Rochigneux presented findings on behalf of colleagues from a review of the data concerning the use of chemotherapy at the end-of-life throughout France and the factors associated with its use.
The investigators designed a nationwide, register-based study that included all patients hospitalised in France between 2010 and 2013 who were aged 20 years and older who died having metastatic solid tumours.
They used multivariate analyses to identify patients, tumour, and the facility level characteristics associated with chemotherapy use. Specific sub-analyses were also computed to investigate the role of the putative chemosensitivity of the tumour, as defined by a response rate of the tumour to standard first-line chemotherapy >30 per cent (literature data).
Data regarding 279,846 metastatic solid cancers in end-of-life patients were included in the register. The rates of chemotherapy administration near the end-of-life were 39.1 per cent during the last three months, 19.5 per cent during the last month, and 11.3 per cent within the final two weeks.
During their last month of life, 6.6 per cent of patients started or resumed a chemotherapy regimen.
Patient characteristics that associated by multivariate analysis with lower rates of chemotherapy included female sex (odds ratio [OR] 0.96; 95 per cent confidence interval [CI] 0.93, 0.98) older age (OR 0.70; 95 per cent CI 0.69, 0.71 for each 10-year increase), and a higher number of chronic comorbidities (OR 0.83; 95 per cent CI 0.82, 0.84) were independently associated with lower chemotherapy rates.
Patients were more likely to receive chemotherapy during the last month of life if their tumours displayed chemosensitivity to standard first-line chemotherapy (OR 1.21; 95 per cent CI 1.18, 1.25).
Another factor that was independently associated with end-of-life chemotherapy were patients having cancer types for which major therapeutic innovations occurred between the years 2005 to 2010 (OR 1.17; 95 per cent CI 1.14,1.20).
End-stage chemotherapy rates were also higher in patients dying in a for-profit hospital compared with university hospitals (OR 1.40; 95 per cent CI 1.34,1.45), and in patients in comprehensive cancer centres (OR 1.43; 95 per cent CI 1.36,1.50).
Higher than average rates of chemotherapy were reportedly administered near the end-of-life in high-volume cancer centres and in hospitals lacking palliative care units (OR 1.21; 95 per cent CI 1.18, 1.24).
The study concluded that chemotherapy rates near the end-of-life remain high in patients with metastatic solid cancers. These rates are especially high in young patients being treated in high-volume centres that lack a palliative care unit.
There is an urgent need to decrease the aggressiveness of end-of-life treatments by making and implementing clear guidelines for end-of-life care, to initiate palliative care earlier on, and to reinforce supportive care training for oncologists and other cancer professionals, the study authors said.
Early palliative care can contribute to more balanced use of chemotherapy during end-of-life, better symptom management, better emotional function and better family care, the Congress was told.
POLE mutations identified in stage II/III colorectal cancer are rare but an accurate biomarker for favourable prognosis
DNA polymerase epsilon (POLE) proofreading domain mutations, a biomarker for enhanced immunogenicity and improved prognosis in endometrial cancer, also confer better prognosis in colorectal cancer, investigators reported at the ESMO 2016 Congress in Copenhagen, Denmark.
Dr Mark Andrew Glaire of the Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, UK, underscored the importance of using biomarkers, even those occurring at low frequencies, in defining distinct tumour subgroups. He explained that while exceptionally mutated (ultra mutated) tumours resulting from mutations that impair POLE proofreading function confer enhanced immunogenicity and excellent prognosis in the approximately 10 per cent of endometrial cancers in which they are found, their effect in colorectal cancer had not yet been defined.
In order to determine the clinical relevance of POLE mutations in colorectal cancer, Dr Glaire and colleagues performed Cox regression analysis on pooled data from more than 4,500 patients participating in three clinical trials (VICTOR, QUASAR2 and PETACC-3) and multiple patient cohorts (LUMC, Oslo, Bern, AMC-AJCC-II, EPICOLON and TCGA), and investigated the association between POLE mutations and prognosis in stage II/III disease.
They detected POLE mutations in just 66 of 6,448 (1.0 per cent) colorectal cancer samples. Although uncommon, POLE mutations were significantly associated with several patient and tumour factors, including young age, male sex, right-sided location, early disease stage and absence of mismatch repair deficiency (MMR-D; p ≤ 0.003 for all associations).
Importantly, multivariable analysis revealed a statistically significant association between POLE mutation and a greatly reduced risk of disease recurrence: hazard ratio (HR) 0.34; 95 per cent confidence interval (CI) 0.11, 0.76 (p = 0.006). This reduced risk was particularly strong in stage II disease, HR 0.22; 95 per centCI 0.02, 0.78 (p = 0.014). This reduction in relative risk was greater than that associated with MMR-D (HR 0.72; 95 per cent CI 0.60, 0.87), an accepted biomarker of favourable prognosis in this setting.
These results may be explained by increased immune activity in POLE-mutant tumours, including increased CD8+ lymphocyte infiltration, expression of cytotoxic T-cell markers and effector cytokines, which was similar to that observed MMR-D cancers, well recognised to be immunogenic.
The study concluded that POLE proofreading domain mutations define a subset of colorectal cancers that are more immunogenic and have a favourable prognosis. This novel biomarker shows promise to improve stratification of patients with colorectal cancer.
Results announced from the first cohort of patients screened within the new EORTC molecular platform for patients with colorectal cancer
agerly-anticipated results of gene panel sequencing from the first cohort of patients with advanced colorectal cancer participating in a large European molecular screening platform were reported at the ESMO 2016 Congress in Copenhagen, Denmark.
New, potentially actionable genetic alterations were identified in these patients, many of whom are now eligible to enter a clinical trial of targeted therapies.
Dr Gunnar Folprecht, University Hospital Carl Gustav Carus in Dresden, Germany, presented findings on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) investigators from the first cohort screened in conjunction with the Screening Platform for Efficient Clinical Trial Access in advanced colorectal cancer (SPECTAcolor).
SPECTAcolor was initiated by EORTC as the first prospective, fully-annotated tumour sample biobank and biomarker analysis platform for genetic profiling of patients with advanced colorectal cancer.
The aim is to facilitate patient-access to a clinical trial for treatment with a targeted agent. Since the inception in 2013, this biobank has enrolled more than 900 patients from 32 clinical centres in 11 European countries and anticipates enrolling at least this many patients yearly in the upcoming years.
Dr Folprecht reported findings from a cohort of 389 patients with colorectal cancer who underwent screening using a large, next-generation sequencing (NGS) panel comprising 328 cancer genes.
Using immunohistochemistry or fragment length analysis, the investigators determined that 370 of the 389 (95.2 per cent) patients overall were microsatellite stable (MSS) and 19 (4.8 per cent) patients were highly microsatellite instable (MSI-H).
Both MSS and MSI-H tumours were found to contain a median of three (range: 0 to 16) driver mutations and a median of eight (range: three to 16) potential driver mutations.
Among patients with MSS colorectal cancer, 77.8 per cent had mutations in APC, 72.2 per cent in TP53, and 47.8 per cent of patients showed KRAS mutation. Mutated PIK3CA, FBXW7 and BRAF were present in 17.6 per cent, 11.1 per cent and 10.5 per cent of patients. Mutations in the SOX9, SMAD4, ARD1A and NRAS were present in less than 10 per cent of patients.
More patients with MSI-H tumours showed TP53 mutations (52.6 per cent), PIK3CA (47.4 per cent) and 42.1 per cent had KRAS mutation. FBXW7 and BRAF mutations were each present in 36.8 per cent of patients and APC and SOX9 were each mutated in 21.1 per cent of patients. No mutations in SMAD4, ARD1A and NRAS were detected in MSI-H patients.
Tumour localisation of APC and TP53 was more often on the left versus right side, 80.8 per cent versus 73.6 per cent, and 76.5 per cent versus 62.3 per cent, respectively, whereas KRAS and PIK3CA occurred more often on the right; KRAS location was 45.5 per cent versus 53.8 per cent, and PIK3CA was 14.1 per cent versus 25.5 per cent, left versus right, respectively.
The prevalence of BRAF mutated tumours was predominately right side: 5.1 per cent left versus 22.6 per cent right (p < 0.0001).
Additionally, the investigators detected BRCA2 mutation in 1.6 per cent of patients, located left at 0.8 per cent versus 3.8 per cent right, and in 5.3 per cent of MSI-H tumours. A total of 1.9 per cent of patients showed ERBB2 mutation, which was found twice as often in left sided tumours; left 2.0 per cent versus 1.0 per cent right. Other potentially actionable targets included ERBB2 amplification in 2.5 per cent of patients, FGFR1/2/3 amplification in 3.5 per cent, and TSC1 mutation in 16 per cent of patients with MSI-H tumours. Single ALK and ROS fusions were also observed.
The presented findings concluded that SPECTAcolor is an effective platform for molecular screening in patients with colorectal cancer to identify rare but potentially-actionable genomic targets and to allow patient access to clinical trials of targeted therapies.
The authors stated that they were able to detect new therapeutic targets by gene panel sequencing in approximately 10 per cent of patients with advanced colorectal cancer who participated in SPECTAcolor.
Cancer support services for patients in the Dublin region
Priscilla Lynch speaks to Ms Deirdre Grant, CEO of ARC Cancer Support Centres, about the services the Dublin-based charity offers cancer patients and their families
ARC Cancer Support Centres is a charity that provides care, complementary therapies and counselling services to people with cancer, their partners, families, friends and carers.
All ARC’s services are provided by professional staff and trained volunteers and are free of charge. It costs over €700,000 to run ARC each year. While grant aid is provided by the HSE and smaller allocations from organisations such as the Irish Cancer Society, ARC still relies on the public for two-thirds of its funding.
The initiative was founded in 1994 at the suggestion of well-known Irish consultant oncologist Prof Des Carney, who saw a need to support cancer patients’ psychological needs and to offer a holistic approach to their care that would work alongside medical treatment.
Since then, the board of ARC has continued to have strong oncologist input, explained Ms Deirdre Grant, CEO, ARC Cancer Support Centres.
ARC’s services are provided from its two centres near the major centres of excellence for cancer care in Dublin (Eccles Street and South Circular Road — the Mater Hospital and Beaumont Hospital on Dublin’s northside and St James’s Hospital and St Vincent’s University Hospital on Dublin’s southside).
ARC’s drop-in centres are open Monday to Friday, from 10am to 4.30pm and provide a sensitive and supportive environment where people can have a cup of tea, relax and chat with staff, volunteers and others who are undergoing their own cancer experience.
ARC also offers a safe and confidential space for people to avail of counselling from trained psychotherapists, where they can talk about whatever is going on in their life, be honest and open about their feelings and gain confidence, hope and inner strength for the future, said Ms Grant.
“Cancer survivors need to maintain a high quality of life, physically, emotionally and mentally during the whole journey with cancer, so that is literally from the stage of diagnosis right through to the end-of-life stage,” she said.
“ARC has developed tried and tested programmes and therapies over the years to help clients cope with all of that, to cope with the emotions of a cancer diagnosis, to manage treatment, to deal with side-effects and to encourage those with a diagnosis to be proactive in making those changes that can facilitate a healthier lifestyle, emotionally and physically.”
ARC’s range of group therapies include mindfulness, relaxation, visualisation and stress management classes, as well as yoga, positive appearance workshops in dealing with the appearance-related side-effects of cancer treatment, and arts and crafts.
One-to-one therapies include reflexology, acupuncture, head massage and manual lymph drainage.
ARC has in place a range of support groups, including breast cancer, prostate cancer and myeloma support groups that meet regularly.
ARC also organises a range of education and support programmes, such as the Living with Secondary Cancer Programme and the CLIMB programme for children aged between five and 11 years whose “significant adult” has been affected by cancer. Other topics covered would include fatigue, nutrition and sexual dysfunction. Many of the talks are delivered by local oncologists.
“It is about giving patients tools and techniques and educating them about these issues. We have fantastic relationships with a lot of consultants who do that for us and they give their time free and come in and talk to our clients, who love those sessions. It gives them time with their consultant on a completely different basis where they can ask questions they mightn’t think of or forget [in hospital]. It is a different atmosphere and environment, so they really get a lot out of it.”
ARC would also like to be formally linked to the Dublin cancer centres of excellence, Ms Grant stated, adding that the organisation had input into the new National Cancer Strategy, which is due to be published shortly.
“Our big aim is to have more support and integration into that cancer care pathway, so that we are part of the formal referral pathway. So people are referred to the most appropriate support at the most appropriate time. So if that is psychological, psychosexual support, then they are directed to their local cancer support centre, which in Dublin is us… We would love to be considered a centre of excellence in what we do. “
Demand for ARC’s services continued to grow in 2015, with 13,676 visits, an increase of 32 per cent on the previous year and 159 per cent on 2012.
One-in-three people will develop cancer at some stage during their lives in Ireland, with approximately 30,000 people newly diagnosed each year. Due to an ageing population, this number will continue to rise, with Ireland likely to see a doubling in incidence by 2040 — the highest rise in Europe. The welcome news is that more and more people are surviving cancer than ever before and going on to lead normal lives, Ms Grant noted.
For more information on ARC’s services and how to refer patients, visit www.arccancersupport.ie, email firstname.lastname@example.org, or telephone 01 8307 333.