Summaries of important publications

The melanoma team and their scientific colleagues at the CRUK Manchester Institute publish a lot of clinical research, reviews and comment in all the prestigious medical and scientific journals. These publications are read by an international audience and may subsequently inform practice and research everywhere.

The research papers are lengthy and written in highly specialised language. They can be daunting to read for non-medical people, or overwhelming if you just want to get a quick overview. 

To address this here we are providing 'lay' summaries of some of our most important publications. These are aimed at the general public and health professionals who are not specialist in melanoma.

Updated 13/09/2017

Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).

Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C.

The Lancet. 2017 August

The Keynote 006 study is a pivotal trial that has helped define a standard of care for patients with advanced melanoma. 834 patients from 16 countries and 87 centres were randomised 1-1-1 to receive either pembrolizumab 10mg/kg IV every 2 weeks, 10/mg/kg every 3 weeks or ipilimumab 3mg/kg x 4 doses. The results confirmed the superiority of pembrolizumab over ipilimumab for response from a progression-free survival and overall survival. The overall survival at 2 years was 55% in the pembrolizumab arm and 43% in the ipilimumab group. There were no new safety signals (information on a new or known adverse event) detected and the majority of patients tolerated treatment well. Based on this trial, pembrolizumab is now established as a standard of care in the first-line setting for patients with advanced melanoma.

Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Ageing.

Law MH, Medland SE, Zhu G, Yazar S, Viñuela A, Wallace L, Shekar SN, Duffy DL, Bataille V, Glass D, Spector TD, Wood D; MuTHER Consortium, Gordon SD, Barbour JM, Henders AK, Hewitt AW, Montgomery GW, Sturm RA, Mackey DA, Green AC, Martin NG, MacGregor S.

Journal of Investigative Dermatology. 2017 May

Loss of fine skin patterning is a sign of both aging and photoageing (skin damage and aging caused by sun exposure). This paper investigated the genetic contribution to skin patterning and ageing to better understand inborn influences on skin photoageing because it is linked to the risk of skin cancer including melanoma risk. The investigators combined three large genetic studies of visible skin ageing pattern which involved data from over 1,600 pairs of twins and over 1,700 individuals. The three genetic locations that they found to be associated with skin ageing and photoageing patterns are linked to genes for red hair and fair complexion. This result confirmed previous findings from other studies that people with low amounts of skin pigmentation who are sun-sensitive are especially susceptible to signs of sun-induced skin ageing.

Prevention of DNA damage in human skin by topical sunscreens.

Olsen CM, Wilson LF, Green AC, Biswas N, Loyalka J, Whiteman DC

Photodermatology Photoimmunology Photomedicine. 2017 May

An effective way of preventing sunburn is by applying an adequate amount of sunscreen before sun exposure. This is because the chemicals in sunscreens filter out the harmful part of sunlight, known as ultraviolet (UV) radiation. UV radiation is also the cause of melanoma and other skin cancer, so this paper investigated how effective sunscreen is in reducing UV-induced damage to the DNA in the genes of cells in human skin that is exposed to UV radiation. The authors did this by reviewing all scientific papers published between 1990 and 2015 that reported studies of DNA damage in human skin exposed to UV radiation after sunscreen had been applied versus when no sunscreen was applied. They found ten relevant studies. Despite differences in the studies, for instance in the sun protection factors of the sunscreens used, the range of skin colours examined, and the amount of UV exposure to the skin, all studies reported markedly reduced (or nil) UV-induced DNA damage in sunscreen-protected skin. Thus experimental evidence supports other research showing that sunscreen prevents sun-induced genetic damage in the skin that is linked to melanoma development.

Immunotherapy: Does adjuvant ipilimumab have little adverse effect on quality of life?

Lorigan P, Green AC.

Nature Review Clinical Oncology. 2017 April

In the European Organisation for the Research and Treatment of Cancer (EORTC) 18071 study, patients with fully resected stage III cutaneous melanoma were randomly assigned to receive either ipilimumab 10 mg/kg or placebo. The results of this trial, published in 2016, revealed a clear overall survival benefit at 5 years of 11% (65% versus 54%). The incidence of toxicity was higher in the ipilimumab group compared with placebo, with 54% of patients experiencing grade 3–4 adverse events (AEs), treatment that was discontinued for one-half of patients owing to drug-related AEs, and five patients (1%) of patients in the ipilimumab group died owing to treatment-related complications. However the subsequent publication of the quality-of-life (QoL)-related data from the EORTC 18071 study reported that health-related QoL, was similar between groups. Lorigan and Green reviewed this publication for Nature Reviews in Clinical Oncology in view of the obvious disparity in findings, i.e. significant toxicity, treatment related deaths, but no impact on quality of life. They showed that a number of factors could have contributed to this unexpected finding including when the QOL assessments were done, that patients with toxicity were probably not filling in the QOL assessments (i.e. were too ill), and that the way toxicity is reported can underestimate the impact on patients. They concluded that whilst the survival benefit seen in the study was real, the conclusion that treatment had little impact on QOL was almost certainly incorrect.

PD-L1 Expression as a Potential Predictive Biomarker (Comment)

Fusi A, Festino L, Botti G, Masucci G, Melero I, Lorigan P, Ascierto PA.

Lancet Oncol. 2015 Oct

Comment articles offer an expert view and guidance and can inform colleagues' translation of the trial data to clinical practice. This article and an earlier Comment piece (see next summary) address a 'hot topic' in immunotherapy - biomarkers. A biomarker is a molecule found in blood, body fluids, or tissues as a sign of a normal or abnormal process, or of a condition or disease. Certain biomarkers can aid with the diagnosis and prognosis of cancer, and also indicate how well a patient may respond to treatment (prediction).

Immunotherapy is an important breakthrough in cancer treatment and the identification of biomarkers helped to develop the current treatments. Recent research has attempted to identify predictive biomarkers to help select patients for those treatments in melanoma and lung cancer. Whether the presence or absence of PD-L1 in particular is predictive, has been studied in most of the pivotal trials. However the answer is still unclear.

The authors describe melanoma trials where the objective response to treatment has not been as markedly different between the two patient groups (PD-L1 positive and PD-L1 negative) as might be expected if PD-L1 was an accurate predictive biomarker. A trial of patients with two different types of lung cancer showed the presence of PD-L1 to be predictive of response with one type but not the other. Questions also emerged as to which clinical outcome PDL1 should be connected with - treatment response, progression-free survival or treatment side-effects?

The inconsistencies of PD-L1 in these trial results and the fact it is a 'dynamic' molecule subject to change over time, means it is a somewhat unreliable biomarker. Clinicians should not use PD-L1 status as their only indicator of treatment choice. Until PD-L1 is better understood there are other potentially important emerging biomarkers to be researched.

The place of PD-1 inhibitors in melanoma management (Comment)

Bowyers S, Lorigan P.

The Lancet Oncology. 2015 August.

This article by Dr. Sam Bowyers (until recently a member of the melanoma team here) and Dr. Paul Lorigan was published in The Lancet Oncology in August 2015.

Outcomes for patients with advanced melanoma have improved greatly in recent years and especially so throughout the last year. Central to this has been an increased understanding of the role of immune checkpoint inhibition to potentiate anti-tumour immunity. The use of the CTLA-4 inhibitor ipilimumab, and PD-1 receptor inhibitors (pembrolizumab and nivolumab) as monotherapy, and recently nivolumab in combination with ipilimumab have led to significant improvements in outcomes important to patients i.e. tumour control and survival.

Published data from recent studies reveals how immunotherapy has revolutionised the management of melanoma, showing chemotherapy to be an inferior treatment choice for patients with ipilimumab-refractory disease. The authors recommend that PD-1 inhibitors be used as first-line treatment, and combination ipilimumab and nivolumab (when approved) should become a standard of care.

To maintain the integrity of future studies however, consideration needs to be given to validating alternative surrogate trial endpoints (e.g. response duration) to prevent patients being disadvantaged in trials where overall survival is the main endpoint and crossover is not allowed.

There is still much to understand about immunotherapy. How can emerging biomarkers help to personalise therapy? What is their survival benefit? How will patients with advanced disease respond in an adjuvant setting? Can non-responding patients be converted into responders? What is the optimum sequencing of targeted therapies and immunotherapy? Studies are now being established to answer these questions.

Pembrolizumab versus Ipilimumab in Advanced Melanoma

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators.

New England Journal of Medicine. 2015 Apr 19.

A randomised phase III trial comparing ipilimumab with two-week and three-week regimens of pembrolizumab has shown pembrolizumab to be significantly superior. This is in terms of progression-free survival, overall survival, and response rate in treating advanced melanoma. 834 patients with inoperable stage III or IV melanoma were evenly assigned to one of the three groups. The estimated six month progression-free survival rates were 47.3% for the two-week regimen, 46.4% for the three-week regimen, and 26.5% for ipilimumab. Each regimen of pembrolizumab reduced the risk of disease progression by 42%, compared with ipilimumab.

Roughly one-third of the patients had died at the time of data cut-off for the second interim analysis. One year estimates of survival were 74.1% for the two-week regimen, 68.4% for the three-week regimen, and 58.2% for ipilimumab. The two regimens did not differ in efficacy. The independent data and safety monitoring committee ended the trial to enable patients from the ipilimumab group to receive pembrolizumab.

These results firmly establish anti-PD-1 antibodies as first-line treatment for advanced melanoma. PD-1 is also showing encouraging activity in head and neck cancers, lung cancer, prostate cancer, and lymphoma. Moreover, the anti-PD-1 antibodies seem to induce durable responses among patients. Like other single agent immunotherapies PD-1 is generally well tolerated by patients; however they do have particular toxic profiles which the oncology health care teams will have to come to understand and manage.

Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma

Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk B, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Carragher N, Macleod K, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais Rand Springer CJ.

Cancer Cell. 2015. 27, 85-96.

We previously showed that in half of human melanomas the BRAF gene is mutated and this makes the cells expand in an uncontrollable manner leading to tumour growth and if untreated, death of the patient. Current treatments that block the action of the faulty BRAF counter its effects on growth and slow tumour growth, but in most cases the melanoma cells learn how to circumvent these drugs and the tumours start to grow again. There is therefore an urgent need to develop new strategies to kill the resistant cells and improve patient's outcomes.

We discovered that targeted therapy resistance is often mediated by reactivation of the factors which drive cell growth, namely BRAF and CRAF proteins and SRC-family kinase (SFK) signalling. This discovery led to the development of new drugs, panRAF inhibitors, which target treatment-resistant melanomas and also inhibit SFK. We tested the new drugs in cells and tissues derived from patients who had relapsed on BRAF inhibitors. We observed that the new compounds stopped the growth of BRAF-driven melanomas and also melanomas that have ceased to respond to currently available BRAF-targeting drugs. Moreover, the new drugs halt tumour growth in cancers where existing BRAF-targeted drugs had never worked, which happens in around 20% of cases.

Thus, we have developed a new family of panRAF inhibitors that also inhibit SFK for use in melanoma patients, both as first-line treatments and in patients who have relapsed to currently approved therapies. Our aim in 2015 is to test these in patients who have developed resistance to approved drugs for melanoma treatment with the aim of improving the survival of this deadly disease.

Expanded access programmes: patient interests versus clinical trial integrity

Lorigan P, Ascierto PA, Dummer R, Eggermont AM, Flaherty KT, Garbe C, Gogas H, Hauschild A, Kefford RF, Kirkwood JM, Larkin J, Long GV, Maio M, McArthur GA, Ribas A, Robert C, Schadendorf D, Sondak VK, Wolchok JD, Hudson AM.

Lancet Oncol. 2015 Jan

The rush of recent advances in melanoma treatments creates promise for patients but has also created an ethical dilemma for clinicians.

Pharmaceutical companies are recognising the positive outcomes of Immunotherapy treatment for patients with advanced melanoma and are developing similar drugs to the limited number of PD-1 and PD-L1 inhibitors currently approved. Whilst these drugs are in trial and await approval by the regulatory bodies the companies are facilitating access to them via Early Access Programmes (EAPs). This is good news for patients but poses a problem for researchers. Do they allow patients who are currently in the control arm of a trial for a PD-1 inhibitor access to a different PD-1 inhibitor before the trial endpoint has been reached? Here there is potential for the original trial results to be affected and this has in fact already happened in a melanoma immunotherapy trial.

Patients' rights can never be undermined by the research process. However if current accepted trial design remain unchanged - with Overall Survival always deemed an essential primary endpoint and an inability in the analysis to allow for crossover to subsequent active drugs - it seems a working compromise may not be achievable. The authors suggest that debate is essential to resolve the dilemma and to allow for this real world activity to be recognised in future trial design.

Discrepancies in cancer genomic sequencing highlight opportunities for driver mutation discovery

Hudson AM, Yates T, Li Y, Trotter EW, Fawdar S, Chapman P, Lorigan P, Biankin A, Miller CJ, Brognard J.

Cancer Res. 2014 Nov

The key to developing new cancer treatments is to identify the genetic mutations that cause a normal cell to change into a cancer cell. 'Next generation sequencing' (NGS) is used to read all the DNA code within a cancer cell to find these mutations. Thousands of cancer cells have now been assessed in this way and to assist researchers the results are available online. We were interested because sequencing results of the same cancer samples, from two different institutes, often varied and the reasons for this had not been assessed.

We found that only half of mutations were reported by both institutes. The main reason for this was that certain areas of the DNA code were not being properly read by the sequencing technology. These regions often landed in areas where the code was less complex. Paradoxically, simple regions of code were actually making it harder for the gene-reading technology to spot any changes.

We then concentrated on regions that were being poorly read by both institutes (sequencing cold-spots). These cold-spots harbor opportunities to discover new cancer-causing genes because most sequencing efforts have missed these regions. We used a different method to read some of these areas and found a genetic mutation hiding in a cold-spot that activated cellular growth pathways. This provided proof-of-principle that mutations hiding in cold-spots have the potential to cause cancer. We therefore performed an analysis on sequencing data to report all the cold-spots in cancer causing genes so that researchers can better assess these genes.

A longer description of this work (in non-medical terms) is available at Cancer Research UK's science blog via Useful Links.

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53

Amaya Viros, Berta Sanchez-Laorden, Malin Pedersen, Simon J. Furney, Joel Rae, Kate Hogan, Sarah Ejiama, Maria Romina Girotti, Nathalie Dhomen and Richard Marais

Nature. July 2014

Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms behind this have not been defined and it is not clear if sunscreen is protective in melanoma as in other forms of skin cancer. The most common mutation in melanoma is a V600E substitution in the BRAF gene. However, this alone does not prompt melanomagenesis (melanoma formation), other genetic events are required.

This study used a mouse 'model' of skin cancer with the V600EBRAF mutation. 80% of such mice develop melanoma as adults (aged about 12 months). We exposed mice with the BRAF mutation to a single dose of non-burning UVR which caused mild sunburn, expansion of the melanocytes (melanin producing skin cells) and rapid induction of naevi (benign moles). When these mice were subjected to weekly exposures of UVR, they all developed about three melanomas in the exposed area at about age 5.3 months. Thus, non-burning doses of UVR accelerated the development of BRAF-driven melanoma. We studied the genetic changes in these tumours and found that 40% of them had changes in theTrp53 gene which was previously unknown to be relevant in melanoma. We then compared our mouse data to human melanoma and confirmed this gene is altered in ~20% of human melanomas, particularly those from patients who have a lot of damage secondary to UVR exposure. Finally, although sunblock (SPF: 50; UVA: superior) blocked the immediate effects of UVR exposure, it provided only partial protection against the development of tumours.

This study provides insight in the mechanisms underlying melanomagenesis by showing that UVR accelerates V600EBRAF-driven melanoma by directly targetingTrp53. The study also reveals that sunblock provides partial protection against UVR in melanoma, validating public health campaigns that promote sunblock use and other sun-avoidance measures in individuals at risk of melanoma.

Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors

A. Marusiak, Z. Edwards,W. Hugo, E. Trotter, M. Girotti, N. Stephenson, X. Kong, M. Gartside, S. Fawdar, A. Hudson, W. Breitwieser, N. Hayward, R. Marais, R. Lo, J. Brognard

Nature Communications, 2014 May 22

Recent progress in cancer treatment is based on the development of targeted therapies, including vemurafenib that targets mutated BRAFV600E, a well-known oncogene present in melanomas. RAF inhibitor therapy results in significant clinical response in the majority of V600E-positive melanoma patients, however resistance occurs within 2-18 months. Therefore, identifying and understanding the mechanisms of resistance is essential to achieve long-term progression-free survival.

Our work demonstrates that the mixed lineage kinases (MLK1-4) can mediate resistance to vemurafenib in BRAFV600E-positive melanomas. We described MLKs as direct MEK kinases that reactivate the MEK/ERK pathway in the presence of RAF inhibitors and promote survival of V600E-positive melanoma cell lines. Furthermore, we showed that MLKs promote resistance to RAF inhibitors in cell line and mouse models and upregulation of MLKs was detected in drug-resistant tumours from melanoma patients. Finally, we characterised several MLK1 mutations observed in melanoma patients to be intermediate-activating mutations that could predispose patients tode novoresistance.

These findings will have broad implications as the MEK/ERK pathway is a critical pathway required to promote cell proliferation and survival in many different types of cancer. In the future we will characterise novel inhibitors that target this family of kinases in collaboration with pharmaceutical companies.

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