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Niche-busting cancer immunotherapies

Targeted oncology treatments are a reason for hope
Hope in the era of the niche buster

Ever since then-US President Nixon declared a 'War on Cancer' in 1971, we have been faced with ever-present newspaper headlines proclaiming the next major breakthrough in treatment. Truly, a 'cure' has seemingly been on the horizon for over four decades now. 

While advances in treatment certainly have been made, it has felt a bit more like chipping away at an iceberg with a toothpick. While new chemotherapies have been developed, improvement has still more commonly been spoken of in terms of “months” or even “weeks” gained, rather than a silver bullet 'cure' that would win the war as Nixon had envisioned. 

Targeted therapy - reason for hope, but not yet a cure

That said, better understanding of the disease on the molecular level has led to true advances in therapy. Tamoxifen, an anti-hormonal drug working to block the effect of oestrogen in driving certain breast cancers, is considered the first truly 'targeted' therapy - a drug that addressed the actual cause of tumour growth. Since then, we have further refined our ability to pinpoint the genetic changes driving tumour growth and are working hard to find drugs that can target and treat those changes. 

Novartis's Glivec represents the first real advance in getting 'under the hood' of cancer at the molecular level. By targeting a protein made by a mutated gene, Glivec has allowed chronic myeloid leukaemia (CML) patients to live nearly normal lives as long as they continue therapy. Roche/Genentech's Herceptin and Rituxan, monoclonal antibodies that block receptors on cell surfaces, have significantly improved patient outcomes for certain breast and haematologic malignancies, respectively. Searching for 'actionable' mutations has become the new paradigm, but still, no one would say that patients are being 'cured'.

Enter the resurgent role of immunotherapy in oncology. Just ten years ago, the thought of developing immunotherapy for oncology might have been met with derision due to the high toxicity with very little benefit to patient outcomes. This all changed with the discovery of the programmed cell death 1 (PD-1) pathway. By creating an antibody to target PD-1, we are now able to 'unmask' cancer cells for certain tumours so that they are visible to the immune system's T-cells, which are then able to attack and kill them. While it is still early days, there are reports that 62 per cent of melanoma patients taking BMS's PD-1 immunotherapy drug nivolumab were alive after one year and 43 per cent were still alive after two years on the drug. In a tumour that has historically killed patients within a year of diagnosis, these are truly amazing results, and it is no wonder that all of the major oncology player pharmaceutical companies are racing to join the immunotherapy 'gold rush'. 

Oncology follows the space race

These breakthroughs have increased hope of turning the tide in the 'War on Cancer' once again. The latest salvo was fired two years ago by the MD Anderson Cancer Center in Houston, TX, in the form of its 'Moon Shots' programme. Spearheaded by Dr Ronald DePinho, the Moon Shots mission is to make significant advancements in overall survival and eventually cure for nine key tumour types - melanoma, triple-negative breast cancer, ovarian cancer, chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), lung and prostate cancer - all which have significant unmet therapeutic need. 

It's a lofty goal to be sure, but three recent key developments make the Moon Shot seem like not such a long shot. 

Next generation sequencing - a road map for treatment

It used to be that in order to identify specific mutations in a particular tumour, the only option was to take as large a biopsy as possible and send portions of the tissue off to possibly multiple labs for individual tests to be run on each sample. The process was expensive and costly in terms of time as patients waited weeks to find out if they were eligible to start on a particular targeted drug. 

With the advent of 'next generation' sequencing (NGS), physicians can have entire genomes sequenced in a matter of weeks providing a 'road map' for treatment by identifying every possible mutation for therapeutic target in each individual's tumour. 

Bucket trials - right patient, right drug, regardless of tumour type

As you would imagine, trying to accrue a trial of patients of a specific tumour type and a specific mutation is very difficult. For example, Pfizer's drug Xalkori targets the rare ALK mutation, found in only 3 per cent of non-small cell lung cancer (NSCLC) patients. Investigators have responded by creating 'bucket trials' - clinical trials where patients share an actionable mutation if not a tumour type. As we know from NGS, while certain mutations can be more associated with a particular tumour type, often they can appear in tumours that no one had previously thought to look in. 

Demonstrated recently by a physician turned patient, Dr Lukas Wartman was diagnosed with acute lymphoblastic leukaemia (ALL), and after many rounds of treatment, had no therapeutic options left. His colleagues sequenced the entire genome of his disease using NGS and discovered that the FLT3 protein was expressed at very high levels. Sutent, a targeted drug usually used in kidney cancer, also targets that protein. Dr Wartman started on Sutent, his disease went into remission, and at the time of this writing, he is still doing well.

Gone are the days of the blockbuster drugs for large tumour types. We are now in the era of 'niche-buster' indications for increasingly small pan-tumour patient populations, where trials focus on a collection of like mutations rather than like tumour types.

Breakthrough status - clinical development at breakneck speed

As indications are increasingly fragmented along rare mutation lines, companies struggle to find enough patients to enrol in trials. This has financial implications, with delayed timelines leading to financial losses as the patent clock ticks down. 

Partly in response to this, and partly to speed much-needed therapies to desperate patients, the FDA in the US has created a new category of accelerated approval called 'breakthrough status'. Products receive this expedited review if they demonstrate a 'significant benefit' over current therapies in phase II trials for a particular indication. Oncology drugs have quickly utilised this new pathway - of the 37 drugs granted breakthrough status since the category was created, 12 (41 per cent) are oncology products, and these ranks are likely to increase dramatically as applications continue to rise.

Oncology market research - new timelines, new techniques

There are a number of implications for market research as we seek to help our clients prepare the branding of their oncology products in this brave new era of the niche-buster. 

First, marketing teams have much less time to react to the accelerated launch timelines that come along with the coveted breakthrough status. As such, there is a need for more efficient, streamlined research that can take this into account. The companies that can bundle buying process and emotional journey research, or positioning and message testing research - and do it well - will have an edge with their oncology clients.

In addition, many clients face a situation where they are looking to make go-no go decisions in a therapy area where multiple products with new mechanisms of action are due to launch around the same time. In this situation, forecasting likely share when oncologists have no experience using these new products can be very difficult. A company that can find a way to provide this 'crystal ball' will aid clients greatly in pre-launch decisions.

Finally, in moving to mutation, rather than tumour-specific indications, positioning is increasingly complex. Previously, the strategy of 'umbrella' positioning regardless of tumour type (think Avastin) or tumour-specific positioning within different tumour types (think Afinitor) were the options. In both cases, the number of indicated tumour types was limited and clients became experts in each tumour type in order to better market within the space. However, we are now faced with a situation where a product might launch in multiple tumour types simultaneously, making it difficult for a company to master each one, much less have a unique strategy for each.  

Helping clients position their niche-buster products will be an interesting proposition in this brave new world. Just as medicine has risen to the challenge of an oncology moon shot, we will find innovative ways to rise to the marketing research challenge as well.

Article by
Kelly Price

senior vice president, Oncology Business Unit,
THE PLANNING SHOP international

24th June 2014

From: Research

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