GSK: Rethinking oncology

GSK’s John Fleming on rethinking oncology from the ground up

What if we could look at cancer treatment from a completely fresh perspective? This is the philosophy GSK’s UK country medical head for oncology, John Fleming, wants to bring to the company as it rethinks its approach to cancer.

Fleming joined Novartis in 2015, when GSK divested its oncology portfolio to the Swiss firm. It might seem surprising, then, that his focus on cancer would bring him back to GSK – but, as Fleming points out, the company never truly left the oncology space, and it seemed to him to be the perfect place to help transform outcomes for people living with cancer.

“When people talk about GSK re-entering oncology, that’s really a misconception,” he explains. “The divestment involved a lot of second-to-market oral therapies, which didn’t have the opportunity to be truly transformational and lead in their classes – so what was left behind was an R&D engine that was free to innovate and discover new molecular entities. It was a blank slate, if you will – an unencumbered starting point for us to look at fresh approaches and discover new modalities and classes of drugs.

“That’s why I chose to return to ‘GSK oncology 2.0’ – because we have this opportunity to build with a start-up mindset at a large pharma.”

With this ‘blank slate’, Fleming says the team can completely rethink their processes.

“We’re now bolting on medical affairs and the marketing infrastructure into our R&D – medical affairs at GSK is now involved three years prior to filing. We’re also bringing patient groups into those earlier discussions.”

Fleming says he wants to re-orientate how the company looks at developing medicines and recognise that they are developing them for patients, not only prescribers.

“You need to start by talking to patient groups, not thinking up the programme first then going to them later. It should never be a question of ‘them and us’. We should always be thinking about how we can work together to develop the best medicines – not just small incremental benefits in progression-free survival (PFS), but perhaps approaching functional cure in some cancers.

“If you’re not in concert with patient organisations, you’re already well behind the curve of innovation because you’re setting things up which are not going to fly when they’re brought into the real world.”

Accelerating the immune response

So, what kind of drugs does an ‘unencumbered’ company look at? Fleming says he is personally excited about the still-untapped potential of immunotherapy.

“We’ve had an explosion in immuno-oncology treatments that are essentially telling the immune system to take its foot off the brake and allowing it to mount a robust response against the cancer.

“With the next generation of immuno-oncology, rather than telling T-cells to release the brakes on the immune system, we’re thinking about how we can move towards actually accelerating the immune system’s surveillance against the cancer returning – an activated immune response.”

This is an area GSK is looking into with research into inducible T-cell co-stimulatory (ICOS) receptors.

“It’s a relatively new approach to treating cancer that essentially increases a patient’s T-cell response by an order of magnitude, supercharging the attacks on the cancer.

“You could combine agonists with antagonists in certain patients and certain tumour types to great effect. You can phase one in and out on the impact of each drug on the cancer and aspire to actually titrate modulation of the immune system with just the right degree of response in each tumour type.

“That’s the potential of balancing agonism and antagonism – we want to move away from just breaking the shackles on the immune system to really doubling down on getting rid of the cancer.”

That’s not to say approaches like these don’t come with their own challenges – for example reduced population sizes.

“We’re now looking at hyper-segmentation within cancer, not just based on tumour types or organ systems but also the genetic signatures of the cancer. This means there are smaller patient populations for studies, and you might have early data in phase 2 with no comparator arm showing a significant survival benefit.

“Regulators have been superbly agile in the way that they’ve embraced this in oncology to allow, in some instances, licenses to be granted from very immature data whilst additional safety and efficacy information is collected. But the need to recruit large numbers of patients to show you’ve got something statistically valid will remain a challenge in these smaller patient populations.”

From soloist to orchestra

Despite the challenges, Fleming hopes researchers can push forward towards real breakthroughs, not just in small niches of genetic signatures and specific subtypes of one mutation – but hopefully in innovation across solid and liquid tumours, looking at the commonality of mutations across phenotypes.

“PD-1 is a great example of this,” he says. “it has been tremendously successful across a range of tumour types.

“You can’t look for a one-size-fits-all approach in all tumours. That’s clearly not going to work. On the other hand, if you can innovate across tumour types, that’s going to be fantastic for many patients.”

Another of GSK’s agonist programmes that seeks to achieve that addresses the STING pathway (Stimulator of Interferon Genes).

“That can stimulate the immune system really broadly – producing type I interferon can mobilise a patient’s adaptive immune response to cancer. That’s another case of active cancer immunity, and active surveillance triggering a patient’s inherent cancer-fighting responses.

“Historically, some therapies have had to be injected into a tumour, which limits their breadth. In STING and other programmes we’re looking at treatments being administered systemically, so you can target more tumours and more cancers.”

Fleming adds that as immuno-oncology matures, the industry will shift its therapeutic focus away from reliance on a few important pathways towards a wider perspective.

“The analogy I’ve heard is ‘don’t think soloist, think orchestra’. What music do you want to play? And what instruments do you need to play that music?

“That speaks to the power of combinations – not just two different medicines but actually combining medicines in one. We have some nice examples in our programmes of combining pathway inhibitors in one compound. Typically, when you suppress or target one pathway, another pathway will come to the rescue of the tumour clone, giving the cancer an escape mechanism. What if we could target both?”

Closer collaboration

It’s not just treatments that need to be acting as an ‘orchestra’, though – the industry and its partners need to be working in concert to truly make breakthroughs in oncology.

“We’re looking at multiple alliances across oncology to address the sheer volume of potential combinations and then finding the truly transformational ones,” Fleming says.

He adds that there is a need for closer collaboration between academia, industrial scientists and companies that will allow a two-way information flow and richer datasets to emerge.

“The better the quality of the inputs and the better the quality of mining you can do in data, the better the outcomes. We need to get better at sharing across industry and academia. We will only succeed if we keep talking with academia, clinicians, patients and other stakeholders.”

Fleming says that, overall, he would like to see progress in oncology “going up in steps, rather than in a jagged line”.

“To do that you need lateral thinkers in the room as well as pure scientists. It’s about changing how you actually approach a tumour, rather than following on from where previous therapies have failed and fallen off.

“We almost need to forget what we’ve learnt and see if we can redesign how to kill a tumour cell. Who are the players? Well, it’s your immune system. It’s nutrition. It’s your genetic make-up. We need to look at combinations and learn how to have that balance between agonism and antagonism to play the symphony rather than just be a soloist.”

Because of this, he says he is optimistic about the future for this challenging disease space.

“I chose to rejoin this organisation to be part of what is hopefully a new dawn in oncology – where we’re looking not at small incremental benefits in PFS to get another me-too on the market, but at actually addressing unmet needs for patients. What can we do that’s going to really change the game in that tumour type?

“Rather than listening to what others are saying the direction of new therapies will be, we want to have a role in defining that and shaping it ourselves.

He adds: “In an organisation like ours, with the resources and the appetite to take smart risks, we have the privileged opportunity to define what that conversation can be and define what the future can be. That sounds grandiose, but we really want to be world leaders in oncology at GSK. We want the organisation to be catalysed around innovation, performance, and trust.

“I think we have a huge role to play with patients, with other top industry players, with academia and clinicians to define and then accelerate what the next innovation will be.”

Dr John Fleming is the UK and Ireland oncology medical head for GSK. He has been in the pharmaceutical Industry since 2014 in local and global medical and commercial leadership roles across Oncology and Haematology at GSK and Novartis. Dr Fleming performed his undergraduate training at Imperial College London and spent nine years in clinical practice at London Teaching Hospitals prior to joining GSK Oncology.

George

George Underwood is a senior member of the pharmaphorum editorial team, having previously worked at PharmaTimes and prior to this at Pharmafocus. He is a trained journalist, with a degree from Bournemouth University and current specialisms that include R&D, digital and M&A.

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