An illustration of T lymphocyte white blood cells attacking pancreatic cancer cells. Image / Getty
Big pharma has spent almost US$1t over the past decade on cancer drug developers, but certain types of cancer have been bypassed.
People with aggressive forms of breast, lung, and prostate cancer have been offered a lifeline in recent years as new treatments hit the market including AstraZeneca’s Enhertu, Merck’s Keytruda and Novartis’ Pluvicto.
But a new weapon to fight pancreatic cancer, the deadliest common form of the disease that kills seven out of eight patients within five years of diagnosis, has not emerged. Go-to treatment Folfirinox is a cocktail of four medicines, one of which was first approved in 1962.
“Almost all patients who come through the door are given a bunch of old drugs put together,” said Anirban Maitra, an oncologist researching pancreatic cancer at the MD Anderson Cancer Centre in Houston, Texas. “It’s the weak link in the fight against cancer.”
Tackling the hardest-to-treat tumours will be essential to public health efforts to turn cancer into a more manageable disease – a challenge given added urgency by an uptick in the disease among younger people in developed countries.
The struggle to discover needle-moving treatments for pancreatic cancer, and other types including colon and brain cancer, comes despite pharmaceutical groups spending almost US$1 trillion ($1.6t) over the past decade acquiring oncology drug developers, according to industry tracker Evaluate.
Why certain types of cancer have been bypassed in the wake of innovation and dealmaking is partly a result of complex biology that makes them untreatable by broadly targeted products such as Keytruda, now approved for 40 forms of the disease.
But the problem is also a consequence of where drugmakers, governments and charities place their research and development bets.
Almost half of the 2143 trials launched last year focused on breast, lung, and blood cancer, while just under 8% were studying pancreatic cancer treatments, according to data provider IQVIA.
Pancreatic cancer research benefitted from just US$317 in public and philanthropic funding per death globally between 2016 and 2020, compared with nearly US$3600 of grant money per death for breast cancer, according to a Lancet study published last year.
Grant funding is dwarfed by research and development spending from drugmakers but is vital for more experimental research. Global grant funding for cancer totalled US$13b in 2019 against US$83b spent by United States pharma groups on research, a large proportion of which would have funded oncology trials, according to the US Congressional Budget Office.
Another problem in the battle against harder-to-treat cancers is that their public profile tends to be overshadowed by other cancer types.
“Pancreatic cancer does not have patient advocates because they all die,” said Julie Fleshman, chief executive of the Pancreatic Cancer Action Network.
She added that drug development in the field had been marked by a “long history of failures”, where companies often spent hundreds of millions of dollars only for a treatment to flop in clinical trials.
Charlie Fuchs, head of oncology at Roche and its subsidiary Genentech, said that “from a commercial standpoint, there’s an easier path forward to consider when it’s a highly prevalent cancer like breast cancer”.
The dearth of new treatments for certain forms of the disease explains investor excitement over Revolution Medicines.
The biotech group’s market value has risen about 50% to more than US$7b this year after it released early-stage data showing that its novel targeted therapy stalled tumour growth in the most common type of pancreatic cancer.
For chief executive Mark Goldsmith, the broader lack of innovation in the field is “an injustice”.
“The last thing you can do inside a big company is go to the head of clinical development and tell them, ‘I’ve got a new drug that’s going to treat pancreatic cancer’,“ he said. “You’ll be sent to the back of the line.”
Claire Myerson, a 54-year-old former IT director who lives in Oxfordshire, is among those to have benefitted from the pharma industry’s focus on highly prevalent cancers.
She has been receiving treatment for advanced, metastatic breast cancer since late 2015. While Roche’s Perjeta had little initial impact, Kadcyla, another of the company’s treatments, has helped hold back the growth of her tumour for eight years.
“It’s possible to live with metastatic breast cancer. It’s not easy but it’s possible,” she said. The drugs tackle cancers such as hers by targeting the HER2 protein present in a quarter of tumours, for which there were once few options.
Progress in this field shows how science can flip the odds in cancer care. Enhertu, developed by AstraZeneca and Japanese group Daiichi Sankyo, has been the most successful antibody drug conjugate to radically shift survival rates by targeting the protein.
“Originally it was simply bad news if you had HER2 expression,” said John Marshall, a gastrointestinal oncologist at the MedStar Washington Hospital Centre. “Now the pharmaceutical industry has developed such effective treatments that you want to be HER2-positive.”
The main two drugs available to Marshall to treat his colon cancer patients, Cetuximab and Vectibix, were approved nearly two decades ago. “There’s been no fundamental advance in colon cancer care in 20 years,” he said.
But new treatments are on the horizon.
BioNTech and Genentech are collaborating on a colorectal cancer vaccine aimed at halting tumour regrowth after surgery, following promising results in a small early stage trial. They are also working on a pancreatic cancer vaccine that is at an earlier stage of clinical development.
Fuchs said the companies were aiming for more than “small incremental benefits”. A pancreatic cancer vaccine “really is a major advance in what has been a very difficult disease ... Not only do we think it’s important in terms of global health but I think it will actually have a legitimate business case.”
Bristol Myers Squibb this year received an accelerated approval from the US Food and Drug Administration for a new targeted therapy drug targeting the same gene mutation as Revolution Medicines’ lead drug, as a second-line therapy to treat a small subset of colorectal cancer cases.
The mutation in question is KRAS, which until just over a decade ago was considered an undruggable target. Now pharma groups are researching different variants of the gene to test how far-reaching its effects can be.
“Is it easy? Absolutely not,” said Samit Hirawat, BMS chief medical officer. “This requires a lot of patience, resilience, and many drugs fail before one succeeds.”
KRAS is present in 90% of pancreatic cancers, about 40% of colorectal cancers and roughly a quarter of cases of the most common lung cancer – the three deadliest forms of the disease.
Pancreatic cancer had been “a wasteland” for new treatments, said Revolution Medicines’ Goldsmith, because it is not an immune-responsive cancer type, meaning it never responded to a class of immunotherapy drugs known as checkpoint inhibitors that redefined large parts of cancer care.
By activating KRAS, these new drugs can turn pancreatic cancer cells into a “hotter tumour” that is more immune-responsive, opening up the possibility that it could even respond to checkpoint inhibitors such as the US$25b-a-year sales blockbuster Keytruda.
“People have tried immunotherapy in those diseases. People have tried targeted therapy in those diseases. It’s not like they’ve been wilfully left behind,” said Jacob Van Naarden, head of Eli Lilly’s oncology division, which is also researching a KRAS inhibitor.
“The science of the tumours has not proved to be sensitive to the things that have worked in other places.”
While a blood test for prostate cancer has been approved in the US for three decades, it was not until last month that a similar test, known as a liquid biopsy, was approved for colon cancer. Such a test for pancreatic cancer is still a long way off.
Helmy Eltoukhy, chief executive of Guardant Health, the company behind a new colon cancer blood test known as “Shield”, said liquid biopsies offered the promise of “removing a lot of the health disparity” that exists around getting tested for cancers.
About 30% of eligible adults aged 45 and over in the US miss out on the colonoscopy examination, which requires patients to eschew food for 24 hours before the procedure and be sedated. Uptake is especially low among younger cohorts.
Christy Williams, a 45-year-old mother-of-three from Davidson, North Carolina, who is free of colon cancer after two surgeries and a dozen rounds of chemotherapy, recalled delaying her colonoscopy because she was busy and embarrassed. “People often die from embarrassment. They’re too embarrassed to just get the test.”
She added that she was not put off by the mammogram, the breast cancer scan, which benefits from much higher uptake in Western countries.
Expanding blood tests to check for multiple cancers was key to screening for pancreatic cancer, said Eltoukhy. Only breast, prostate, colon, and lung cancer have wide-scale screening programmes in the US.
But products from device makers Grail, Exact Sciences and Freenome have so far struggled to get off the ground or overcome concerns about false negatives and positives.
Scientists at the City of Hope National Medical Centre in California have developed an early stage pancreatic cancer test that preliminary findings suggest may have more than 90% accuracy.
“If you find pancreatic cancer early, you can surgically treat these patients but also use some of the new treatments in development on later-stage patients,” said Ajay Goel, who led the research.
Despite it taking a long time for much-needed new treatments and tests to arrive, oncologists specialising in the deadliest cancers have not given up hope.
“I’ve never been more hopeful — with the better understanding of biology and the huge markets waiting to be seized from screening all the way through to novel therapies — that we are on the verge of breakthrough for the hardest-to-treat cancers,” said Marshall.
Written by: Oliver Barnes in New York and Ian Johnston in London
© Financial Times
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