The first real hopeby Donna Chisholm
A new group of drugs that target the immune system is being hailed as the most revolutionary cancer treatment in decades.
Grant Looker could see the future – and he wasn’t in it. “You know what’s coming,” he said then. “There are no mysteries for me.”
It was November 2014, and Looker, a 55-year-old Taranaki nurse manager, was predicting his own death, probably within a month or two. He had stage 4 melanoma, and you usually don’t recover from that. He’d got the news in May, when they found the brain tumour. He told his daughter, Abbey, and son, Isaac, first, then his brothers, and found himself comforting them rather than the other way around. He invited his friends over for a pot-luck dinner and a big party the same night. As they arrived, he told them, “I’ve got my scan results and it’s terminal.”
He sorted out his will, gave up his job at the hospital and took the kids on holiday to Sri Lanka. By the time they got back, new tumours were on his bowel and pancreas. They’d grown from the size of grapes to that of mandarins in three weeks. “I’ve got nothing to offer you,” the doctor said.
He was wrong. Because for Looker and hundreds of other terminally ill melanoma patients, a new group of immunotherapy drugs is offering the first real hope of long-term survival.
The drugs, known as immune-checkpoint inhibitors, are being fast-tracked into clinical use around the world. Merck Sharp & Dohme, developers of one of them – pembrolizumab, known commercially as Keytruda – have just applied for the drug to be registered and funded here.
Until that happens, though, the new therapies are available only through clinical trials, on compassionate grounds, or for an extremely expensive $120,000-200,000 a year, with dosages calculated on weight.
Looker, whose children launched a crowdfunding web page to raise money for the treatment, paid more than $70,000 for two courses of a forerunner to the drug in Australia, and has now qualified to receive pembrolizumab on compassionate grounds here. He started the three-weekly infusions in January. Six months on, he’s back at work and his latest MRI scans show no discernible evidence of melanoma.
A GAME CHANGER
Looker’s recovery may seem miraculous, but he’s not alone. In clinical trials of melanoma and lung cancer, 30-50% of patients are showing a response to the new drugs, known in scientific circles as PD-1 pathway inhibitors, or anti-PD-1 antibodies. Now trials have been expanded to dozens of other cancers, with encouraging early results.
University of Auckland’s Professor Rod Dunbar, a cancer immunologist and director of the Maurice Wilkins Centre, says in the history of cancer treatment, this is a revolution. “I’ll hang my hat on it. With the PD-1 drugs, we’ll look back at this time historically and point to the first trial and say, ‘This is the moment that our understanding of cancer completely changed.’ It’s that important.”
The scientific explanation of how the anti-PD-1 drugs work has filled hundreds of pages in international medical journals. Dunbar explains it this way: “The [immune system’s] T cells that can recognise and kill cancer cells have a big red ‘off’ button on them. The tumour cell can press that button and switch them off over time. What this drug does is put a whacking great plastic shield over the button so the tumour can try to press the button but it can’t switch the T cell off, so the T cell keeps going and keeps doing the killing.”
Of course, that big red “off” button does serve a purpose in healthy individuals – it’s part of the combination of brakes and accelerators that control the immune system, with the brakes preventing harmful inflammatory reactions. When these drugs have had adverse side effects – and these were more common and more severe with a forerunner of pembrolizumab, called ipilimumab, which acts on a different pathway – it’s been just this problem: an out-of-control immune system attacking the body’s organs, such as the bowel.
Hype over the “next big thing” in anti-cancer treatments isn’t new. But this time, it’s different, says Dunbar. The anti-PD-1 drugs aren’t just buying a few months of extra time. The “tail” on the survival charts, which usually declines inexorably to zero as cancers become resistant to treatment and the patient dies, is flatlining. About 50% of patients with stage 4 “desperate” disease treated with a combination of ipilimumab and pembrolizumab have responded to the treatment, with a large proportion likely to survive long term, he says. “In other words, this may be a life-saving combination.”
Of about 30 different cancers in early trials, only colorectal and pancreatic have so far failed to respond well, but already, says Dunbar, those puzzles are beginning to be solved. “This is the revolution we’ve said is coming for 25 years. While there’s clear evidence the immune system can fight cancers in a small number of patients, suddenly we’re finding this particular pathway means the immune system can fight lots of cancers. One of the reasons I’m getting excited is that it’s a field I’ve watched growing over a number of years and suddenly it’s come to fruition.”
AT WHAT PRICE?
At Pharmac, director of operations Sarah Fitt reacts to the excitement with a world-weary sigh. She says she’s heard this sort of thing many times before and it’s early days yet. “It looks promising in the early studies, but many of these drugs do, and a lot get so far down the track and never eventuate. You want to be seeing long-term benefit.”
It’s an attitude Dunbar considers “a real worry”. “There is a big difference between these clinical trial responses and what we normally think about a successful cancer drug. I don’t normally leap into the media every time a new cancer drug comes along, but this one really is dramatic.”
He says Pharmac and the Government “need to act urgently”, because patients desperately ill with melanoma have heard about the huge impact of the drug overseas. “They’re in the torturous position of not being able to access a treatment that will save many of their lives.”
It’s inevitable, he thinks, that Pharmac will eventually find a way to provide anti-PD-1s. “But in the meantime, the lack of access is fundamentally unfair to patients who happen to get sick in 2015 rather than in another year or two.”
Internationally, the drug has been fast-tracked for registration in the US and Australia and recommended for registration in Europe. It’s funded in the US, largely by insurers, and is about to be funded in Australia. It is available in the UK through the Cancer Drugs Fund, and some New Zealand patients with British citizenship have gone there for treatment.
Cost, however, remains an enormous barrier, with one delegate to the recent annual meeting of the American Society of Clinical Oncology in Chicago saying that if the anti-PD-1s were funded for every cancer in which they’d been shown to act, it would double the US’s national drug budget. And if even the US is pushing back against the cost, you know you’ve got an affordability issue.
Merck Sharp & Dohme’s New Zealand director, Paul Smith, says with $4 billion spent internationally on research and development on pembrolizumab last year alone, those costs must be reflected to some degree in the drug’s price. The company is funding 180 clinical trials around the world and spending $19 million on trials in New Zealand.
Smith says he’s been talking to Pharmac representatives for “a couple of years” about pembrolizumab and its cost implications. Like Fitt, they’re “poker-faced”, he says. If and when a deal is done, it’s likely to come after months of horse-trading over cost, and it will probably involve the portfolio of 38 Merck Sharp & Dohme drugs that Pharmac funds or part-funds. “Pharmac is less interested in the cost of this drug and more interested in how much it will cost in total and what we will offset around that.” There are various options, he says, including offering a rebate on other drugs, or capping the spend so any number of patients can be treated for a fixed amount.
Before the negotiations begin, however, the drug must be registered by Medsafe and then recommended for funding by Pharmac’s clinical advisory committee, PTAC.
Pembrolizumab earned Merck Sharp & Dohme $100 million in the first nine months on the market, and though sales are increasing exponentially, it could take three years or more to recoup the money spent on research and development.
It’s clear Fitt thinks the price is too high. “Personally, I think the trouble is it probably overshot and there’s been a real pushback from insurers and clinicians. They are saying this is just unaffordable.”
Although she says Merck Sharp & Dohme is entitled to recoup what it spent “up to a point”, New Zealand is such a small part of the market “we shouldn’t be paying for that research here”. That sounds a bit like those who are anti-vaccination taking advantage of herd immunity, but Fitt says it’s simply about trying to wring out every last dollar from Pharmac’s $800 million annual budget.
To those who say Merck Sharp & Dohme and other big pharmas are just a bunch of greedy multinationals cashing in on the sick and needy, Smith says pembrolizumab, being an antibody, is an expensive drug to make. Production is ramping up quickly, though, and prices should come down with the efficiencies of scale. But so rapidly is the field developing that better drugs could come along relatively soon and knock pembrolizumab off its world-leading perch, meaning the company will want to recoup its spend as fast as it can.
As a member of both PTAC and its oncology sub-committee, Auckland medical oncologist Dr George Laking – co-investigator for a trial of anti-PD-1s in lung cancer – is in a unique position to see both sides of the funding debate. “Pretty much all I do now is treat lung cancer,” he says, “and with all the new people I see, I think, ‘Could they be a candidate?’”
He says if he had advanced melanoma, he’d probably pay for the drugs. “I’m in a fortunate situation in society, but our society is quite unequal nowadays.”
Pharmaceutical companies, though, are in business to make a profit. “If you’re the vice-president at a major pharma and you say, ‘Oh, have some sympathy for people, cut the price’, I don’t think you’re going to be the VP for very long. Publicly listed companies have a fiduciary duty to shareholders to maximise returns – it’s their responsibility. Whether or not you call that greedy, I don’t know.”
Laking says he’s thought deeply about the tension between his perspective as a clinician and as an adviser to Pharmac. A clinician needs only think about the good of his patients, but at Pharmac, the gain for a few from a high-priced medicine must be set against the greater good.
He says though anti-PD-1s won’t help everyone, “I feel as positive as I’ve ever been about a new cancer treatment. I think we’re getting probably the strongest clue that we’ve had so far that something of value is happening for the immune system. Alas, not for the majority, for the minority, but it’s there.”
Northern Cancer Network director Dr Richard Sullivan, the principal investigator on two lung cancer trials of anti-PD-1s, says although the drugs are arguably the biggest breakthrough in cancer treatment since chemotherapy was invented, there are still “more questions than answers. Who do you give it to, how do you work that out, how long do you give it for and what can you do to make these drugs more effective?”
It was initially thought the anti-PD-1s might be most effective in cancers whose tumours had higher numbers of mutations – such as lung cancer and melanoma – therefore allowing the immune system to more readily recognise them. But “it appears they may work in virtually every cancer there is. This is potentially one of the greatest breakthroughs we have seen if it’s as promising as it looks.”
There is plenty of reason for optimism, says Sullivan, but also for caution. “The cautions are that you could end up offering treatment when it might be a disadvantage, because a standard treatment is better – for example, if you have cancers like lymphoma or testicular cancer, which have a 60-90% cure rate. The other problem is the duration of treatment – do patients need to be on it continuously to maintain their wellness? There are massive cost implications of that.”
He says one of the first patients on pembrolizumab came off a trial for other reasons after just one dose. Eighteen months later, the patient is still well.
A POLITICAL ISSUE
With about a third of patients responding to the anti-PD-1s alone, the big questions are how to predict who will respond and how to increase the number of responders. At the Maurice Wilkins Centre, Dunbar’s team are trying to work out ways to extend the effectiveness of the drugs to more patients. He says the anti-PD-1s seem to work best in patients who already have T cells that have recognised and started to attack the tumour – albeit cells that the tumour then neutralises by pushing that red “off” button he refers to.
But another group of patients have never produced any T cells in response to the tumour because they’ve never recognised it. It’s called immunological ignorance, and in that case, the PD-1 pathway hasn’t been initiated, so blocking it isn’t going to work. The solution here, he says, is to somehow prime those patients’ immune systems to recognise the tumour. The Maurice Wilkins researchers are working on vaccines that carry parts of the tumour molecules into the body to wake up the T cells. “We think at least some of the patients who aren’t responding to the anti-PD-1s basically need to have their T cells switched on before the drugs will work.”
Cancer vaccine work has been going on for 15-20 years, and although a small number of patients have shown dramatic responses, eventually tumours switch off the T cells. “Now we can pair a cancer vaccine with an anti-PD-1 drug and suddenly we have a really good chance of it working,” says Dunbar.
The institute is manufacturing vaccines that it hopes to take to clinical trials in about a year.
Dunbar wants New Zealand to consider launching a cancer drugs fund like the one the UK started in 2011, saying Pharmac must recognise the dramatic difference in anti-PD-1 outcomes “as fast as possible. Even the most hard-bitten oncologist looks at this data and goes, ‘Wow!’ Pharmac has to fast-track this as a highly innovative medicine, the most highly innovative medicine we’ve had in decades, possibly ever.”
He says if it’s simply too soon for Pharmac to make a decision, “then it becomes a political issue. We need to take it very strongly to the current Government and say this is a case where, for a short period, a small investment of the kind you would put into a road or an America’s Cup team will enable New Zealanders to survive, at the same time buying us the time to do a proper assessment of where these drugs sit and provide information from close monitoring that will help in the pricing of this drug and others long term.”
However, Fitt describes the British scheme as “a bit of a disaster”, which has seen cancer drugs funded ahead of others. “It was very political. They have a National Institute for [Health and Care] Excellence that does the appraisals but doesn’t hold the budget, and then the Cancer Drugs Fund overrules its decisions and it’s all got really messy.”
She believes the scheme has created more inequity than before. “It seems quite a good idea, but there are lots of people out there with chronic diseases who all want treatment – why should one group get higher priority than another?”
Melanoma New Zealand trustee and medical oncologist Dr Rosalie Fisher, who was working in the UK when the Cancer Drugs Fund was launched, doesn’t think it’s a disaster at all, describing it as very effective. She says doctors are obliged to tell terminally ill patients about the drugs and their cost. “There is an element of despair on our patients’ behalf. Most can’t afford it. You can see them thinking wildly even before you’ve finished, wondering, ‘What can I sell, how can I get the money?’, and it feels cruel. But you can’t withhold the information and you can’t make assumptions about their financial situation.” She knows of several young patients who are considering mortgaging their homes to raise money.
THE LUCKY ONES
At this stage, the best hope to get more New Zealand patients on the new drugs is through clinical trials, and Fisher is about to start recruiting for a study of pembrolizumab in stage 3 melanoma. About 50% of stage 3 melanomas develop into stage 4 disease. The trial will involve 10 Auckland patients and about the same number from the rest of the country.
Fisher is regularly fielding calls from patients with other cancers who want to know how to get the drug, reflecting the “huge excitement that’s been generated in the medical community spilling over into the public forum”. She says she’d be hesitant to recommend the drug for cancers without clinical trial evidence or which were in the very early trial phases, particularly because of the cost involved.
For Looker, who was so close to death a year ago, the realisation that he might, in fact, have a full life to live has been a humbling experience. He’s filled not with euphoria, but with a profound sense of relief.
It’s only now that a couple of his friends have confided that they wondered why he went chasing the hope of a cure when there was, realistically, no hope. “They thought it was too late, that I should accept it and spend time with my family.”
He walked Abbey down the aisle at a garden ceremony in Oakura on December 23 when she wed her boyfriend, Cameron Mace; the couple hadn’t been engaged but she couldn’t bear the thought of marrying without her dad to give her away.
She and brother Isaac went to Sydney with Looker for most of his treatments and she says they wouldn’t have wanted anything other than for him to try everything he could to beat the cancer. “I feel really thankful for the time we’ve got, because we’ve got him. You know how lucky you are.”
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