This article by Jane Cadzow appeared on 19/8/2016 in The Age Interactive:
http://www.theage.com.au/interactive/2016/fight-club/
When Steven Jones-Evans was diagnosed with bladder cancer, the prognosis was grim. His only hope was new – and expensive – immunotherapy. His response to the treatment was nothing short of astonishing. By Jane Cadzow
The email Steven Jones-Evans sent his doctor began like this: “Andrew, I’ve been telling strangers in the street. Service-station attendants have become my best friends. I’ve hugged petulant next-door neighbours and small dogs. The whole gamut of humanity looks so beautiful and real today. The only thing I haven’t done is punch the air: best left to tennis players and white rap artists …”
Jones-Evans, 58, is one of the Australian film industry’s leading production designers: his credits include Romper Stomper, Ned Kelly and, more recently, The Railway Man, starring Nicole Kidman. The recipient of the email, Andrew Weickhardt, 38, is an oncologist and senior researcher at the Olivia Newton-John Cancer Wellness and Research Centre at the Austin Hospital in Melbourne. Both men were giddy with elation that day in July last year: Weickhardt confesses that in the privacy of his home, he did punch the air. When Jones-Evans came to see him at the cancer centre, he adds, “it was high-fives and big hugs”.
Among those who wandered into the consultation room to join the celebration was Jonathan Cebon, the centre’s medical director. He had long been excited about immunotherapy, a new form of cancer treatment that mobilises a person’s immune system to fight the disease, but he recalls reflecting as he looked over Weickhardt’s shoulder at the scans displayed on the computer screen that its potential was almost unlimited. “The way cancer medicine is practised from now on is going to be profoundly influenced by this science,” Cebon says. “It genuinely is a game-changer.”
Jones-Evans and I meet at the South Australian Film Commission studios in Adelaide, where he is working on a new movie. He is medium height, with floppy brown hair and dark-framed glasses. Though the urge to embrace passers-by has worn off in the past 12 months, an air of wonderment lingers about him and he’s keen to tell his remarkable story. “It really does offer people out there a lot of hope,” he says.
Scientists have long dreamed of empowering the immune system to attack cancer in the same way it combats bacteria and viruses. That dream is at last becoming a reality. Immunotherapy has been hailed as the biggest breakthrough in cancer treatment in a generation and one of the most important medical advances of our time.
Jones-Evans knows this now. In September 2014, when he noticed blood in his urine one morning, all he knew was he needed to see a doctor. His GP suspected an infection but the final diagnosis was transitional cell carcinoma, the most common form of bladder cancer. Jones-Evans didn’t panic: “I thought things would be okay.” Sure enough, an operation to remove a kidney and some lymph nodes seemed to go well. He sent a bulletin to friends and family saying, “Fantastic news, they’ve got it all.”
Then he had a PET (positron emission tomography) scan, a type of imaging test in which a radioactive substance acts as a tracer, travelling through the bloodstream and highlighting areas of disease. Ominously, the scan found “hot-spots” in two of his lymph nodes. A biopsy of the node in his neck confirmed the presence of a malignant tumour.
Jones-Evans vividly recalls the oncologist originally in charge of his case explaining that once cancer like his had metastasised – spread from its original site to other parts of the body – it was virtually impossible to eradicate. “He said, ‘We can give you chemotherapy and shrink your tumour by up to 80 or 90 per cent, but we can never get rid of it. It will grow back. Eventually it will become resistant to the chemo drugs we’ve used, so we’ll have to try new chemo drugs. And eventually it becomes resistant to those, too.’ ”
Jones-Evans and his wife, costume designer Joanna Park, who live in Sydney, had read online about a new drug known as MK-3475, reported to be having some impact on bladder cancer in clinical trials. According to Jones-Evans, the oncologist showed little interest.
“He said, ‘Basically what you’ve got is incurable.’ ”
The message could scarcely have been clearer, Jones-Evans realises now. “But because of the sort of person I am, it didn’t register. I didn’t go, ‘I’m dead.’ I just thought, ‘Well, you can’t cure me, but there will be someone else who can.’ ”
He went to a second oncologist, who said the same thing as the first. And this time, the words hit home. “Joanna and I went back to the car and I was kind of crying,” he says. “Crying and angry at the same time.” He phoned his mother to tell her his cancer was terminal. “I remember her saying, ‘It’s okay, I’m sure there’s something we can do.’ She couldn’t process the information.”
Jones-Evans didn’t want to accept the verdict, either. He meditated, exercised, stocked his pantry with health foods and tried to make sense of the plethora of “alternative” treatments recommended on the net. “There’s so much information out there,” he says, “and so much of it is hearsay and anecdotal.” He started skyping with men in white coats who ran private clinics overseas and claimed they could help him, at a price. Frankly, he says, he was willing to try just about anything. “I had three children and a wife and I didn’t want to leave the Earth just yet. I wasn’t ready.”
A third Sydney oncologist he consulted ordered another PET scan, and this one lit up with many more cancer hot-spots. “It had got into my vertebrae,” Jones-Evans tells me. “It had got into a shoulder bone. A rib. About six more lymph nodes. It was basically spreading throughout my body.” By now, he was in constant pain, and losing weight. He had been told chemotherapy probably would extend his life by only a few months but he decided to embark on a course of it anyway. To his dismay, the first dose flattened him. “It was like someone had pulled the batteries out,” he says. “I thought, ‘If this is what my life’s going to be like, I’m not taking it. I’d prefer to die quickly.’ ”
With Joanna, he made plans to go to a clinic in Israel for treatment, but just before their departure they learnt that its supply of the drug intended for Jones-Evans had run out. At this low point, when he was wearily contemplating heading to a German clinic instead, Jones-Evans’ luck changed.
One of his close friends, the Melbourne fashion designer Alannah Hill, had broken her toe. The doctor who examined her foot noticed a small spot, which proved to be a malignant skin cancer – a melanoma. Fortunately, it had been caught early, but Hill’s relief was tempered by her anxiety about Jones-Evans. She asked her oncologist for advice: what course of action should a person with stage-four bladder cancer be taking? Hill then made some calls on Jones-Evans’ behalf. As a result, he caught a plane to Melbourne and, on April 29 last year, walked through Andrew Weickhardt’s door.
“He was certainly in a fairly bad way,” Weickhardt says. “His energy levels were declining, his appetite was poor, he was quite depressed. His prognosis, with the cancer growing and untreated, was probably somewhere between three to 12 months.” Weickhardt hoped to get Jones-Evans onto one of the immunotherapy trials being run at the Olivia Newton-John centre. As it turned out, that wasn’t possible: the only suitable trial was restricted to patients who’d had no chemotherapy. So Weickhardt offered him another option. An expensive one.
In overseas trials, an immunotherapy drug had reduced the size of tumours in 20 to 30 per cent of people with advanced bladder cancer, Weickhardt told Jones-Evans. In some cases, the shrinkage was significant, and the effect appeared to be long-lasting. The drug, Keytruda, was available for the treatment of melanoma under the Australian government’s Pharmaceutical Benefits Scheme, which subsidises the cost of approved medicines, but not for the treatment of bladder cancer. If Weickhardt prescribed it for him, Jones-Evans would have to bear the full cost.
“I said, ‘Great, I’ll pay for it. Let’s just organise it,’ ” recalls Jones-Evans, who already knew about Keytruda: it was the brand name of MK-3475, the drug his first oncologist had dismissed as not worth considering. The initial infusion cost $12,000, and afterwards Jones-Evans noticed no difference in his condition. But when he returned to Melbourne for the second dose three weeks later, a nurse gave him encouragement. “She said, ‘You look a bit better.’ I said, ‘Really?’ I didn’t feel better. She said, ‘Yes, your demeanour has changed.’ ”
During the three-week interval before the next dose, Jones-Evans’ appetite picked up a bit and he seemed to have more energy. One day he realised with a start that the lymph node in his neck was no longer swollen. “I thought, ‘Something’s happening here. This is starting to work.’ I had my third infusion and the nurse said, ‘You look so much better.’ ”
It seemed a good time to take the holiday he and Joanna had promised themselves when the cancer was diagnosed. With their kids – Olive, now 17, Ivy, 15, and Penn, 11 – they spent a month in Italy, from Bologna in the north to a villa in the Tuscan countryside and the village of Positano on the Amalfi coast. To Jones-Evans, the beauty and sunshine felt healing. He sensed he was getting stronger every day: “I couldn’t work out when I got back whether it was Italy or Keytruda that had saved me.” Either way, he had high hopes that the scan scheduled immediately after his next infusion – his fourth – would show his tumours had contracted.
Weickhardt was optimistic, too, but when he studied the image of Jones-Evans’ body on his computer screen, his first reaction was disbelief: “I had to double-check that I had the right scan.” Then he phoned his patient, catching him in a noisy cafe. Moving outside, Jones-Evans asked the oncologist to repeat himself. Did he say there were no hot-spots? Weickhardt confirmed that not a single tumour was evident on the scan. As incredible as it seemed, the cancer looked to have disappeared.
Jones-Evans doesn’t mind admitting he screamed. And he wasn’t the only one: “I phoned my wife and she screamed. Phoned my mum and she screamed.” His gratitude knew no bounds. “I’m sitting on the wings of angels in a never-ending circle of bliss and joy,” he wrote in his email to the oncologist, “and it’s all due to you and your spicy, clever and frightfully brilliant ways. You’re the man, the dude, the chic researcher and clinician in your crisp grey suit. I love you and what you’ve done and do …”
The only blot on Jones-Evans’ happiness was his concern that others were missing out on immunotherapy, just as he would have done if Alannah Hill hadn’t intervened. “I wanted to tell other patients, ‘I’ve had this miraculous response. You could possibly have it, too. You should be trying this.’ ”
We now know that T-cells have built-in brakes, known as checkpoints, to prevent them from attacking a person’s own healthy tissue. It was Allison who first identified one of these checkpoints – a protein called CTLA-4 found on the surface of T-cells – and theorised it might also have a role in stopping the immune system from killing tumours. “Let’s take the brakes off,” he says he reasoned, “and the immune-system response can keep going until it eliminates the tumour.”
In Allison’s laboratory, mice with tumours were injected with an antibody that blocked CTLA-4, effectively letting the immune system go for broke. The result? “The tumours just melted away,” he says. Drug companies were sceptical at first, given immunotherapy’s reputation as a great idea impossible to put into practice, but eventually one of them agreed to develop a human version of the antibody. Marketed as Yervoy, it was approved for the treatment of advanced melanoma in the US in 2011. (In Australia, which has the world’s highest melanoma rate, it did not receive PBS listing until two years later.)
Since then, the pharmaceutical industry has spent billions trialling more so-called checkpoint-inhibitor drugs. A sizeable chunk of the initial $US1 billion the US government has committed to its “cancer moonshot” program will go to immunotherapy research. Philanthropic funds are flooding into the arena, too. Silicon Valley billionaire Sean Parker, the 36-year-old co-founder of the online music service Napster and first president of Facebook, declared in April he was giving $US250 million to establish the Parker Institute for Cancer Immunotherapy. At a glittering party to launch the institute, actor Tom Hanks gave the keynote speech and Lady Gaga sang.
Allison, based at the M.D. Anderson Cancer Centre in Houston, is something of a rock star himself these days. Reported to drive a Porsche convertible with the number plate CTLA-4, and widely tipped to win a Nobel Prize, he is a headline act at gatherings such as the 16th International Congress of Immunology, to be held in Melbourne this week. In his spare time, Allison plays harmonica in a cancer immunologists’ blues-rock band, the Checkpoints, and recently he made a guest appearance in Willie Nelson’s band: “Right up there with the biggest thrills of my life,” he says.
Dead man walking. That was the reasonable conclusion to be drawn from a PET scan taken in November 2012 of Melbourne property developer and businessman Ron Walker. Diagnosed earlier that year with stage-4 melanoma, Walker had tumours in his brain, lungs and bones. The former Fairfax Media chairman and federal Liberal Party honorary treasurer had tried one immunotherapy drug with disastrous results: Yervoy, Allison’s checkpoint inhibitor, had attacked his stomach wall and almost ruptured it. But neither Walker nor his oncologist, Grant McArthur, was willing to give up.
McArthur knew of a promising drug, Keytruda, that wasn’t yet on the market. “The only way Ron could be treated with it was on a clinical trial,” McArthur says, “and the only spots I could find for him were in Paris or Los Angeles.” Walker joined the LA trial in January 2013, crossing the Pacific for his infusions until a place was found for him in a Sydney trial. The results were better than anyone expected. By the fourth dose, his tumours had diminished and eventually they vanished altogether.
Walker, now 76, who declined to be interviewed, has said previously that to get onto the US Keytruda trial, he pulled every string he could, including calling “anyone who knew anyone at the FDA [US Food and Drug Administration]”. Nonetheless, McArthur is adamant that Walker’s wealth and position played no part in his being accepted. “He didn’t get onto the trial because he was Ron Walker,” McArthur says. “In clinical trials, we don’t reserve spots for VIPs. It’s first in, first served.”
Of course, Walker had the advantage of being able to afford to travel. “If you’re on a healthcare card, you’re not going to have the money to get on a plane and go to the US,” McArthur readily concedes. At the Olivia Newton-John centre, Jonathan Cebon argues that most melanoma patients would never have found out about the Paris or LA trials – nor, possibly, about trials in Australia – because they wouldn’t have had an oncologist as plugged in as McArthur. “If someone walked in off the street from a working-class suburb into the local hospital, they wouldn’t necessarily be seen by someone who’s got the connections,” Cebon says.
A year ago, former US president Jimmy Carter announced that he was suffering from melanoma, which had spread to his brain and liver. In March, after treatment with Keytruda, he reported that his tumours were gone. Grant McArthur says stories like this are becoming more common among late-stage melanoma patients:
“We’re now looking at between 10 and 20 per cent of people treated with these drugs having a complete disappearance of all tumours that we can see on scans.”
Mind you, that leaves 80 or 90 per cent with tumours that don’t disappear. Immunotherapy cruelly discriminates between individuals: a drug given to 20 people with the same type of cancer might take two from the brink of death to perfect health, reduce the tumour size of five more and do little or nothing for the rest. “Performance seems to depend on an individual’s immune health and their cancer’s genetic make-up,” says Weickhardt.
To add to the unfairness, the immunotherapy drugs that have been developed to date work much better against some kinds of cancers than others. In Australia, where PBS listing depends on proven effectiveness against specific illnesses, they are available cheaply only for the treatment of melanoma so far. That will certainly change – Keytruda alone is undergoing clinical trials for the treatment of 20 different kinds of tumours – but in the meantime, people with other types of cancer who want to try immunotherapy and can’t get onto trials have to pay a lot for the drugs.
Weickhardt says the price of Keytruda has dropped since Steven Jones-Evans dug deep: “It currently sits at about $8800 per dose. But I mean, that’s a huge amount of money.” He is aware that some doctors do not mention immunotherapy to patients for fear of completely demoralising those with no chance of meeting the cost. “It makes me uncomfortable raising it,” he says, “because I intuitively guess that many patients can’t afford the treatment.” Still, Weickhardt wouldn’t dream of withholding the information. “I feel really strongly that it has to be discussed.”
Pharmaceutical firms charge anything up to $150,000 for a year’s worth of an immunotherapy drug. It isn’t as if the ingredients are expensive, says Jonathan Cebon. “You can make it for the cost of brewing beer … but there are massive research and development costs to recoup.” And as the patent-holders for these potentially life-saving medicines, the drug companies can put whatever price tag they like on them. The Cancer Council’s Sanchia Aranda says charges vary from country to country. “The cost is really based on what the market will bear. Some of this is unethical in my view.” Aranda adds: “This is a global issue. You can feel the outrage that is starting to build about access.”
A few months ago, more than 100 French cancer specialists signed an open letter slamming the greed of the pharmaceutical industry. “Drug companies are among the world’s most profitable,” says Stephen Duckett, health program director at Australia’s Grattan Institute and a former federal health department secretary. (Merck, the firm that sells Keytruda, reported a $US4.5 billion after-tax profit last year. Bristol-Myers Squibb, which sells Yervoy and another checkpoint inhibitor, Opdivo, made $US1.6 billion.)
In this country, many contend that the high cost of immunotherapy drugs adds to the urgency of reducing delays in approving them for PBS listing. After all, people with advanced cancer cannot wait for treatment. The delays are due in part to the tendency of pharmaceutical firms to launch new drugs in bigger markets before they bring them to Australia, but the slow grinding of bureaucratic wheels here doesn’t help. In a submission to last year’s Senate inquiry into the availability of new cancer drugs, John Zalcberg, who is co-chair of the Cancer Drugs Alliance and head of Monash University’s cancer research program, argued it was essential to find a way to speed up access to cancer medicines that were available elsewhere in the world “but not to Australians who need them”.
One of the people in the consultation room with the jubilant Jones-Evans and Weickhardt that July day last year was Amy Auden, a Melbourne lawyer whose husband, Nick, was diagnosed with metastatic melanoma at about the same time as Ron Walker. The Audens, who were then living in the US with their young family, tried desperately to have Nick treated with Keytruda or Opdivo. “They were in late-phase trials,” Amy says, “and had been given ‘breakthrough’ status by the FDA, meaning: ‘These drugs are phenomenal. Let’s race them to market as quickly as we can.’ ”
When Nick failed to secure a place in the trials, the couple mounted a social-media campaign called Save Locky’s Dad and lobbied hard for permission to buy the drugs, asking that access be granted on compassionate grounds. More than 525,000 people supported them via an online petition, but the pharmaceutical firms knocked them back. “I kept getting this line, ‘We don’t want to play God,’ ” recalls Amy. “I kept saying, ‘Well, hang on, you are playing God.’ ”
Nick died, aged 41, in late 2013. Amy and their three children then returned to Melbourne, where she started working on a development strategy for the research institute attached to the Olivia Newton-John cancer centre. She happened to be having coffee with medical director Jonathan Cebon when Weickhardt invited him around to check out Jones-Evans’ “before” and “after” scans. Amy went along, too.
“Having seen so many of Nick’s scans, I could read them quite well,” she says. “And I was blown away. It was an extremely emotional moment.” Here was indisputable evidence of the magic that could be worked by a drug that had been denied to her husband. Nick was dead and this other man was alive. Still, what Amy felt most strongly was delight for Jones-Evans. “I was relieved he and his family did not have to go through what we went through,” she says.
Jones-Evans does not know how long his remission will last, but so far his tumours have shown no sign of returning. In his email to Weickhardt, he wrote: “I’m over the moon and beyond: somewhere between Pluto’s icy mountains and Saturn’s rainbow rings.” Though he’s come back to Earth, he says he is permanently changed by his experience: “There’s a kind of lightness that has crept into my life.”
Weickhardt has a printout of the email on his office wall. “Best feedback I’ve ever received,” he says.