I am no racing fanatic. I have never been to the track, know virtually nothing about horses, and can go years without seeing the Kentucky Derby on TV. I have never seen the Preakness, and the Belmont Stakes only rarely. I have never placed a bet in my life. While I find them quite beautiful, I am aware of the price these highly inbred animals pay for our amusement. But like many I was caught up in the recent Triple Crown mania and its protagonist, American Pharoah.
In the days leading up to the Belmont stakes I read an article saying that it was unlikely, indeed almost scientifically impossible, for American Pharoah to triumph, no matter how good a race he ran. The odds were stacked against him. The tight schedule of Kentucky Derby to Preakness to Belmont took too much out of even the best of horses. Other horses, having missed one or both of the other two races, simply had greater reserves, more stamina, and more stored glycogen to burn. It had been 37 years since the last Triple Crown winner for a reason. In fact, the odds were against any horse winning the Triple Crown.
Certainly his trainer must have shared that concern, and the jockey that rode American Pharoah. They had been in the same situation before, winning the first two races only to lose the third. One might hope that this time things would be different this time, but what were the odds? Upsets weren't just common, they were ubiquitous.
As I sat in front of my television over the weekend, my mind drifted to the ASCO annual meeting I had just attended. As at every ASCO, I had caught up with old friends, attended talks, gone to innumerable side-meetings, and inhaled the Onco-zeitgeist.
Some years ASCO seems unalloyed triumph. Some years are years of consolidation. This was the latter, though “consolidation” barely seems to describe the forward progress of the checkpoint inhibitor juggernaut.
‘Drug of the Year’
If a prize were given for “drug of the year” at ASCO, surely nivolumab would be the winner. The pride of the plenary session was Jedd Wolchok's presentation of the combination of nivolumab and ipilimumab for melanoma. The combination's median progression-free survival of 11.5 months easily beat out either single agent nivolumab (at 6.9 months) or ipilimumab (a piddling 2.9 months). Median overall survival for the combination has not yet been reached, but it was clear to all that we have passed an inflection point in the history of metastatic melanoma.
And not just melanoma. The Checkmate 057 nonsquamous non-small cell lung cancer trial (do we really have to say “nonsquamous non-small cell lung cancer” from here on out?) compared nivolumab with docetaxel in the second-line setting, and demonstrated a survival advantage, as well as the impressive “tail of the curve” effect we have seen repeatedly in immune checkpoint inhibitor trials. And there was nivolumab in hepatocellular carcinoma, with a 19 percent response rate, including complete responses: amazing for this disease. Nivolumab also looked like it might have a place in small cell lung cancer, a disease that has gone many a year since finding a new champion.
And not just nivolumab. Pembrolizumab is a star in Mismatch Repair (MMR) deficient colorectal cancer, with a 62 percent response rate (and inactive in MMR-proficient colorectal cancer, which makes for interesting biology). And pembro, like nivo, looked interesting in small cell lung cancer.
Recently a friend told me that he had called a major pharmaceutical company to speak to an individual involved in a trial he was opening. The voice at the other end of the phone asked: “Is he in Immuno-Oncology or Rest of Oncology?” Imagine having that conversation five years ago. Times have changed.
I think of the Annual Meeting's immune checkpoint story as the first leg of the Triple Crown, its Kentucky Derby, if you will. But what about the other two races in oncology's Triple Crown?
If I had to chose a topic for this year's Preakness race I would chose the word “value.” Value kept coming up, both in the plenary session, in other sessions I attended, and in conversations in the halls of the McCormick Convention Center.
Len Saltz gave his “Perspectives on Value” in the Plenary session, noting the astonishing cost of the new checkpoint inhibitors. The price of Ipi, for instance, is “approximately 4,000 times the cost of gold” on a weight for weight basis. Cancer drug prices bear little relationship to value, or to the cost of production, or even the cost of the research that goes into the making of the drugs. The prices are, quite simply, “what the seller thinks the market will bear.”
These comments made their way to that altar of modern capitalism, the Wall Street Journal, whose well-insured readers no doubt considered Len's comments heretical. But the Value meme has taken hold in the oncology community, and I suspect will remain a concern and challenge for doctors and patients, just as it did for many speakers in many sessions. ASCO has taken some first awkward steps toward defining value, a difficult but necessary transition.
Defining value is tricky business, of course. I look at those first ipilimumab patients in melanoma, some now a decade out and still in remission, and think “what a wonderful time to be an oncologist.” Decades of research, the cynicism of most of us (about both melanoma and immunotherapeutic approaches), preceded this wonderful merger of science and clinical practice. I repeatedly find myself saying, “How cool is that?”
I love the basic science, the clinical-translational elements of the story, and the very real patient benefits, but I dread the financial consequences. A presentation that caught my eye was Aasthaa Bansal's study of the health effects of bankruptcy in cancer. It is quite simple: if you file for bankruptcy you are far more likely to die of your cancer. The adjusted hazard ratio for death was 1.79. Since health care costs are a leading cause of bankruptcy it is only a small stretch from the 4,000-times-gold cost of a checkpoint inhibitor to, not just the poorhouse, but also the mortuary. Scary, but also an indictment of our dysfunctional American health care system.
“Value” too often ends up being about money, and rapidly devolves into sterile cost/benefit analyses. But what physicians value most is their time. While you can cost out time, doctors resent the unforgiving, irreplaceable, forever-gone nature of lost time. It is a major “value” issue. I saw this everywhere at this year's ASCO. There was a full education session devoted to the bureaucratic inefficiencies that waste our time. And, in the “New Drugs in Oncology” pre-meeting session, which I co-chaired, Tony Tolcher spoke eloquently of the ridiculous and unnecessary time burdens inflicted on clinical researchers.
These time-sucks are largely self-inflicted wounds. It is easy to blame the government, or the makers of electronic health records, or Pharma and the remora-like CROs attached to them, but we put up with this nonsense. If we are not quite losing the “Value” Preakness, we are certainly not winning it.
Which leads me to the Belmont Stakes, the third leg of the Triple Crown. I heard about this race mostly in side conversations with colleagues. The basic story was this: “I have no control over my life.” Physicians in general, and oncologists in particular, have suffered a progressive loss of autonomy. They now feel firmly in the grasp of hospital bean counters who view them as interchangeable widgets, and information technology geeks who look on them as not very smart data entry specialists.
By chance, Dana Farber was transitioning from one electronic health record system to another while the Annual Meeting proceeded, and no one I met from Harvard thought it anything other than a massive waste of their time. Knowing the fate that awaited them I offered my condolences. The modern EHR is non-intuitive, treats doctors as secretaries, fails in its basic promise of inter-hospital connectivity, and is sold to hospitals for its billing benefits rather than for its timesaving characteristics. What's not to love?
I also heard from a young oncologist bullied by superiors over work RVUs. This doctor covered her salary, but that apparently was not enough: more was expected. She had gone into academic medicine in hope of a research career, and now she saw that career vanishing. The needs of the hospital corporation outweighed the needs of the individual. The time she needed to write protocols, produce papers, and perform research were considered unimportant. She was a widget, a part in the machine.
This is not just a complaint of the academics I met. All over the country the old private practice groups are disappearing, swallowed up by corporations. Few of the doctors I know are happy with these transitions. One I spoke to belonged to a practice that had been purchased by a large health care company, which then decided that the purchase had not met the corporate definition of a positive cost: benefit analysis. They had simply decided to stop paying physician salaries until the books balanced. The practice got out from under the corporation, at great cost, and now resides under the umbrella of an academic health organization, the lesser of two evils.
If the first leg of the Triple Crown was science, and the second value, let's call the third leg, for want of a better word, “happiness.” Happiness is undervalued as a reason to come to work every day. Physicians burn out, or at least the ones I see leaving the profession, because they are no longer happy. By and large they still love their craft, adore their patients, and are thrilled by the scientific and clinical advances. The reasons they went into their profession are still there.
But I heard, over and over again, their unhappiness, and sometimes a feeling of desperation. I don't think I was projecting (really, I don't). These seem to be general stresses brought on by a change by medicine to something more corporate, more dollar-dominated. Perhaps more efficient as well; the old way of doing things was anything but efficient. But certainly we have arrived at a place where physician autonomy now resides in a very narrow space.
I saw bewildered-looking fellows navigating McCormick Place for the first time: enthusiastic, delighted to be in Chicago, a bit confused about what they had gotten themselves into. An old friend, standing next to me, turned and asked, “If you had to do it all over again would you still be an oncologist?”
I don't mean to leave this admittedly peculiar and particular view of the Annual Meeting on a down note. Nor do I mean to suggest that everyone is swigging Prozac cocktails, beating their collective chests, and wailing at the moon. They are not. But happy? Less so now than ever.
I do not think that there is anything inevitable in life, other than death and taxes, and I am not even sure about those. One of my favorite quotes is from Pericles of Athens' famous funeral oration: “The secret to happiness is freedom, and the secret to freedom is courage.” As a profession we need to find our courage, seize our freedom, and then we will, perhaps, find happiness.
American Pharoah won the Belmont stakes, blowing away the field. No one was even close when horse and jockey crossed the finish line: he led by more than five lengths. Courage and heart still mean something, and nothing is impossible. He joins War Admiral and Seattle Slew and Secretariat in horse racing's version of immortality.