Richard Lehman’s weekly journal review—27 April 2015

richard_lehmanNEJM 23 Apr 2015 Vol 372
Last week, dear friends, we kicked off with alirocumab and evolocumab. This week it’s the turn of nivolumab, ipilimumab, and pembrolizumab. It’s driving me mab. Whoumab canumab possiblyumab remememberumab whatumab theseumab drugumabs actuallyumab doumab? When monoclonal antibodies started to be marketed as therapeutic agents, wise and distinguished men (with no doubt a few women in their midst) decided to impose a system of nomenclature on the new drugs.

I’ve occasionally tried to explain this to you en passant. It took hold seriously in 2010 and I suggest that in the interests of human sanity it should now be abandoned. For clinicians it’s of no interest at all that whether a given mab is pegylated or partly chimeric or completely humanized. If there’s a clue to its action in the name it’s usually too deeply hidden to be of any use. I hereby suggest getting rid of the whole olumab, izumab, imumab nonsense and just ending any drug that’s an antibody with an “a.” And that’s only part one of my rantumab.

Before part two, let’s turn to the trials:

OL Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. Sounds just a bit silly, doesn’t it? But of course it is deadly serious: we are talking about first-line treatment for a metastatic (they forgot that in the title) cancer that is uniformly lethal and often affects younger people. In a situation like this, I think it’s perfectly OK for a leading journal to publish a phase 1 trial, though it can only hint at things to come rather than determine clinical practice. Niva and ipila (as they would be called under my reformed system) are both inhibitors of T-cell checkpoint pathways. I won’t try to explain for fear of sounding like a Charlie. Suffice to say that in most BRAF wild-type melanomas, this produces a growth check which can be dramatic. Combined treatment is more effective but causes twice as many severe adverse effects.

OL Just to illustrate that last point, the NEJM publishes a letter reporting on a patient with a large chest-wall melanoma metastasis who received a single dose of ipilumab and nivolumab. The metastasis simply evaporated, leaving a large hole: you can see the pictures for free. But such dramatic results could be life-threatening—think if the metastasis had been in a common place like the myocardium or the bowel wall.

OL Now for pembrolizumab. This attacks a different guardhouse: the programmed cell death 1 (PD-1) immune checkpoint. It is compared with ipilumab in a phase 3 trial of impressive size—834 patients from 16 countries. The trial was run by Merck and blinding was abandoned for the last 6 months. The Kaplan-Meyer plot paints the picture that matters: at 18 months 50% of the ipilumab group are dead as opposed to 40% of the pembrolizumab group. Tricky. Such an oddly conducted trial. Mike Rosenblatt, CMO at Merck, has recently made several pronouncements proclaiming his support for the principle of data sharing, and I’m sure he will want to release the full datasets from this trial immediately for independent scrutiny before this product becomes widely used.

OL Finally another Merck-funded trial of pembrolizumab, this time a phase 1 trial in advanced non-small-cell lung cancer. The trial was partly for dose-finding and also for determining the value of measuring the expression level of the PD-1 ligand 1 (PD-L1). Suffice to say that these initial results are a bit underwhelming.

Time for part two of my rant about monoclonal antibodies. When penicillin was first produced in Oxford in 1940, it was life-saving and literally priceless. But soon Norman Heatley invented a way of producing a few grams of it using bedpans and milk bottles, and in 1941 he travelled to the USA to persuade Merck to mass-produce it. There was no question of a patent. Within a few years, penicillin had become one of the cheapest yet most valuable drugs. Now when monoclonal antibodies first appeared in the 1990s, they were rare and expensive. Hundreds have since been patented, and they remain eye-wateringly expensive—£75,000 is the UK cost of a course of ipilumab, for example. The ones we have been discussing this week are last-ditch treatments for aggressive disseminated cancers. Are we to believe that there have been no production advances which could have brought down costs for all these izumabs and ilumabs and olumabs? That £10K per month of postponed death will forever be the fixed price that manufacturers can reasonably demand? I’d be for calling their bluff. There should be an international production facility for producing monoclonal antibodies at cost for use in cancers and for carrying out independent, rigorously conducted trials. The present system is a blot on medicine.

JAMA 21 Apr 2015 Vol 313
1534 The Andrew Wakefield affair still leaves a bad taste. Once an irresponsible scare story gets currency the genie cannot be put back in the bottle. No amount of observational research can disprove the idea that every now and again, a particular vaccine might cause an idiosyncratic reaction leading to some ill-defined condition such as autistic spectrum disorder (ASD). You can only repeatedly demonstrate that there is no reason to believe it will happen, that on a population level it does not happen, that the purported evidence for it happening was bogus. The strongest evidence so far comes from families who already had a child with ASD.” In this large sample of privately insured children with older siblings, receipt of the MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.”

1541 Let them eat insulin? This is the latest idea for preventing type 1 diabetes in high-risk children. The tiny quantities of exogenous insulin which cross the oral mucosa can induce antibodies to insulin, which sounds like a bad thing. But not so—this trial shows that this immune response does not induce autoantibodies to islet cells and may in fact protect against this by inducing immune tolerance. I think it’s still a long shot strategy, but worth testing in a properly powered phase 3 trial.

JAMA Intern Med Apr 2015
OL In a couple of week’s time I’m due to give a talk entitled “Heart Failure and Other Misnomers.” The epidemiology of heart failure is a mass of perplexity. Rule number one is to forget the systolic ejection fraction and go by clinical criteria like those from Framingham. The EF may help align your management strategy with the clinical trials (usually very inaccurately), but you will then ignore at least half of the patients who have the clinical syndrome. Let me shut up now and commend the Olmsted County cohort to your attention. Between 1 January 2000, and 31 December 2010, the age—and sex—adjusted incidence of HF declined by 37.5%. Do you hear this shouted with joy by every cardiologist in the land? No, because they are all Jeremiahs, or rather Jonahs, like the Old Testament prophet who went into a sulk when his preaching succeeded so well that God didn’t have to smite the people of Nineveh. But the people who got heart failure in Olmsted continued to die at the same rate. Why? Because heart failure is a signal for the gradual approach of death, and our treatments for it, though numerous, are largely futile in the elderly. We fail to switch our humanity on and address it as a form of dying. We are incentivized to pile on drugs and monitor everything by the day. Personally I would prefer to die with less molestation and more kindness, accepting mortality as inevitable and wishing for an honourable truce rather than a pointless battle. And in fact most of these patients, though they died as surely as in the past, ended up with something other than “heart failure” as their primary cause of death.

Lancet 25 Apr 2015 Vol 385

OL The Lancet‘s Online First website is pretty crowded at present with trials of some general interest. This one finished in Jan 2009. Its primary outcome was a composite of clinically significant shoulder dystocia, fracture of the clavicle, brachial plexus injury, intracranial haemorrhage, or death in newborn babies. Since you can tell if a baby has or doesn’t have these things within a day or two, five years seems a long time to write up the study, even by my standards. The trial compared a policy of waiting for spontaneous delivery or inducing birth between 37-8 weeks in mothers with foetuses over the 95th centile for size. There was a bit less shoulder dystocia in the induced group, and a higher rate of vaginal delivery. The title of the editorial is a Lancet classic: ” Should pregnancies be induced for impending macrosomia?” I would suggest that the best way of avoiding impending largeness of body may not be to get pregnant.

OL I prefer the title of another editorial on the website: “Donor heart preservation: straight up, or on the rocks?” As you might have guessed, it’s about a study of donor hearts flown in on ice versus fresh local hearts. The chilled ones can work very nicely if carefully prepared. Oh, and could I have a twist of lemon with mine, please.

OL “We found no evidence that mindfulness based cognitive therapy is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence. Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence, residual depressive symptoms, and quality of life. ” That’s how the modest authors of this cluster-randomised primary care trial summarized their results. It’s interesting how the media reported it the other way round.

OL I don’t think any amount of mindfulness therapy or psychotropic medication will get me to the point where I understand effect sizes in vaccination trials. For me, vaccines need to be the sort where if you have the jab you won’t get the disease: anything short of that and I get confused. So if you want to know if we’re at the point of a breakthrough in malaria prevention through vaccination, don’t ask me: try and access the final report of the trial of the RTS,S/AS01vaccine in African children. “It prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose… Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.”

The BMJ 25 Apr 2015 Vol 350
Odd studies from the USA continue to pop up in The BMJ. “This results (sic) of this trial on the effectiveness of transcranial direct current stimulation for the reduction of pain and disability do not support its clinical use for managing non-specific chronic low back pain.” Mmm. Can’t say that it ever occurred to me that it might. This finding is unlikely to reduce the electricity bills of most British GPs.

I am hardly the most ardent advocate of cancer screening, but I had come to think there might be a place for some kind of screening for colorectal neoplasia. Now I’m not so sure. Flexible sigmoidoscopy appears to have the best effectiveness, but this survival meta-analysis states that it took 9.4 years (7.6 to 11.3) to observe an absolute risk reduction of 0.001 (one colorectal cancer related death prevented for every 1000 flexible sigmoidoscopy screenings). Have a think whether that would persuade you to go and have one.

A huge exercise in individual participant data meta-analysis from over half a million people in 25 cohort studies. This is what the German word fleissig was invented for. Well done, all of you from Heidelberg and other places. From these data we can be certain that it’s still well worthwhile to give up smoking at the age of 60 and older.

Plant of the Week: Clematis montana “Primrose Star”

We have exhausted all ground space in our little gardens, so we now intend to saturate everything vertical with clematis. The only problem is that our soil is rife with clematis wilt fungus and clematis-eating gastropods. We are lucky if anything other than a montana or viticella cultivar lasts for more than a single season.

The montanas are the big ones that flower at the start of May. For a few weeks they cover whole thatched cottages with flowers of pink or white, almost choking the passer-by with a dusty scent of vanilla sugar. I wouldn’t normally look at a montana clematis without scent, but this one is stunningly beautiful for its flowers alone. These are of the usual starry montana shape but mostly semi-double and of an enchanting palest straw-yellow, developing the thinnest verge of subtle pink. Not really primrose then, but I suspect that “Straw Star” would sell fewer plants.

It is still in its pot and I haven’t been able to detect any scent on it at all. It is said to be relatively unvigorous, growing to about 3m. I want to put it to grow into a lilac tree but it might look even more stunning with a dark blue ceanothus.