Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Friday, January 19, 2018

On Lists

I am a sucker for end-of-the-year list. You know the type: Best Books of the Year, Best Movies, Best Albums, Best Songs, Best TV show, Best Whatever. I read them religiously, especially the Best Books lists. There are even lists of lists, collating the "bests" by number of lists in which a particular body of work is to be found. George Saunders's fascinating Lincoln in the Bardo is the list of lists book winner, if you haven't read the novel. For what it's worth, the Sledge family agreed: three copies of the novel were bought independently and placed under the Christmas tree. Maybe we all read the same lists.

Though I like the book lists, and find them convenient for holiday shopping, I find many of the books themselves unreadable, a problem they share with National Book Award winners. "Literary" books don't have to be dry tomes emanating from academic writer's workshops, though all too many are. And the lists, of course, are created by individuals with interests, biases, and their own agendas.

I remember, back in the day, the intelligentsia's vicious takedown of President Dwight David Eisenhower: the man read mystery novels in his free time. How smart could he be? It was the sort of criticism that appealed to me when I was a college student, but one that lost its charms over time. Crime and Punishment was a pretty good mystery novel, after all, and a great number of crime novelists can write rings around their "literary" counterparts, offer more acidic and pertinent societal diagnoses, and provide far more hours of enjoyment to more human beings, fulfilling the Benthamite prescription for happiness.

Then there are the science lists, the ones with the most important breakthroughs of the year. I've always been partial to the Science magazine list. Its breakthrough of the year involved the collision of two neutron stars on the edge of the galaxy NGC 4993, detected first by the LIGO gravitational wave detector and ultimately studied by (according to Science) 3,674 researchers from 953 institutions.

Nature magazine's list of the "10 people who mattered this year" is also an interesting list. I think they really wanted to say "the 10 most important people in science," but that would have attracted unwelcome attention from the next 287-odd people who thought they belonged on the list. The list includes, to our shame, an American political leader both disinterested in and destructive of science.

I've contributed to such lists in a minor way, having come up with my "Top 10" for oncology in general or breast cancer in particular. Looking back on such lists, whether my own or others, reveals embarrassing flaws in judgement. What I thought was important wasn't, or was but for the wrong reason. I remember 2011, the year everything changed in oncology with the advent of CTLA-4 inhibition for melanoma. My thought, at the time, was something along the lines of "How cool. Those melanoma docs really needed a new drug." Again, right, but for the wrong reason: checkpoint inhibition, not just CTLA-4, and cancer, not melanoma; rather like mistaking the French Revolution for a small riot that preceded it.

But in oncology, the real lists that matter are created by the FDA: the annual lists of New Drug Approvals. Experimental findings, the stuff of New England Journal of Medicine editorials, only really signify when a drug makes it into the clinic. I count 57 of what the FDA calls "Hematology/Oncology (Cancer) Approvals and Safety Notifications" for 2017. By comparison, if one looks at the 2007 list, the number of approvals was 17. Of course, not all of these are individual drugs (drugs could be approved for more than one disease), and not all of them are new drugs (some old dogs have been taught new tricks), and not all of them are even drugs (more on this in a minute). But the sheer increase in number over the past decade suggests that cancer research has increased in pace and scope and (one hopes) in impact.

Looking over the list provides an interesting overview of the state of the field. A dozen of these approvals were for checkpoint inhibitors. The immuno-oncology band marches on, with new treatments for common cancers (non-small cell lung cancer (NSCLC), bladder cancer, Hodgkin lymphoma), and for more obscure malignancies (Merkel Cell, anyone?). Similarly, the "ib" revolution, with kinase inhibitors for specific oncogenic drivers, is well into its second decade with no sign of abatement. The past year saw a combination "ib" approval (dabrafenib and trametinib for metastatic NSCLC with BRAF V600E mutation), similar to a prior 2014 melanoma approval. Shutting off BRAF alone doesn't do much, as we learned in melanoma: whack-a-mole oncology rears its head in short order, and a combined approach of BRAF and MEK inhibition provides better (though still imperfect) results. I suspect we will see more of these over time as we tease out cancer biology in lab and clinic.

The diagnostic space was also interesting. The dabrafenib/trametinib BRAF V600E approval, for instance, comes with the caveat "as detected by an FDA-approved test." The approval tells its own story. The BRAF V600E mutation is rare, somewhere on the order of 1-3 percent of NSCLC. Had you told a Novartis exec 2 decades ago that we would be intentionally targeting 2 percent of lung cancer with two targeted therapies informed by a companion diagnostic, the reaction might have been an interesting one. But such is the way of the world in 2017, and no one finds it at all surprising.

The larger companion diagnostics story involves so-called "tissue-agnostic approvals." The first of these occurred in May 2017, and it is a big deal. The FDA approved the use of the checkpoint inhibitor pembrolizumab "for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H), or mismatch repair deficient (dMMR) solid tumors." Prior to this, the FDA approved agent X for disease Y; for every X there was a Y. But with MSI-H or dMMR tumors (Lynch syndrome cancers and their relatives), the organ no longer matters: it's the biology that counts. "Y" has changed.

How often will we see such tissue-agnostic approvals? Not very often, I suspect: much, or even most, of tumor biology is context-dependent. EGFR-inhibitor drug resistance is different in colorectal cancer than in lung cancer, and the presence of an oncogenic mutation in a cancer doesn't always define that cancer as being a good target for a particular kinase inhibitor. But we will see some.

In 2017, the FDA gave two drugs (entrectinib and larotrectinib) Orphan Drug status for treatment of NTRK fusion-positive solid tumors. If your cancer has an NTRK fusion protein, you have a great chance of responding to one of these agents regardless of organ. Alas, NTRK is uncommon. But the Orphan Drug status is interesting, for both drugs are the result of phase II basket trials. Sometimes you get lucky: most "positive" basket trials are positive in one or two disease buckets, not across the board as seen with NTRK.

Another diagnostics story is also of genuine interest, and perhaps greater ultimate importance. Late last year, the FDA approved the FoundationOne CDx test "to detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type." This is a device, rather than a drug, approval. Device approvals require a different type of evidence than drug approvals, in that they do not carry the same requirement for clinical benefit. But this approval is very broad ("any solid tumor type") and comes with a proposed national coverage determination from the Centers for Medicare & Medicaid Services. So, basically, the government just approved next-generation sequencing for everyone with an advanced solid tumor.

This is another of those milestones that will pass essentially unnoticed. And yet it answers an important question. For several years after the Human Genome Project announced completion of the "rough draft" sequencing of our DNA in 2000, there were real questions regarding its utility. Seventeen years later, genome sequencing has moved from a multi-billion-dollar one-off to an off-the-shelf, relatively cheap (relative to the therapeutics, that is) FDA-approved diagnostic device. Exactly what physicians will use it for is an interesting question, but as the MSI-high and NTRK fusion stories suggest, this will rapidly become not just an option for patients but a requirement for patient care. For while MSI-high and NTRK are individually rare, like all medical zebras, no one will want to miss them if they can be tested for with ease. The convergence of next-generation sequencing with the immuno-oncology and precision medicine ("ib") revolutions is now complete.

One hesitates to call FoundationOne (and the onslaught of next-gen diagnostics to follow) a "companion diagnostic." One orders it to find a "companion therapeutic," which is conceptually something quite different than ordering ER and HER2 for breast cancer.

In most years, the additional members of the list would be viewed as impressive additions to the therapeutic armamentarium. The FDA approved two additional CDK 4/6 inhibitors (ribociclib and abemaciclib) for breast cancer and approved pertuzumab for adjuvant therapy in breast cancer. The first PARP inhibitor approval occurred, with niraparib providing stellar results as maintenance therapy for ovarian cancer, a spin-off of the 1990's BRCA diagnostic revolution.

We also saw the first FDA approvals of CAR T-cell gene therapy for acute lymphoblastic leukemia and advanced large B cell lymphoma, an exceptionally cool, "gee-whiz science" technology with curative potential for some cancers. CAR-T is not for the general medical oncologist, at least not yet. It has the boutique feel of the bone marrow transplant unit, with expenses to match: Novartis launched its CAR-T product with a price of $475,000, which of course is not the real price for anyone once one adds hospitalization, in-house processing, and drug administration costs. You know you are in trouble when the press release touting a new therapy uses the cost of allogeneic stem cell transplantation as a reference standard.

If 2017 was both an exceptional year for "Oncology Lists," at least in the context of FDA approvals, the very length of the list is chastening. How does a general medical oncologist keep up with 57 FDA approvals? I used to think that being a primary care physician was the toughest job in medicine, but being a general medical oncologist is giving it a run for its money. We have not yet found a good way to transmit this firehose of information to cancer doctors, who are drowning in data.

And what impact will the 2017 list have on cancer patients? Here the picture is even murkier. A plethora of new $10,000 per month drugs cannot be good for health care system economics, or family finances, unless such drugs actually wipe out a patient's cancer. Few of these do. One of the most embarrassing, depressing medical articles of the last year, published in the BMJ, reviewed the impact of 5 years' worth of EMA (the FDA's European equivalent) approvals. The EMA approvals (from 2009-2014) overlap significantly with contemporaneous FDA approvals.

The results were not pretty. The EMA list, which was heavy on precision medicine kinase inhibitors (the "ib" drugs) improved the overall survival of patients with metastatic cancers by an average of only 2.7 months where this endpoint could be measured in a phase III trial (BMJ 2017;359:bmj.j4530). Most drugs on the list were approved with a progression-free survival endpoint instead of an overall survival endpoint, rendering the data even drearier. Quality of life was demonstrably improved in only 10 percent of the new drug indications. So, we have quite a way to go.

That is the nature of lists. Like the book lists I obsess over, many of the individual therapeutic listings will disappoint, money poorly spent on a product I won't like. But some things on the list will have lasting value, and the sheer length of the list indicates the rapid pace at which science is entering the clinic. Like many cancer doctors, I am a pathologic optimist. I believe the future will work for my patients. I'll keep looking at the lists.