Nexavar misses. But did it really?

News today that Nexavar flunked its' Phase III trial in lung cancer. (NSCLC)

I'll be curious to see the data present at ASCO, because I'm not sure that they really failed. While Nexavar missed the primary endpoint (overall survival (OS)), there was an improvement in the secondary endpoint (progression-free survival(PFS.))

(I've yet to see the relevant figures. All I can go on are news reports.)

Also: every patient in the Nexavar trials had failed at least two previous (standard) therapies, with some having failed three. For NSCLC, you're talking about surgery, radiation, and chemo (2 or 3 of the 3 therapies) before being treated with the experimental targeted drug.

NSCLC is a huge market (~250,000 annual cases in the US alone) but has not yet been broadly cracked by a targeted therapeutic. (Iressa had approval, and Xalkori has approval for use in a very small %age of patients. Tarceva and Avastin both have approval, but clinicians are skeptical and the economic argument is suspect.)

But we have every reason to believe that NSCLC can be impacted by targeting EGFR and/or VEGF - Sutent (Pfizer's competitor to Nexavar) is also in late stage NSCLC trials, and a variety of not-yet-approved targeted therapies are also likely to try to impact NSCLC. Because of the large number of annual cases, and the need to audition as a thrid-line therapy, perhaps we're just setting the the bar too high or setting these trials up for failure.



(please pardon the upcoming rant)

Independent of the judgement on Nexavar in NSCLC, I am very disappointed at the FDA mandate of a placebo arm for oncology trials using late-stage, terminal patients such as the Nexavar trial discussed above. I fully appreciate that to run the most scientifically bullet-proof trial requires a control arm, but what is the humanity in dosing late-stage cancer patients with a placebo? Not only are you potentially generating false hope for the patient and their family, it seems utterly wasteful. With nearly a million cases of NSCLC every year, and decades of data tracking patient outcomes, don't we know by now what the OS and PFS are for NSCLC patients at a given stage?

I'd like to see an FDA/NCI-led project to calculate baseline survival expectation across the most lethal cancers, with these standards to serve as stand-ins for placebo arms. I'm not suggesting relaxing approval standards (I will in a minute), but instead normalizing for humanitarian reasons and economic reasons. Even better, such an FDA/NCI study would be a springboard to genomic-level understanding of outcomes.

Eliminating the placebo arm of trials of late-stage cancer patients would immediately double the base of trials-eligible patients - something very important as on of the hardest things of trial design is recruitment. (The Nexavar NSCLC trial was based on ~700 patients recruited at ~150 locations. Imagine what a pain it is to manage numbers like this, and how much $$$ could be saved if ~350 patients were not needed.)

The two reasons that the use of placebo arms continue (other than seeking perfection in experiments) are that

1) for many drug/disease combination, the survival benefit may be tiny (4.5 months versus 3), to the point of being very difficult to detect.

2) regulators have a negative biased (against approval), mostly for CYA reasons. No one ever got fired at the FDA for being too picky with approvals, while a sure way to get fired at the FDA is to be too permissive.

Combining these two arguments raises the bar for drug approvals. To obviate this, I would make the survival standards generated by the FDA/NIH (discussed above) a simple hurdle - if a drug clears the baseline hurdle survival rate or just ties it, approval is automatic, in contrast to the current approach of requiring placebo arms in order to demonstrate the statistical significance of the trial outcomes.

(Yes, I did just argue against a fundamental aspect of data analysis, but we're talking about cancer here. We need more shots on goal, and more importantly, more learning. We don't really learn anything from a placebo arm patient when we already have millions of data points in our databases.)

(end rant)

Interesting new research

1) A sign of research advances to come: a research team used DNA sequencing to find effective uses of approved cancer drugs in new cancer applications.

Study details
target disease indication: colon, lung. (CRC & NSCLC)
core technology: exome sequencing
genes of interest: RET and ALK.
Nutshell: Nexavar, Sutent, and Calpresa ("N,S&C") are each multi-kinase inhibitors approved for other cancers, but they happen to also inhibit RET in addition to their effectiveness against other primary targets (VEGFR). The researchers - backed by Foundation Medicine - found unexpected RET fusion genes in a small subset of samples, and found N,S&C effective in vitro against the cancers with RET expression. The kicker is that neither of the diseases in this study are approved applications for N,S or C. The problem is that the RET or ALK incidence was in only ~2% of the ~600 samples studied.

(Presumably the ALK findings would similarly advance the cause of PFE's Xalkori, and ALK inhibitor.)

This is the type of personalized medicine progress that we've been on the cusp of for awhile, so it is nice to see the promise of personalized medicine become tangible. I expect that we'll see many more studies like this just this year, and each one will advance treatments (and the market for therapeutics) by a tiny bit (in other words, bunt singles, not home runs), but that collectively they'll add up to a big impact, if clinicians can keep all of the findings straight, and if the FDA can fast-track approval for these minor extensions to existing drug approvals. If so, the makers of N,S&C just got a little more valuable and outcomes for patients with CRC or NSCLC just got a little better.

2) new class of anti-cholesterol drugs look tremendously effective. Anti-PSKC9 drugs from Amgen (Phase I) and Regeneron (P II) dramatically cut LDL by using a new way to interdict a known pathway. (The same one targeted by statins.) The AMGN drug is a biological delivered by monthly injection, which makes me wonder: what delivery method has higher effective compliance, a single monthly shot, or daily pills like Lipitor?

Given how early the findings are, though, I don't think we'll see either AMGN or REGN drug on the market until late 2016 at best.


(disclosure: I own a tiny amount of AMGN stock.)

Who wins from DNA sequencing? (Multi-target drugs)

First came the notion of specific inhibitors of kinase signaling, and Gleevec was originally the embodiment of the idea of inhibiting just a single gene fusion - BCR-ABL. With the fine targeting came low financial expectations - I recall NVS predicting that Gleevec could have annual revenues of as much as $200M. (Actually Gleevec annual revenues for NVS are ~$4B, both because they had most expectations of the market, and because Gleevec isn't so specific, which is a good thing.)

Then, Exelixis introduced the idea of intentional multi-kinase inhibition, though some wondered if this was less of a design intention, and more of a tolerance of the notion that complete specificity may be impossible.

Last year saw the introduction of FDA approval of inhibitors not just for a single gene target, but a specific mutation of a specific gene (e.g. Zelboraf for BRAF V600E, though it comes with certain problems.)

It appears that the next wave is being unleashed by Foundation Medicine - DNA sequencing to match drug to cancer and suggest mixes of drugs, where appropriate.

The conclusions put forward by Foundation Med are not novel in theory, but a very exciting in practice.

What is also exciting is how use of DNA sequencing may unlock new markets for existing drugs. Big Pharma, I think, has generally worried that personalized medicine may result in lower revenue ceilings for new drugs, thus tilting the economics of drug discovery out of favor. (Because it generally costs about the same to develop a blockbuster as it does a niche drug.)

But if the Foundation Med results are indicative of future broader results, the economics may become even more favorable. Case in point is Pfizer's Sutent, FDA approved in 2006, and a $1B blockbuster as of 2010, based on its' application in renal cell carcinoma and GIST (specific stomach tumors).

Foundation Med's research is suggesting that Sutent could be very effective in about 2% of all lung cancer patients. What's that means to Pfizer?

US annual lung cancer incidences: ~225,000
Worldwide (rough): 675,000
Sutent-beneficial lung cancers: 13,500 (worldwide)
Sutent treatment cost (rough): $40,000 per patient
Sutent lung cancer "niche" market potential: $540,000,000.
Pfizer price/sales ratio: 2.43x
Implied increase in Pfizer's stock value from the new lung cancer "niche:" $1.3B or a stock price about $.17 higher.

Realistically, Pfizer & Sutent can't capture all of that market, but finding another half-a-billion dollar market - with the hope for more - has got to be exciting to Pfizer. It should also be exciting to other targeted drug makers and researchers.

Also exciting is the notion that Foundation's research results are the tip of the iceberg - we can expect tumor DNA sequencing research to reveal more mutations and drug gable opportunities. Let's just hope that the FDA becomes much more flexible in approving novel sequence-specific applications (or at least tolerating widespread off-label use).