The past couple of days have seen a flurry of activity in the mainstream media, on Twitter and in the blogosphere about what many are hailing as a new breakthrough in the treatment of breast cancer. Frankly, I’m not so sure….
Every year the American Society of Clinical Oncology (ASCO) hosts a giant meeting that attracts perhaps 30-40,000 clinical oncologists and others interested in clinical cancer research from around the globe. It is one of the most important scientific meetings of the year if you are interested in cancer. And every year, from among the thousand of posters and other presentations, all of them of merit, rise a few that capture not only the scientists’ and clinicians’ attention, but that of the mainstream media which translates of course into tremendous interest to patients, families and those living with, or at risk of cancer.
This year, one of those stories that seems to have gained a lot of attention is the one that was presented on Sunday at the ASCO Annual Meeting gin Chicago. It details the use of two “old” drugs in a novel combination. The drugs, Herceptin (Trastuzumab) which is a targeted antibody and emtansine, which is a chemotherapy drug have been linked together in a novel way so as to get the best of both worlds. The combo, called T-DM1, has been likened to a “smart bomb”, a “heat-seeking missile” an “armed antibody” and no doubt lots of other militaristic terms.
Without perpetuating the military analogies, the promise of this type of approach is that one component of the new drug is the targeting mechanism and the other part of the drug is the killing mechanism. Whereas Herceptin binds to and block signals from the so-called HER2 receptors and thereby controls HER2+ breast cancer cell growth, the addition of the emtansine portion actually now kills the cancer cells that the Herceptin has channeled right to the target cell. This one-two punch is no doubt a more powerful approach that just Herceptin alone, and avoids a lot of the unacceptable side effects of the chemo drug since it is only delivering this toxin to the cancer cells and not all of the innocent bystanders – the reason for such terrible and toxic side effects of chemo.
And at ASCO, the makers of T-DM1, Roche/Genentech indeed released preliminary data from a Phase III clinical trial that showed that this new and more powerful drug combo was effective. The headline of the press release (click here for the full PR) reads: “Genentech’s Targeted Investigational Breast Cancer Medicine, Trastuzumab Emtansine (T-DM1), Reduced the Risk of Cancer Worsening or Death by 35 Percent in Pivotal Phase III Trial”.
So how new is this type of approach? If you read a lot of the headlines you would guess that no one ever thought of this before and that this brilliant insight to combine a targeting molecule and a killing molecule was the path to the Holy Grail of cancer treatments. Now I do not in any way, shape or form wish to trivialize the delicate molecular engineering that has to be done to make this kind of approach work – indeed my hat is truly off to the researchers for being able to construct this hybrid molecule and make it work.
But the idea is decades old.
The idea of developing and using immunotoxins, for example, has been around since at least the 1980’s. Immunotoxins are proteins that contain a toxin (analogous to the emtansine of T-DM1) along with an antibody or growth factor (analogous to the Herceptin of T-DM1) that binds specifically to target cells. Toxins that have been tried in the past include things like diptheria toxin and ricin (a powerful plant toxin from castor beans). Finding toxins was never the problem – delivering them to the target cell, and ONLY the target cell, and making sure they didn’t do any damage along the way until the got to the target cell was always the problem.
As far back as 1998, in a review article entitled “Drug targeting systems for cancer chemotherapy” in Expert Opinion on Investigational Drugs” M.S. Sachdeva wrote
Tumour specific drug targeting has been a very actively investigated area for over 2 decades. Various approaches have involved the use of drug delivery systems that can localise the anticancer agent at the tumour site without damaging the normal cells.
For this purpose, various delivery systems that have been utilised are liposomes, microspheres and recently, nanoparticles. Two liposome formulations containing anticancer drugs for example, adriamycin and daunomycin are already on the market in the USA and Europe. Microspheres are also being investigated for delivering various anticancer drugs and protein/peptides for anticancer treatment, and several formulations are in Phase I/II clinical trials. Antitumour drugs have also been linked to tumour specific monoclonal antibodies via various chemical linkages. …
What he wrote next is both a testament to how long these ideas have been around, but also how hard it is to make an immunotoxin molecule (e.g. like T-DM1) really work in the the clinic:
Another approach with monoclonal antibodies has been the use of immunotoxins. Immunotoxins initially showed promise as potential anticancer agents at pico-molar concentrations but several clinical and preclinical studies have not shown much promise in this regard. … New therapeutic approaches are presently emerging based on natural products like cytokines, peptide growth factor antagonists, antisense oligonucleotides and specific genes. These approaches need the help of delivery systems to deliver these complex molecules to tumour cells.
More recently antibodies are being linked to heat sensitive dyes – the idea is that the antibody delivers the dye, and then heat can be applied and the cell dies. A variant of this is using iron oxide particles linked to antibodies – use infrared light waves then to heat up the magnetic particles and kill cancer cells.
The point of all of this is that the idea of linking an antibody like Herceptin to a chemo drug or other toxin-like molecule and delivering a targeted punch to a cancer cell is a very old idea. Nothing revolutionary about this at all.
But making a combo molecule that actually survives in the body and delivers the payload only to the cancer cell and then having it actually work at that point to kill the cancer cell is indeed a real accomplishment. To me, THIS is where the main interest should have been in the story.
Why am I less enthused about the actual results of the trial for women with breast cancer?
The trial involved almost 1000 women with already pretty advanced breast cancer. The patients were either given the new T-DM1 combo drug or a combination of two other individual drugs that are usually used as the standard of current care for patients like these – Tykerb (lapatinib) pills plus Xeloda (capecitabine).
So, what was the big breakthrough result? According to Genentech’s PR: “There was a significant improvement in the time people receiving trastuzumab emtansine (n=495) lived without their disease getting worse compared to those who received lapatinib plus Xeloda (n=496), as assessed by independent review: median PFS was 9.6 months compared to 6.4 months, respectively.”
In other words, the average (median) time until cancer got worse was just over 9 and a half months in the women given T-DM1 versus almost 6 and a half months for the others. And keep in mind, this three month average is the time that patients lived BEFORE GETTING WORSE.
This “end-point” of so-called “progression-free survival” or PFS is commonly used in cancer drug trials but is under a lot of criticism in many circles since it does not really tell us anything about the really important endpoint – OVERALL SURVIVAL. Many have called into question the benefit of measuring how much longer it takes for someone to get worse, if in the end death from the disease is not pushed back or staved off.
To be fair, the T-DM1 regimen also seems to have caused far fewer side effects than the more usual combo of drugs did. This is not trivial at all – according to the study authors most patients did not lose hair, or need nausea meds and so on. That alone may be a good enough reason for changing the standard of care from the current to the new regimen.
But so far, the study cannot and does not tell us if women on T-DM1 will actually outlive their counterparts on the current regimens. Again, to be fair, Progression-free survival can and has served as a proxy for overall survival, so while the results are tantalizing that there will be a benefit on overall survival, that is not at all certain yet and needs much longer follow up.
But even at that, as Liz Szabo of USA Today correctly pointed out in her well-balanced article “The experimental drug, T-DM1, doesn’t cure anyone.”
Another very well balanced article that you should note is from Dr. Elaine Schattner in her blog “Medical Lessons”. To my mind, this is the type of reporting we need to see more of – balanced, fair and stripping away the hype.
In summary, when confronted by “breakthroughs” it is easy to get caught up in the excitement, or the hype. The results from T-DM1 are indeed worth noting, if only for the fact that the molecular engineers actually got the molecule to work. No small feat. By Genentech’s own account, they have some 2 dozen more combi-drugs in development. No doubt, so do many other researchers and companies. This is indeed a fruitful line of investigation, but let’s not get carried away with preliminary results on a disease like breast cancer where big blockbusters are almost impossible to come by.
Why do I say that? Well, the good news for breast cancer patients is that current day survival rates are actually very high – by most accounts a woman diagnosed with breast cancer today at ANY stage (average) has about an 87% overall probability of surviving that disease. Caught at Stage 1, that survival rate jumps to perhaps as much as 97%. Admittedly the women in the T-DM1 study with advanced and aggressive disease are at the wrong end of those statistics – they have aggressive and spreading disease – and so anything we can do for them is worthy of our every effort. But when overall survival stats are so high to begin with, it is almost impossible to come up with any new drug or other therapeutic that is going to make an overwhelming difference.
We are doomed by our successes of the past to, at best, small incremental gains, at least for breast cancer. That’s the good news and the bad news…