Pharma Strategy Blog

The other day I highighted the phase II data from the T-DM1 (trastuzumab emtansine) trial as one of my top four abstracts at the ECCO European Multidisciplinary Cancer Conference (#emcc2011) in Stockholm.

For those of you interested in ADC technology, I wrote about the fascinating concept previously, if you want to check it out.

I think T-DM1 is a really exciting development for several reasons, so let’s take a look at the study in more detail.

1. T-DM1 is an antibody drug conjugate (ADC), which combines the trastuzumab monoclonal antibody with a cytotoxic agent, maytansine, via a linker. This new molecule is stable and allows the structure to hold together until it reaches the cancer cells, wherein the chemotherapy is released in a much more targeted fashion than giving chemotherapy and Herceptin as separate drugs by infusion. With the traditional approach, it means that the chemotherapy will target normal cells as well as cancer cells, leading to significant side effects, including cardiotoxicity.
2. ADC technology is designed to allow the combination to be delievered more specifically to the tumour, while also potentially reducing the side effects for patients.
3. In this study (TDM4450g), T-DM1 was compared with the standard of care, trastuzumab (Herceptin) plus docetaxel in women with HER2+ metastatic breast cancer who had been previously untreated ie first-line therapy.
4. It should be noted that maytansine is a very powerful cytotoxic that was originally seen as too toxic when given by traditional infusion. Combining it as an ADC therapy, however, reduces some of the associated adverse events since it can now given in a more localised fashion where it is most needed, ie in the tumour itself.

One of the challenges with the T-DM1 trial, though, as Martine Piccard, the Discussant correctly pointed out, is the open label design. One must be careful in interpreting data from them, as Kaufman et al., (2007) observed:

“Placebo controlled, double-blind trials can reduce bias when efficacy is studied. Open label designs can falsely suggest efficacy and fail to uncover harmful effects. Placebo controlled trials are considered ethical when there is no standard treatment better than placebo, and when participants are informed about the use of a placebo.”¹

Unless a trial is blinded, we can never completely be sure the patients weren’t selected to either arm without bias, even if unconscious. Now, I’m not saying that was the case here, merely that one must be aware of both the limits and potential possibilities.

That said, my least favourite studies are open label single arm trials, but that wasn’t the case here, since half the women were randomised to receive the standard of care, ie trastuzumab plus docetaxel, making it a good comparison to see if any improvement can be attained. However, a double blind placebo controlled (in place of docetaxel) randomized trial is always a more reassuring design than an open label one.

That said, unlike pills, it is much harder to give chemotherapy blinded because the dosing is calculated as per kilogram of body weight, a dead giveaway. Thus, T-DM1 is given as 3.6 mg/kg, while the trastuzumab dose is given per 6 mg/kg, whereas docetaxel (75 or 100 mg/m2) versus placebo can clearly be be more easily blinded.

We must also remember that this is an exploratory phase II trial designed to see whether there is an efficacy signal or not. The study endpoint was PFS. Phase III trial designs are often much more robust.

What do the results show?

The proof of the pudding is ultimately in the analysis, not the theory, though.

The good news is that Dr Sara Hurvitz (UCLA) presented data that was actually much better than I expected, which is very heartening to see. Usually, in metastatic disease, where there is a very high disease burden, we sadly see increments of ~2 months or less in many investigational agents, so anything more than that is a real standout.

In the TDM4450g trial, the efficacy and tolerability results were impressive:

1. Patients lived a median of five months longer without their disease worsening ie the median progression free survival (PFS) was 14.2 months vs. 9.2 months (HR=0.59, P=0.035) in favour of T-DM1 over the standard of care.
2. Note: any HR under 0.60 is scarily good news – that means a huge 41% reduction in the risk of the disease worsening or death was seen.
3. Overall survival had not yet been reached at the time of the presentation in the T-DM1 arm, another good sign that the data are likely to be durable.
4. Women in the T-DM1 arm generally experienced fewer adverse events compared to those who received Herceptin plus chemotherapy: the rate of Grade 3 or higher adverse events was reduced by nearly half (46.4% vs. 89.4%).
5. In addition, more women on Herceptin plus docetaxel discontinued therapy due to side effects compared to T-DM1 (28.8% v. 7.2%).

Here’s a snapshot of the PFS curves – you can decide for yourself what you think:

So far, so good.

However, in the interests of fair balance, there were some side effects that appeared more in the T-DM1 arm, namely:

• Thrombocytopenia (30.4% v. 6.1%)
• Increased liver enzymes such as aspartate transaminase (AST) (39.1% v. 6.1%)

The most significant adverse event for me though, was cardiotoxicity, which is a well known side effect of standard Herceptin plus docetaxel therapy. Here’s how that data looked at the time of the analysis:

As you can see, it was less in the T-DM1 arm than the standard of care, which is most encouraging.

Patient sentiments are important

I did a quick search to see what patients in the trial were saying and came across these two heartfelt posts I encourage you all to read – it will put your day into perspective. Participating in clinical trials is not a bed of roses by any stretch of the imagination and I salute these brave women in their fight:

• T-DM1 drama
• Patients having to travel nearly 1000 miles for T-DM1

In conclusion…

These data from the phase II T-DM1 versus trastuzumab plus docetaxel study are an excellent start, with promising efficacy and safety signals in favour of the ADC over standard of care.

The big unanswered questions are whether the overall survival (OS) will also be better (I really hope so) and whether the data is reproducible in a large scale phase III trial (ditto). We will have to wait a while to see the more extensive phase III trial results.