One of the current challenges with developing new targeted agents in oncology is the tendency to rush various agents, whether monoclonal antibodies (mAB) or tyrosine kinase inhibitors (TKIs) into the clinic before we know how they might best work or in what potential combinations based on the precise underlying biology.
Another challenge I see is old school chemotherapy approaches permeating new development thinking. By this, I mean the traditional concept of testing therapies in advanced, metastatic and highly refractory disease where the tumour burden is high and the chances of getting a decent response is low.
This is one reason I love the I-SPY neoadjuvant concept in breast cancer. Testing a range of compounds prior to surgery based on the potential drivers of the cancer will let us know very early which agents are working or not and which could potentially be selected for subsequent adjuvant treatment after surgery.
Recently, I reading a couple of papers (see references below) on phase I and II trials with a MEK inhibitor (PD-0325901), but it was a little bit with a sinking feeling because the trial design was rather old fashioned and traditional, ie take a bunch of solid tumours in phase I, see what (mixed) signals you get:
"PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped."
Where RVO was retinal vein occlusion.
Next, do a phase II in a big (ie large potential patient numbers), advanced, metastatic and highly refractory cancer. Predictably, the results were unsurprising:
"PD-0325901 did not meet its primary efficacy end point."
If we looked at those results in isolation, we might be tempted to dismiss the idea that the MEK inhibitor doesn't work and abandon it.
A different way of thinking
That said, I was much more encouraged by another article from another group that looked at the problem completely differently with exactly the same MEK agent. If you think about it, a focused sniper rifle strategy is often going to be more effective than a bludgeoning blunderbuss.
They looked at the basic evidence that:
"Mutational activation of PIK3CA, which commonly co-occurs with KRAS mutation, provides resistance to MEK inhibition through reactivation of AKT signaling"
And then set out to look at this relationship more clearly in animal models:
"to determine the MEK dependence of tumors with mutational activation of the pathway. These studies indicate that many KRAS mutant tumor cell lines are, contrary to the prevailing view, sensitive to the MEK inhibitor PD0325901, and hence, dependent on the RAF/MEK/ERK signaling arm.
Resistance to MEK inhibitors in the relevant cell lines is not an intrinsic feature of KRAS oncogenic function but instead mutational activation of PIK3CA is present in most, but not all, MEK resistant KRAS mutant cancers."
It's hard to argue with that logical approach.
The article is well worth reading and nicely put together, but here are the main findings of the research:
- A subset of KRAS mutant cells depends on MEK/ERK signaling
- Coexistent KRAS and PIK3CA mutations prevent cyclin D degradation and sensitivity to MEK inhibition
- Selective knockout of mutant PIK3CA allele confers MEK/ERK dependence
- Sustained cyclin D expression and bypass of MEK inhibitor–induced G1 arrest correlates with MEK antagonist efficacy
- Combined inhibition of both MEK/ERK and PI3K/AKT pathways suppresses the growth of tumors with coexisting KRAS and PIK3CA mutations
Implications for the future
The thoughtful approach behind Halilovic et al's data is particularly interesting:
"Mutational activation of KRAS is a common event in human tumors. Identification of the key signaling pathways downstream of mutant KRAS is essential for our understanding of how to pharmacologically target these cancers in patients.
We show that PD0325901, a small-molecule MEK inhibitor, decreases MEK/ERK pathway signaling and destabilizes cyclin D1, resulting in significant anticancer activity in a subset of KRAS mutant tumors in vitro and in vivo."
KRAS mutant tumours are particularly relevant to colorectal cancer. Recently, we have seen that patients with colorectal cancer who have wild type, but not mutant, KRAS are more much more likely to respond to treatment with EGFR therapy ie Erbitux and Vectibix, allowing for careful patient selection and exposure.
What about melanoma where mutant RAS may stop the activity of RAS inhibitor such as PLX4032? Could adding a MEK inhibitor help overcome the problem in some cases, or perhaps that would be too simple? We don't know, but I'd love to see some research data in appropriate xenograft models in this area.
The problem is that there is currently no therapeutic agent that directly inhibits KRAS function, so the Halilovi data have very important implications for tumours driven by mutant RAS.
What the new data tells us:
"These data suggest that tumors with both KRAS and phosphoinositide 3-kinase mutations are unlikely to respond to the inhibition of the MEK pathway alone but will require effective inhibition of both MEK and phosphoinositide 3-kinase/AKT pathway signaling."
Bingo! Now that's a much more elegant approach to defining which patient populations are most likely to respond based on preclinical research before attempting clinical trials and randomly exposing patients who had no hope of responding to the systemic side effects of a treatment.
Personally, I would dearly love to see more clinical trial selection based on logical, well researched preclinical data rather than a scattergun let's hope and see approach.
We need to get smarter and faster at well designed research that points us in the right direction to increase the chances of better success and improved outcomes. It will also conserve precious R&D dollars and focus it where it's needed most.
Halilovic, E., She, Q., Ye, Q., Pagliarini, R., Sellers, W., Solit, D., & Rosen, N. (2010). PIK3CA Mutation Uncouples Tumor Growth and Cyclin D1 Regulation from MEK/ERK and Mutant KRAS Signaling Cancer Research, 70 (17), 6804-6814 DOI: 10.1158/0008-5472.CAN-10-0409
Haura, E., Ricart, A., Larson, T., Stella, P., Bazhenova, L., Miller, V., Cohen, R., Eisenberg, P., Selaru, P., Wilner, K., & Gadgeel, S. (2010). A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer Clinical Cancer Research, 16 (8), 2450-2457 DOI: 10.1158/1078-0432.CCR-09-1920
LoRusso, P., Krishnamurthi, S., Rinehart, J., Nabell, L., Malburg, L., Chapman, P., DePrimo, S., Bentivegna, S., Wilner, K., Tan, W., & Ricart, A. (2010). Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK Kinase Inhibitor PD-0325901 in Patients with Advanced Cancers Clinical Cancer Research, 16 (6), 1924-1937 DOI: 10.1158/1078-0432.CCR-09-1883