So, I have noticed in the electronic press some quite critical, almost cynical, commentaries and blogs on ASCO, its content and the way it manages abstracts and press communication. These on-line blogs are great for creating discussion and controversy and airing views. However, I for one agree with the stance of some of the comments that it just isn't feasible for everything interesting, novel, and especially very early stage, with longer term potential, to attract coverage. In fact these topics often feature more prominently at conferences such as AACR, or the excellent joint meeting of the NCI-AACR-EORTC. Trawling the poster halls, and attending the poster discussion sessions at ASCO are still a great way to drill down into some of the less mainstream areas. In my first ASCO blog, I tried to include some examples of data that aren't necessarily headline grabbers and my colleagues who will be on the ground at ASCO will also be highlighting some other examples that pique their varied interests. However I do feel that a key role for ASCO is to focus on some of the more advanced data, for drugs that are on the cusp of impacting medical practice.
As for the criticisms that too much is made of small improvements in survival again I feel this is harsh. For clinicians treating terminally ill patients on a daily basis of course they feel motivated by even small moves in the right direction. Often we are led to focus on median effects, and what can be lost in the data for larger Phase III trials is the impact on the individuals while I appreciate that many patients derive little benefit from new treatments and all may suffer some side-effects, for every median improvement of 2 months there will be a proportion of patients who gain 9, 10 or more months of life. How important this additional time is for individual people. But of course, always, clinicians are having balancing the potential benefit with the burden of cost both side effects and financial. Plus, we all know we need markers to help predict which patients will most likely derive clinically relevant benefit from treatment, and this will also feed into needing smaller more focused trials and potentially, more rapid drug development.
And if we take more of a helicopter view, over time the few months of survival gain start to add to a few years progress is slow, yes, but it can also be additive. For the admittedly few drugs that make the move to the adjuvant setting we also witness an increase in disease free survival, potentially cures. Herceptin is a great example of this it has transformed the outcomes for many breast cancer patients. Similarly if we look back to the addition of oxaliplatin to 5-fluourouracil treatment post-surgery for colon cancer although many patients endure the toxicities for the few that benefit, our estimates suggest as many as 600 U.S. patients a year are transformed to a "cure" (alive an disease-free at 5 years) due to the impact of oxaliplatin treatment in this setting with obvious benefit for patients and their families. Clearly, we need more drugs to demonstrate activity in this setting and patient selection will be key to enable statistically significant improvement to be demonstrated on top of exiting outcomes.
So back to some ASCO data: the Phase I/II study of Binomics BNC105P a tubulin destabilizing agent that in pre-clinical studies appears to selectively target tumor vasculature - is being studied in combination with everolimus in metastatic renal cell carcinoma patients that have progressed on one or two lines of TKI therapy, a setting with a high need. The abstract describes a strong scientific rationale for the combination: upregulation of mTOR in hypoxic tumors that are refractory to VEGF- inhibitors, so combining a vascular targeted agent, which should induce hypoxia, with an mTOR inhibitor has the potential to improve outcomes. The interim data shows that some grade 3 toxicities were experienced but seven out of the twelve patients studied achieved stable disease. We know from our primary research that many oncologists treating renal cell carcinoma would like to see investment in drugs hitting novel targets, and they would also like head-to-head data to enable them to compare with the current standard of care and help guide optimal treatments and sequence. If advanced clinical trials of the BNC105P/everolimus combination show promise, it could perhaps start to address some of these needs.
PI-3 kinase is a target that is enjoying attention at the moment. Oncotheryon are developing PX-866, a pan-isoform, irreversible inhibitor of class 1 PI-3K, through a Phase I/II program of trials based on preclinical activity including additive activity when combined with docetaxel. Biomarker assessment of PI-3K, KRAS and PTEN are included in the trial which recruited 43 patients with a variety of solid tumors. Half of the evaluable patients experienced stable disease or better for at least six cycles of therapy and there was a trend for a longer time on treatment for patients with mutated PI-3KCA. The combination of PX-866 with taxanes could have wide-reaching application in solid tumors Phase II trials incorporating biomarker studies will take place.
Johnson and Johnsons Zytiga is enjoying enormous success since it's launch for docetaxel-treated, castrate resistant prostate cancer last year, although stiff competition in the shape of Medivation/ Astellas Pharma's enzalutamide (MDV3100) is imminent. Loss of PTEN, which results in activation of the PI-3K/AKT pathway, is a common feature of advanced castrate-resistant prostate cancer and is associated with poor prognosis, so combining the proven effects of Zytiga with a PI-3K inhibitor was the rationale behind Genentech's Phase I trial. The study is designed to explore two novel agents, GDC-0068 (a selective ATP-competitive inhibitor of AKT1, 2, and 3) and GDC-0980 is (a pan-inhibitor of Class I PI3K including wild-type and mutated p110 isoforms, and mTOR) kinase in one trial. Multiple endpoints will be assessed; progression-free survival being the primary end point, but other efficacy measures including PSA levels and pharmacokinetics and biomarker assessment and monitoring of circulating tumor cells are included. Thus ensuring the maximum amount of data is gathered from patients, which will help inform the future development strategy for one or both of these drugs.
ImmunoCellular Therapeutics will be presenting an update from their two year data for efficacy outcomes from their small Phase I trial in patients with newly diagnosed glioblastoma multiforme . At four years 50% of the 16 patients on the study remain alive and 38% of these are disease-free at 48-66 months; three patients beyond 5 years. The assessment of the cancer stem cell population trial, measured by CD-133, has shown a decline. One U.S. glioblastoma key opinion leader interviewed by Decision Resources highlights the importance of an agent that acts on stem cells; I think the biggest need is simply treatments that succeed in killing tumor cells. It's possible that a treatment that focuses on glioma stem cells could emerge as an important player. And some think that if we had a treatment that works against only stem cells, it could be highly effective. The Phase II trial is a long way through enrollment and interestingly, a sub-analysis is planned between patients with HLA-A1/A2 immunological subtypes.
Look out for more Decision Resources blogging direct from ASCO over the next few days.