The notoriously difficult-to-treat tumours causing non-small cell lung cancer (NSCLC) appear to have claimed another promising pipeline candidate. The failure of Regeneron Pharmaceuticals (REGN) and Sanofi-Aventis’ (SNY) aflibercept (VEGF Trap) to improve overall survival compared to Taxotere is just the latest setback to a field which will need all the shots on goal it can muster ("Therapeutic focus - Shots on goal could be the key for lung cancer," February 10, 2010).
Luckily for Regeneron, investors are currently distracted by the excitement surrounding development of the same drug as a treatment for multiple eye disorders. Shares in the New York biotech reached a 10-year high last week of $39.84, valuing the company at an impressive $3.6bn; since then the stock has slipped just 3% to $38.47 in early trade today. Nevertheless, both companies will want to avoid further setbacks to the product’s development in cancer, with little to show so far from heavy investment.
Latest lung cancer setback
Since EP Vantage’s review a year ago into pipeline prospects for lung cancer, the news has not been good.
Just about the only positive outcome was progression-free survival (PFS) data for Abraxane and even that did not reach statistical significance – the drug’s new owners Celgene are nevertheless pressing ahead with regulatory submissions for the treatment of advanced NSCLC.
In light of Celgene’s (CELG) decision to press ahead with less than ideal PFS data, it is interesting to note that aflibercept did significantly improve PFS, as well as an objective response rate, both secondary endpoints of the Vital trial which enrolled 913 patients who had failed one platinum-based therapy.
However, there was little sense from the jointly issued press release for any desire to press ahead with developing the product for NSCLC. The fact that aflibercept caused significantly more adverse events and treatment discontinuations than the control arm of Taxotere and placebo probably didn’t help either.
While the companies claimed the adverse event profile was similar to that seen in previous studies with anti-VEGF agents, Avastin being the biggest graduate from this class of drug, it’s becoming clear that aflibercept will not hold any safety advantage over the incumbents.
Significant survival advantages over current standard of care are therefore an absolute must, the problem is that aflibercept has so far struggled to demonstrate it is capable of doing so.
Failure of the Phase III Vital trial follows a late-stage setback for the product in treating pancreatic cancer – the so-called Vanilla Phase III trial was stopped in 2009 after an interim analysis indicated aflibercept would not improve overall survival, when compared to gemcitabine and placebo.
As such, the importance of generating positive data from the remaining late stage trials has increased.
By the middle of the year the companies should report final data from the Velour Phase III, as a second-line treatment for metastatic colon cancer, and interim analysis from the Venice trial as a first-line therapy for hormone-refractory metastatic prostate cancer. In addition, a Phase II trial, Affirm, as a first-line option for metastatic colon cancer, should report during the second half of the year.
Results from these trials will go a long way to determining aflibercept’s future as a cancer therapy and whether Sanofi in particular will see any return on what must be significant investment so far.
Clinicaltrials.gov lists no fewer than 42 trials ongoing or completed with the product, involving almost 6,400 patients. By any measure that kind of commitment must add up to a significant investment.
Originally licensed to Aventis in 2003, Sanofi took over the reigns in 2004 and under terms of the original deal Sanofi is funding global development of the drug. Only if "the collaboration becomes profitable," according to Regeneron, will the biotech have to reimburse Sanofi for 50% of development costs - a scenario that seems possible only if aflibercept reaches the market.
This could therefore explain why Sanofi’s shares appear worse affected by this latest setback in cancer, down 5% since the news broke, compared to the apparent ease with which Regeneron’s shareholders have dealt with it.
It helps of course if the drug is showing significant potential in other settings, such as macular degeneration and macular oedema ("Regeneron ends year on a high note," December 20, 2010).