Pazdur’s smiling face was accompanied by the announcement that, on March 4th, the FDA had rapidly approved Bristol Myers Squib's drug, Opdivo (nivolumab), citing “a dramatic increase in survival in second-line squamous non-small cell lung cancer.”
“The Cancer Letter” characterized the approval as activism by the FDA, saying that it was an example of the “extraordinary activist stance” the FDA can take when it sees an advantage in overall survival. They went so far as to say that the FDA, had “sprung into action” when they received the clinical trial data, moving toward approval before the results of the study were even clear to the sponsoring drug company.
It would have been amusing if it wasn’t so sad.
PD-I inhibitors are a new breed of therapy that inhibit cancer cells’ ability to evade its host’s immune system. Every lung cancer specialist in the country has known that PD-1 inhibitors such as Opdivo are the most important advance in the treatment of advanced non-small cell lung cancer to come along in 40 years. For the last two years, in fact, most oncologists have been seeing data on the effectiveness of these drugs presented at national meetings and widely discussed among investigators.
Some might say defend the FDA by saying that the food and drug laws require that the FDA determine that a new drug is both safe and effective before it is approved for general use. True, in a general sense. But in this case, we know that the two PD-1 inhibitors now in advanced clinical testing, Opdivo (nivolumab) and Keytruda (pembrolizumab) are safe. In fact, the FDA said so itself when they approved both drugs for patients with advanced melanoma. (Though, as usual, they tied doctors’ hands—allowing them to be used only in patients who had failed other therapies and listing all the prior treatments the patients had to have failed before their doctors were allowed to use them).
What are the odds that these drugs, which were deemed safe enough for some patients with advanced cancer, would have proven to be unsafe in patients with advanced lung cancer? The answer: between slim and none. In fact, the data show that they are even effective in patients with poor performance status, i.e. patients who are frail and bedridden, making them ideal for older and unstable lung cancer patients, especially those who have smoked.
But the real irony of the FDA seeing themselves as activists is the failure to approve the drugs for all subtypes of all non-small cell lung cancer, given that the data show them to be universally effective. Only 25% of advanced lung cancer patients have the squamous cell subtype for which the FDA has approved Opdivo. That means the majority of patients are excluded from this advance.
All lung cancer specialists already know the PD-1 inhibitors are far better than any existing drug doublet in use today. If they were approved for all lung cancers today the use of the myriad of doublets of far more toxic drugs would disappear overnight. In the meantime, many patients who might benefit from these drugs are getting old hat treatment. But when the family members and friends of physicians are diagnosed with lung cancer, these physicians find a way to get the new drugs to them using any loophole possible.
The FDA will eventually approve both drugs for all subtypes of advanced lung cancer and even as a first line treatment. They will have no choice. But they will do it in their own good time. Meanwhile, thousands of patients with lung cancer will die without the chance of getting access to these drugs to extend their useful lives. If the FDA really wants to be considered an activist, they should approve these drugs for all lung cancer patients now.
-Vincent T. DeVita, MD