Ed Silverman, writing in the Boston Globe October 19th, pointed to lung cancer drug Iressa as a “cautionary tale” against using “surrogate endpoints” – signs that point to, but don’t guarantee, a given clinical outcome – for FDA drug approvals. He suggests that the 21st Century Cures Act, which encourages the FDA to expand use of such tools during drug approvals, is wrongheaded — a view echoed by prominent voices in The New York Times and the New England Journal of Medicine. But the example he used – centered on lung-cancer drug Iressa – proves just the opposite, giving us a textbook case of why surrogate endpoints are a critical tool for advancing new therapies to patients that demonstrate early promise.

Silverman worries about how many patients might have been treated with an ineffective drug. The equally important question is how many effective drugs are not approved because they are tested on the wrong population.

Left unmentioned by Silverman was the fact that Iressa recently returned to market in the U.S., with a full FDA approval granted last July – and that Iressa had been marketed for years outside the U.S., in 90 other countries as of 2014. How the FDA rejected and later accepted Iressa vividly illustrates the need for the 21st Century Cures legislation.

In Silverman’s telling of Iressa’s history, the FDA gave patients false hope, approving an expensive, ineffective drug, which manufacturer AstraZeneca (AZ) would later have to pull from the market. But the Iressa story, when fully told, actually demonstrates how surrogate measures can streamline the drug approval process and accelerate the delivery of life-saving treatments.

Iressa was effectively withdrawn in the U.S. in 2005, but it remained on the market in Europe and Asia, where most of the critical research showing its effectiveness took place. In the United States, Iressa had initially received accelerated approval based on its ability to significantly shrink tumors – a surrogate endpoint – in a number of patients. In the confirmatory follow-up trial AZ completed in 2004 (conducted in accordance with standard FDA trial protocols required as a condition of receiving accelerated approval), Iressa-treated patients on average, however, did not fare any better than those who received the standard of care. The FDA responded by limiting access to Iressa to the patients it was already benefiting.

Was the original surrogate endpoint study a fluke and the accelerated approval a mistake? Or was something else happening? In 2004, we just didn’t know why some patients responded so well to Iressa, while others did not.

In a National Research Council Report from 2011, “Towards Precision Medicine,” the authors explained the problem:

"In 2004 two drugs were in development, Gefitinib [a.k.a. Iressa] and Erlotinib, which inhibited the function of certain receptor tyrosine kinases, including epidermal growth factor receptor (EGFR). These receptors were known to send signals that promote cellular proliferation and survival, and increased signaling was thought to contribute to some cancers. In early trials, the drugs were shown to produce dramatic anti-tumor effects in about 10 percent of patients with non-small-cell lung cancer (MSKCC 2005). Other patients did not appear to respond at all. However, the dramatic tumor shrinkage in some patients was enough for Food and Drug Administration approval in 2003, even though the molecular basis for the response was then unknown.

In retrospect, some clinical trials with these agents probably failed because the actual responders represented too small a proportion of the patients in the trials (Pao and Miller 2005). Subsequently, it was discovered that the responding patients carried mutations that activated EGFR in their cancers (Kris et al.2003, Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). This made it possible to predict which patients would respond to the therapy and to administer the therapy only to this subset of patients. This led to the design of much more effective clinical trials as well as reduced treatment costs and increased treatment effectiveness. [Emphasis added]"

In short: Iressa worked, but it appeared ineffective because we didn’t include enough patients with the correct mutation in the trials.

In short: Iressa worked, but it appeared ineffective because we didn’t include enough patients with the correct mutation in the trials. It was only years later that AZ was able to identify the biomarker (an EGFR mutation) for response to Iressa; years after that, the benefit was finally established in confirmatory trials.

But at least the outlines of this challenge were known much earlier. My colleague Peter Huber, in his book The Cure in the Code, noted:

"…Bruce Johnson, a researcher at Boston’s Dana-Farber Cancer Institute and one of the doctors involved in the original Iressa trials, remarked in 2005, “For us as investigators, at this point, there are at least 20 different mutations in the EGF receptors in human lung cancers, and we don’t know if the same drug works as well for every mutation…which is why we want as many EGFR inhibitor drugs available as possible for testing."

It wasn’t Iressa but rather the FDA’s traditional randomized controlled clinical trial (RCT) paradigm that had failed. Moving beyond the RCT paradigm is one of the central focuses of the National Cancer Institute’s Exceptional Responders Initiative: “a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.”

The science of biomarker development has advanced a great deal since 2004... Whole genome sequencing is increasingly becoming a routine tool in cancer treatment.

Silverman worries about how many patients might have been treated with an ineffective drug. The equally important question is how many effective drugs are not approved because they are tested on the wrong population. Ed Levitt, a terminal lung cancer survivor and exceptional responder to Iressa, remains active and keeps his cancer in check thanks to the drug. In an interview we conducted with Ed in 2013, he asked why people weren’t eager to understand why he is still alive when many other lung cancer patients aren’t. Thanks to biomarker research – studies exploring our biological makeups and how different patients respond to different drugs – we now know why Iressa saved Ed’s life.

The science of biomarker development has advanced a great deal since 2004. New trial designs developed by the National Cancer Institute, such as MATCH and TAPUR, are tackling the problem of population selection head on, matching patients with the molecularly-targeted drugs to which they will most likely respond, regardless of their tumor’s original organ type. TAPUR specifically looks at off-label uses of targeted cancer treatments, with companies donating the drugs in order to expand to new label indications. Whole genome sequencing is increasingly becoming a routine tool in cancer treatment.

It’s true that AZ pulled Iressa off the market in 2012, but only so it could reintroduce the drug specifically for the patients exhibiting the biomarker suggesting Iressa would be effective. Iressa returned to the U.S. market in July 2015, with full FDA approval, “for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by an FDA-approved test.” (Iressa is designed to treat the most common types of EGFR mutations, but there are other rare variants.)

The bottom line... is that the FDA and drug manufacturers need more tools, not fewer, with which to evaluate new drug candidates and get them to targeted populations more quickly.

Also in 2015, the FDA’s oncology staff published research demonstrating that tumor shrinkage (“overall response rate”), the surrogate endpoint used for accelerated approval, correlates with progression-free survival, or a disease being kept in check longer – most strikingly for molecularly targeted therapies. (The endpoint was not, however, strongly correlated with overall survival – perhaps because the benefits of new targeted therapies are so impressive that most patients switch over to the treatment arm of the trial before it is completed, making it impossible to measure overall survival against the standard of care. Arguably, faced with a significant response rate, it may be unethical to even randomize a trial in a targeted patient population to begin with.) The authors noted that:

"When studying a rare subset of patients, even in a common malignancy such as [non-small cell lung cancer], it may be difficult to screen patients and power a study for the gold standard end point of overall survival. This may be particularly challenging if a high ORR is observed early in clinical development, where allocation of patients to a toxic and marginally effective control may violate the principal of clinical equipoise. In the case of a targeted therapy with a large treatment effect, intermediate endpoints such as ORR and PFS may be indicated to characterize the benefit-risk profile and establish safety and efficacy."

Challenges still abound. Almost all tumors will eventually develop resistance to molecularly targeted therapies, as the tumors mutate around the drug’s line of attack. Even among the newer and most promising lines of immuno-oncology treatments, many patients fail to benefit, but those that do seem to achieve dramatic and durable responses. For all the progress we’ve made in understanding cancer biology, there’s still much more to learn.

The bottom line, as the case of Iressa demonstrates, is that the FDA and drug manufacturers need more tools, not fewer, with which to evaluate new drug candidates and get them to targeted populations more quickly.

This is exactly what the 21st Century Cures Act is designed to do.

The advent of new tools, such as whole genome sequencing, should allow us to learn as we go, improving physicians’ ability to get patients the medicines they need, and amplifying the role that surrogate endpoints and biomarkers play both in drug development and the clinic.