Stephen Gately, PhD

	Drugmakers have a hard time letting go of a drug in development, even when all signs indicate they should. If early evidence shows that a compound fails to meet target criteria, or if it shows a lackluster performance when tested in models predictive of clinical success, development should stop. Then the focus, as well as those valuable resources, should shift to other drug candidates with greater potential for success.

: Cancer trials have a dismally low success rate, they said, because the industry has trouble moving promising preclinical research into clinical wins. A few years later, they coined a term for it: the 

	The numbers stunned-more than half of researchers couldn’t replicate their own findings, according to the journal’s survey of more than 1,500 scientists.

	Why do so many drugs get past the preclinical floodgates, only to fail? Maybe sponsors are desperate to keep searching for any positive signal for their drug. Perhaps they face investor pressure to keep going, or they might not have a backup plan.

	It’s likely a combination of all these variables-but the most crucial mistake is not having a clinical strategy at the get-go. A smart, defined clinical strategy sets objective expectations at the beginning of a drug’s development for when and on what criteria development will be terminated. This forces drug developers to ask, “Why are we creating this drug in the first place?”

	If you lack a specific answer, you have more work to do. Great drug development is born from a thorough understanding of the best available science-that is what strengthens every go-to-market plan. You need to know the best target(s) for the drug, and the related rationale for its development. Only when you marry the two will you fully understand the development opportunity.

	Strategic sponsors-the ones who see the most success at clinical endpoints-typically have one thing in common: They identify the clinical mechanisms that give their drugs purpose and search for a sensitive patient population to go with them.

	A successful example using this approach is Loxo Oncology. The company establishes the clinical strategy in preclinical testing, and then test its drugs rigorously in the patients for whom it expects to be highly sensitive to the drug-no matter how rare the indication.

	This is the model of “drug-to-patient” matching that works. The medicine has a purpose, and the sponsor holds true to it all the way from its genesis to its approval.

	So how do we influence the industry to be more strategic from the start? It will take an intentional and widely adopted pivot in perspective, driven by these three research ideals:

There’s a difference between obstinacy and persistence. 

How can you know when it’s worth holding on and when it’s best to let go? You follow the clinical strategy. When there are clear indications that the drug has missed its intended purpose, overcome the temptation to become obstinate, and move on to the next project.

	But be persistent if there is evidence that you should. There’s a difference in routine challenges you can overcome and impassable roadblocks you can’t.

Phase I trials aren’t just about safety. 

If you’re not thinking about the patient from the very start clinically, you’re not doing your drug justice. Think beyond safety to efficacy-do you see any activity that would, in the future, tangibly benefit patients? If not, the project likely has little runway for success, safe as it may be.

Failure doesn’t mean losing funding. It doesn’t mean not getting published. Failure means that you are not bringing a promising drug forward. Certainly, revenue and reputation matter. But, at the end of the day, do what is best for the patient.

	When it comes down to it, it’s a question of quality, not quantity. We don’t need 

	Clinical strategy gives us the foresight to know the difference.

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Patients stand to lose the most when sponsors hold too tightly to drugs doomed to fail. This wastes precious time that patients don’t have and squanders valuable resources.

When is it Time to Kill Your Drug? Maybe Sooner Than You Think

	In the earliest days of science, researchers thought that if you had cancer, you just had cancer. Then, as classifications evolved, they thought if you 

had lung cancer, you just had lung cancer. But now, advanced molecular profiling has necessitated a more complex analysis: You not only have lung cancer, you have EGFR mutated, KRAS mutated, or ALK gene rearrangement non-small cell lung cancer.

	Welcome to the driving force behind the precision medicine movement. We’ve taken a general disease, narrowed that down to a specific disease classified by its organ of origin, and further classified the cancer by one or more defining genomic defects.

	The process has turned the term “rare cancers” on its head. You might not consider lung cancer, which is diagnosed in 234,030 patients a year, a rare cancer. But what about ALK+ nonsmall cell lung cancer, which is diagnosed in just under 10,000 patients every year?

	Because those 10,000 patients have a specific type of lung cancer, they don’t respond to the standard treatments that work for most people. Instead, they need drugs made specifically for their genomically defined cancer.

	The same thing goes for those who have other cancers few people have heard of, like small intestine cancer, which also affects about 10,000 people a year. Small intestine cancer is a “rare cancer,” but so are certain types of more commonly diagnosed cancers-because cancer “rareness” means more than cancer incidence. It’s about the molecular makeup of each tumor.

	That’s why the future of research for any cancer is entirely, and unequivocally, molecular. Drugmakers have caught on-and it has changed the calculus for cancer research.

	Investigators should no longer pack as many patients as possible into a global clinical trial just to find responses to a new medicine in a few patients. Instead, they need to identify patients whose cancers share molecular defects, and match those molecular defects with a medicine that targets that particular defect.

	You might think that finding very specific people with very specific diseases slows down research. And in a way, it can…at the start.

	But here’s the reality: Targeted clinical trials yield the most dramatic results. When tumors rely on a single genetic mutation, medicines that target those mutations see response rates as high as 100%.

	And if you’re a drugmaker, clinical investigator, or patient, once a new medicine makes headlines touting its benefit in nine of 10 patients, any slowdown is quickly reversed. People get excited and there is a singular focus on getting the medicine approved quickly by the FDA.

	Then, it’s not about finding the right patients-the right patients find the right medicines.

	That’s what happened with Gleevec, the milestone drug that marked the first step in molecular

	profiling. Built for patients with chronic myeloid leukemia (a rare subset that affects about 10% of leukemia patients), Gleevec saw an 88% response immediately. These were the patients for whom other drugs had failed.

	In many of these cases, you don’t need a lot of patients to respond in order to get a drug approved. They’re rare cancers, after all. This kind of drug discovery means that researchers can spend less time in development, get their drugs approved faster, and start helping patients immediately. It just requires a sound clinical strategy that targets the right people.

	When I think of the impact that one small change could make on the lives of patients, it gives me hope. I think of patients with uveal melanoma, which has zero drugs approved for treatment. I think of patients with fibrolamellar hepatocellular carcinoma that impacts young adults and has no drugs approved for treatment.

	Each is a rare cancer in its own right. Each has known molecular or genetic defects. We need to

	find the right drugs to match to these cancers. Precision medicine provides physicians with the opportunity to avoid less effective treatments and focus on rationally selected medicines that improve clinical outcomes for patients. 

With more common cancers now increasingly broken down by specific genomic defects, the future of research for any cancer is entirely, and unequivocally, molecular.

Stephen Gately, PhD

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When is it Time to Kill Your Drug? Maybe Sooner Than You Think

Any Cancer Can Be a 'Rare Cancer'