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Why Cancer Patients And Doctors Should Rethink The Value Of Phase 1 Trials

This article is more than 7 years old.

Of all the reports being presented at this year’s big cancer meeting, the one I think most important is not about a particular drug or malignancy. It’s about the design of clinical trials.

For cancer patients trying an experimental drug, participating in a “matched” study–using biomarkers, like genetics, to link their condition to a treatment–offers much greater chances of clinical benefit than does participating in a similar, unmatched study. The abstract*, authored by a geographically wide research group, will be delivered in Chicago by Maria Schwaederlé, PharmD, of the University of California in San Diego.

The results, while not surprising, are remarkable for their clarity. In phase 1 trials, a precision strategy boosted the response rate from 4.9%, to 30.5%. That is a huge difference. The meta-analysis included 346 studies published from 2011 through 2013, a fairly recent data set, involving 13,203 research subjects. The “p-value”–a statistical term–is impressive, at <0.0001. The point is, this is a clinically meaningful and significant find.

This study, and others like it, have the potential to upend our clinical trials system. It should jolt some colleagues with MPHs and randomized clinical trial (RCT) devotees (how I was trained 25 years ago) out of their “gold standard” trance. And, by the way, this paper offers the clearest demonstration, yet, of the value–to patients–of precision medicine in oncology.

Many doctors have intuited that matching cancer patients with drugs designed to target particular defects in their tumors makes sense. But until now, there’s never been proof that up-front “precision” yields superior clinical outcomes overall. Some might argue that this study, a meta-analysis, and any of the phase 1 trials included, does not meet the level of knowledge or certainty offered by an old-fashioned, prospective and, ideally, double-blind RCT.

But there are many reasons, in 2016, to question the continued value of RCTs in oncology. First, they’re expensive, costing tens of millions of dollars, besides years, oncologists’ work and patients’ lives. The fact is, those giant “landmark” studies comparing cancer treatments take so long that they’re irrelevant by the time they’re completed. This out-of-date effect happened, for instance, with the recently reported, and disappointing, study of intraperitoneal chemo in ovarian cancer. During the decade of enrollment and follow-up, new drugs got approved.

Besides, RCTs may be flawed in their design or analysis.

Meanwhile, patients with advanced and previously hard-to-treat cancers, and their doctors, face the ethical dilemma of possibly giving or receiving a placebo or the standard of care. When there’s good, mature phase 1 and 2 data for a matching drug, putting cancer patients through a randomized phase 3 trial could be equated to withholding best care.

Another benefit of smaller, personalized Phase 1 trials, over Phase 3, is that they cost much less to complete, to analyze and to follow up (including Phase 4, post-marketing) for long-term effects. The lower expense of clinical studies can–and should–reduce the price of future cancer drugs by lowering the costs of drug development, typically cited by pharma as a justification for high prices. If cancer meds become more affordable, access increases. More patients could be helped.

Some details on the ASCO abstract, which might draw criticism, is that the Phase 1 studies were not designed to assess survival with one experimental treatment or another. Rather, they looked at overall responses, including stable disease and toxicity. Still, the investigators found that the matched studies correlated with improved PFS (5.7 vs. 2.95 months). That’s not much, although it was statistically significant.

Until recently, phase 1 trials were not designed to help individual patients, but to see how toxic drugs were, if they could be tolerated and at what dose. When I became an oncologist, there was a concept we had to regurgitate on rounds and exams, that you had to test 14 patients with a new drug, and see no responses at all, before establishing that the drug was useless. Phase 1 gave oncology and oncologists a bad reputation because we were putting patients, “research subjects,” through the mill.

Now, we have tools to predict who’s likely to respond to an experimental drug. That makes all the difference.

I’d have a hard time, if I were in a clinic today, suggesting to a patient with a known, targetable mutation or vulnerable molecule in their malignancy, a study in which they might receive an unmatched experimental drug. And if I had cancer that was growing through medications, or unlikely to respond to standard care, I’d be comparatively eager to try, or at least consider, a targeted agent in a Phase 1 clinical trial.

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*Abstract 11520: Impact of precision medicine in refractory malignancies: a meta-analysis of 13,203 patients in phase I clinical trials, at the American Society of Clinical Oncology (ASCO) annual meeting, Chicago, June 7, 2016

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