NorthWest Biotherapeutics Inc (NWBO)

[Evaluate]

http://jco.ascopubs.org/content/32/12/1277.full?ijkey=0474691db1bdae5a8b916390208050295e8a695d&keytype2=tf_ipsecsha

2014 by American Society of Clinical Oncology
American Society of Clinical Oncology Perspective: Raising the Bar for Clinical Trials by Defining Clinically Meaningful Outcomes

As articulated in the American Society of Clinical Oncology (ASCO) research blueprint,9 these advances should allow us to implement clinical trials where meaningful advances in patient outcomes can be achieved with smaller numbers of trial participants (ie, smaller and smarter trials).

Although OS was selected as the primary end point by all working groups, this does not diminish the value of progression-free survival (PFS) and other surrogate end points as valid end points in certain clinical situations. This is especially true in cancer types that often produce symptoms related to progressive disease, for example, painful bone metastases, where a significant prolongation in PFS may provide meaningful palliation and improved QOL.

The primary goal of the working groups was to help guide the development of definitive, randomized phase III trials, although each group recognized that it is imperative for investigators to obtain data from well-conducted early-phase trials that will provide a strong foundation for the development of ambitious phase III studies. It is necessary to observe extremely strong signals in phase II studies if we are to expect clinically meaningful outcomes to be achieved in subsequent phase III studies. Although this statement may be obvious, we sometimes are more optimistic about results from phase II trials than is warranted.10 It is even possible that phase III studies will not be necessary if results from well-conducted phase II trials demonstrate exceptional activity that clearly benefits patients.11 A recent example is the development of crizotinib for treatment of ALK-translocated non–small-cell lung cancer, where phase II studies were sufficient to convince patients, oncologists, and the US Food and Drug Administration that accelerated approval was warranted because phase III studies were in progress.12

Each working group first selected a patient population as the focus of its deliberations and then selected primary and secondary end points for potential trials that would reflect clinically meaningful benefits to patients. Issues frequently discussed with respect to primary end point selection included the relationship of PFS to OS in a given clinical context. Although PFS is a commonly used end point, the working groups each preferred to use OS as the primary measure of clinically meaningful outcome. The groups acknowledged the challenges with OS, such as the need for longer follow-up and the potential confounding effect of poststudy therapies on assessment of the OS end point.

The working groups acknowledged that crossover in clinical trials is increasingly common, because it offers patients a greater chance to receive the experimental treatment than fixed-arm trials. Clearly, trials can be designed that demonstrate clinically meaningful outcomes without affecting OS, such as trials that demonstrate noninferiority compared with existing therapies with significantly less toxicity. In addition, we are now able to identify secondary mutations that drive tumor growth after progression during first-line targeted therapies.14 Although this information provides an opportunity for success in second-line therapies, it also makes OS a more difficult end point to attain. Thus, the use of PFS as a clinically meaningful end point may be appropriate in particular disease settings and has, in fact, been accepted by regulatory authorities on many occasions already.15–17

Patient symptoms resulting from cancer progression and tolerability of treatment-related toxicities are of critical importance when considering whether a new treatment produces a clinically meaningful outcome for patients. For the most part, the working groups agreed that if a therapy is less toxic than prevailing treatments, a smaller improvement in efficacy is acceptable.