Targeted therapy agents
In clinical trials of targeted therapy agents, sometimes the target is such a crucial driver of the neoplastic process, that its inhibition is able to stop the growing tumor in its tracks. This appears to be the case for some recently approved agents such as vemurafenib for BRAF V600E melanoma and crizotinib for ALK+ NSCLC. Careful screening of patients for these mutations ensures the likelihood of improved progression free survival (PFS) and longer survival times. Unfortunately, because patients are switched from the control regimen in the Phase III trials, the chances of proving better survival are greatly diminished, if not completely eliminated.
In a recent opinion piece in Nature Reviews: Clinical Oncology, Robert Doebele argues that when patients are screened for the relevant oncogene "the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients....There might be oncogenes that will not follow this paradigm, but that should not deter us from trying to extend the benefit of this precision medicine approach to patients that may fall into one of these uncommon oncogene categories."
Crizotinib for ALK+ NSCLC
One example is crizotinib, a tyrosine kinase inhibitor (TKI) for the treatment of ALK gene rearrangement-positive (ALK+) non-small-cell lung cancer (NSCLC), which was approved by the FDA in 2011 based on the results of phase I and phase II clinical trials. Phase I observed an objective response rate (ORR) of 61% and a PFS of 9.7 months. Phase II observed an ORR of 53% and a PFS of 9.1 months.
Considering the estimated ORR and PFS for most single-agent chemotherapy drugs in pretreated patients with lung cancer is 10% and 3-4 months respectively, was there really a need for a Phase III RCT in this case?
The outcome of a phase III randomized trial, PROFILE 1007, of crizotinib in patients with ALK+ lung cancer merely provided further proof that cizotinbin is superior to standard chemotherapy for these patients that included a better quality-of-life and physical and emotional function. Based on the results of this study, it seems reasonable to argue that the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients, especially in lung cancer.
Not limited to TKI
Calls for the elimination of Phase III trials are not limited to TKI. During the presentation of a melanoma Phase II trial of a combination of two immunomodulators, ipilimumab and nivolumab at ASCO this year, one of the questions from the audience was, "Do we really need a phase III trial?" The results of the trial being presented were certainly impressive, with one year survival in the 80% range.
Time to shift the burden of proof?
Based on these examples, some feel that it may be time to eliminate the Phase III trial in targeted therapy agents when such overwhelming proof is given that a therapy induces remarkable tumor responses in Phase I and II. This will allow studies to move along more quickly, minimize the need to switch patients from the control regimen, and provide more rapid approval for certain therapies.