Monday, July 23, 2012
Evidence for pCR
FDA's draft guidance on the use of pCR as a surrogate
endpoint cites several studies that suggest a correlation between the
laboratory measure and clinical endpoints like disease-free survival (DFS) and
overall survival (OS).
For example, in the NSABP
B-18 trial comparing preoperative and postoperative delivery of four cycles of
doxorubicin plus cyclophosphamide, patients in the preoperative arm who
attained a pathologic complete response had about a 68% reduced risk of death
(HR: 0.32, p<0.0001).
The NOAH trial of Genentech
Inc.'s Herceptin trastuzumab in neoadjuvant breast cancer showed a pCR rate
in the Herceptin plus chemotherapy arm of 38% vs. 19% for chemotherapy alone
(p=0.001). With 3.2 years of median follow-up, the three-year DFS was 71% for
Herceptin plus chemo vs. 56% for chemotherapy alone (p=0.013).
There was no statistically
significant difference in OS, but fewer deaths occurred in the Herceptin arm
(18 vs. 26; HR=0.62).
According to Philippe
Bishop, VP of clinical development for Genentech's Avastin bevacizumab, the Roche
unit uses pCR to screen new agents because of this correlation between pCR and
Bishop would not disclose
the pCR rate a compound must achieve for Genentech to advance it into Phase
III. "Internally, we are looking for big differences that our own modeling
predicts will have an impact on disease-free and/or overall survival," he
Mark Benyunes, senior group
medical director for clinical hematology/oncology, cited the company's Perjeta
pertuzumab as an example.
"NEOSPHERE told us that
pertuzumab was likely to be very active in early breast cancer, and we then
designed the large adjuvant study APHINITY," he said.
In the Phase II NEOSPHERE
trial in neoadjuvant breast cancer, patients on Perjeta plus Herceptin and
docetaxel had a pCR rate of 45.8% vs. 29% for patients on Herceptin plus
In June, FDA approved
Perjeta in combination with Herceptin and docetaxel in first-line metastatic,
HER2-positive breast cancer.
According to Debasish
Tripathy, professor of medicine at Keck School of Medicine, there is no
specific pCR threshold for I-SPY 2, an adaptive trial that is evaluating
several agents in neoadjuvant breast cancer.
The investigators will use
Bayesian statistics to analyze the pCR rates and the patients' genomic
signatures to determine a drug's likelihood of success in the Phase III trials.
Drugs predicted to have at least an 85% likelihood of success will graduate.