GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.
GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.
The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.
"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."
Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.
The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.
The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.
A 4-Week PFS Advantage ...
GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.
The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.
Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).
The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.
According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).
Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.
The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.
... May Not Have Been Enough for the FDA
The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.
This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.