GlaxoSmithKline Pulls Tykerb sNDA Ahead Of FDA Panel Review

The sponsor withdrew the application for combination use of lapatinib with Roche’s Herceptin in breast cancer less than two weeks before a scheduled advisory committee review, because of questions from FDA “that could not be addressed with the data currently available.” Those questions may have been driven by concerns about the clinical meaningfulness of a four-week median progression-free survival benefit and other efficacy issues.

GlaxoSmithKline PLC’s decision to withdraw a Tykerb (lapatinib) sNDA less than two weeks before a scheduled FDA advisory committee review may have stemmed from agency questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA for lapatinib, in combination with Roche’s Herceptin (trastuzumab), for use in patients with HER2+ metastatic breast cancer who received prior trastuzumab therapy.

The timing of GSK’s withdrawal announcement suggests the application would have faced a challenging ODAC meeting, had it gone forward.

The sNDA was scheduled for review by FDA’s Oncologic Drugs Advisory Committee on the morning of July 24 (Also see "Tykerb/Herceptin Combination Will Go Before FDA Advisory Panel" - Pink Sheet, 30 May, 2012.). Since GSK would have received the agency’s briefing package for that meeting two to three weeks ahead of time, the timing of the withdrawal announcement suggests the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

“Our discussions with 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 U.S. 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 EU 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 combination use with capecitabine in patients with advanced or metastatic HER2+ breast cancer who have received prior therapy, including an anthracycline, a taxane and trastuzumab; and in combination with letrozole for the treatment of postmenopausal women with hormone-receptor positive, HER2+ 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+ breast cancer. In June, the agency approved Genentech Inc.’s Perjeta (pertuzumab), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2+ metastatic breast cancer (Also see "Perjeta Approval Heralds Roche’s Next Wave Of Breast Cancer Drugs" - Pink Sheet, 10 Jun, 2012.).

Four-Week PFS Advantage …

GSK declined to comment further on 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+ metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at 2008 American Society of Clinical Oncology annual meeting (Also see "GSK Study Shows Tykerb/Herceptin Combo Increases Progression-Free Survival In Breast Cancer" - Pink Sheet, 16 May, 2008.).

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every four weeks through week 16 and every eight weeks thereafter. Patients with disease progression after receiving at least four weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to the study results published in the March 1, 2010 issue of the Journal of Clinical Oncology.

The primary endpoint was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary endpoints 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 (HR: 0.73; 95% CI: 0.57-0.93; p=0.008). The median PFS with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement in PFS (HR=0.71; 95% CI: 0.52-0.98, p=0.027).

Median overall survival was 51.6 weeks in the combination group compared to 39.0 weeks in the lapatinib monotherapy arm. “Although these data are not mature (56% censoring rate), they show a trend in improved OS after combination therapy (HR=0.75; 95% CI: 0.53-1.07; p=0.106),” the study’s authors, led by Kimberly Blackwell, Duke University, wrote.

The overall incidence of AEs was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

… May Not Have Been Enough For 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 PFS advantage of four 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 Genentech’s Avastin (bevacizumab). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label E2100 trial, which demonstrated a median PFS advantage of 5.5 months; however, confirmatory trials showed smaller median PFS improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in E2100.

The agency also may have had concerns about the Tykerb study’s use of a PFS primary endpoint based upon investigator assessment.

For open-label trials using PFS as the primary endpoint, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using a PFS endpoint (Also see "FDA Asks ODAC To Consider Looser Parameters For PFS Analysis" - Pink Sheet, 12 Jul, 2012.).

The fact that independent blinded review was not the Tykerb trial’s primary endpoint might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting On Other Studies

Although GSK said it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, Phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab versus trastuzumab alone as maintenance therapy in women with HER2+ metastatic breast cancer. The 280-patient study, which is being conducted in the U.S. and Canada, is expected to complete in August 2014.

Another Phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone-receptor positive, HER2+ metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.