GlaxoSmithKline Pulls Lapatinib Submission Ahead of ODAC Review

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GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive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.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, 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 this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point 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 that 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 vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States 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-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

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.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, 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 this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point 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 that 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 vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States 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-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

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.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, 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 this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point 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 that 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 vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States 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-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.