Patrice Wendling

CHICAGO – Bevacizumab maintenance after first-line chemotherapy for advanced non–small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.–affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

To control for survivorship and selection bias, researchers excluded patients with disease progression or death within 30 days of chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology–Baylor Sammons Cancer Center in Dallas. The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).

Bevacizumab monotherapy was associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide "significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research."

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients’ out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients. Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

CHICAGO – Bevacizumab maintenance after first-line chemotherapy for advanced non–small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.–affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

To control for survivorship and selection bias, researchers excluded patients with disease progression or death within 30 days of chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology–Baylor Sammons Cancer Center in Dallas. The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).

Bevacizumab monotherapy was associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide "significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research."

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients’ out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients. Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

CHICAGO – Bevacizumab maintenance after first-line chemotherapy for advanced non–small cell lung cancer was associated with longer overall survival in a retrospective study of 403 patients who were treated in outpatient community settings.

Median NSCLC disease progression was 10.3 months among patients who continued on bevacizumab (Avastin) until disease progression after they received first-line chemotherapy plus bevacizumab, compared with 6.5 months for those who discontinued the monoclonal antibody after chemotherapy.

Median overall survival reached 20.9 months vs. 10.2 months, respectively, Dr. Eric Nadler reported in a poster at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Although it is standard practice in clinical trials to continue bevacizumab until disease progression, recent assessments of treatment patterns in the United States have shown that bevacizumab is often discontinued when chemotherapy ends. Price has been an issue, with the typical monthly cost of bevacizumab for advanced lung cancer placed at about $8,800 in 2006. Only 38% (or 154) of the 403 patients in the study received bevacizumab until disease progression.

The industry-sponsored study identified patients with nonsquamous NSCLC from an electronic health records system that contains data from 884 community-based oncologists in US Oncology Inc.–affiliated practices or clinics in 20 states.

Patients were treated from July 2006 through June 2008, with 31% located in the Southwest and 30% in the Southeast. In all, 37% of patients had private insurance, 57% were covered by Medicare, and 6% had some other payer.

The maintenance group tended to have better pre- and postchemotherapy performance status scores and a greater number of completed chemotherapy cycles (median, six vs. four). Overall, 56% of the maintenance group and 39% of the no-maintenance group received a second-line therapy.

To control for survivorship and selection bias, researchers excluded patients with disease progression or death within 30 days of chemotherapy completion; landmark analyses were conducted at 18, 21, and 26 weeks from initial treatment.

Among those who were alive and progression free at 18 weeks, bevacizumab monotherapy until disease progression was associated with a 46% reduced risk of death (hazard ratio, 0.54), reported Dr. Nadler of the Texas Oncology–Baylor Sammons Cancer Center in Dallas. The association between bevacizumab and longer residual overall survival persisted among patients who remained progression free and alive at 21 weeks (HR, 0.58) and 26 weeks (HR, 0.61).

Bevacizumab monotherapy was associated with longer progression-free survival at 18 weeks (HR, 0.73), but the association was no longer observed at 21 weeks (HR, 0.82) and 26 weeks (HR, 0.79).

Although the nonrandomized nature of the study precludes making any conclusions about causality, the authors concluded that the findings provide "significant insights into real-world patterns of care and associated outcomes and provide important evidence on which to base future comparative effectiveness research."

In a separate national survey of oncologists, Dr. Nadler and associates at Tufts University in Boston reported that 84% of oncologists say that patients’ out-of-pocket spending influences treatment recommendations, even though only 43% frequently or always discuss costs with patients. Among the 787 oncologists surveyed, 79% favored more comparative effectiveness research and 80% supported more cost-effectiveness data, but only 42% felt well prepared to interpret it (Health Aff. [Millwood] 2010;29:196-202).

Genentech supported the study. Dr. Nadler reported no conflicts of interest. Three coauthors reported employment with Genentech and ownership interest in Roche Holdings.

Adding the investigational PARP inhibitor iniparib to the chemotherapy doublet gemcitabine/carboplatin significantly extended survival in metastatic triple-negative breast cancer in a phase II study involving 123 women.

Progression-free survival increased from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin to 5.9 months with chemotherapy plus iniparib.

Women who received the combination regimen lived nearly 5 months longer – a median of 12.3 months vs. 7.7 months for those receiving chemotherapy alone, Dr. Joyce O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas, and her associates reported (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMoa1011418]).

The primary efficacy end point of rate of clinical benefit, a measure of complete or partial response or stable disease for at least 6 months, was 34% in the chemotherapy arm vs. 56% in the iniparib arm.

Iniparib also significantly improved the overall response rate from 32% to 52%, suggesting that it may overcome the intrinsic drug resistance of some triple-negative breast cancers, the investigators reported. No standard-of-care therapy currently exists for patients with triple-negative breast cancer, a subgroup that represents 10%-15% of all breast cancer cases.

Iniparib inhibits poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), a key regulator of the DNA repair pathway, thereby enhancing the cytotoxic effects of chemotherapy.

If the phase II results are confirmed in a larger, ongoing phase III trial involving 500 women, PARP inhibition could be a rational approach to treating triple-negative breast cancer and the first therapy showing a survival advantage over chemotherapy alone, Dr. Lisa A. Carey and Dr. Norman E. Sharpless wrote in an accompanying editorial (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMe1012546]).

Although the results warrant excitement, the editorialists also urged caution. They pointed out that the cohort was small, the end points were investigator assessed, the chemotherapy regimen is unconventional, and there were imbalances in important prognostic factors favoring the iniparib group. It was also unclear whether the benefit of iniparib accrued to all triple-negative tumors equally or whether responders are mostly BRCA-positive patients, a smaller subset of triple-negative breast cancer.

"Caveats notwithstanding, these are exciting results presaging improved therapy for an underserved subgroup of patients with breast cancer and, we hope, heralding a new approach of ‘setting cancers up for the next blow’ by combining cytotoxic chemotherapy with agents directly targeting the DNA-damage response," wrote Dr. Carey and Dr. Sharpless, both with the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.

The study enrolled 123 women with estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative breast cancer and a median of three metastatic sites; they had received no more than two prior cytotoxic regimens for metastatic disease. In all, 62 women were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (area under the curve [AUC] = 2) IV on days 1 and 8 every 3 weeks and 61 women received the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11. Twenty women initially received iniparib at a dose of 4.0 mg/kg IV, but the study protocol was amended in 2008 to reflect emerging phase I safety data.

During a formal presentation of the data at the 2010 congress of the European Society for Medical Oncology in Milan, concerns were raised over whether the control arm received an insufficient dose of carboplatin. Dr. O’Shaughnessy responded that they chose an AUC of 2 rather than 2.5 because they couldn’t administer carboplatin AUC 2.5 consistently.

[PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival]

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, she reported. The incidence of grade 3 or 4 adverse events was 81% in the chemotherapy-alone arm vs. 86% in the iniparib arm. Notably, patients in the iniparib arm completed more treatment cycles (seven) than those in the chemotherapy-alone arm (four). Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression within 30 days of treatment.

One of the important questions remaining from the open-label trial is whether the activity of iniparib results from PARP inhibition or an unknown mechanism, Dr. Carey and Dr. Sharpless wrote. They raised the question because other PARP inhibitors have not shown promising results outside of BRCA-associated breast cancer, iniparib produced reduced toxicity compared with other PARP inhibitors when combined with chemotherapy, and iniparib is a much less potent inhibitor of PARP1 than most other agents of this class, with approximately 0.1% the potency.

There are also outstanding questions as to whether PARP inhibitors can enhance the effects of chemotherapy administered to other breast cancer subtypes or other tumor types, which chemotherapy regimens best synergize with PARP inhibitors, and whether PARP inhibitors may exhibit as yet unknown "on-target" toxic effects such as the diet-induced obesity and insulin resistance seen in PARP1-deficient mice.

"In addition, the risk of secondary cancers from DNA-repair inhibition needs to be considered carefully if these agents are used for longer periods in healthier patients," Dr. Carey and Dr. Sharpless cautioned.

Dr. O’Shaughnessy reported receiving speaking and consulting fees from Sanofi-Aventis, which recently bought study sponsor Bipar Sciences. One coauthor reported receiving travel support from Sanofi-Aventis and another reported stock ownership. Several coauthors are employees with stock options in the study sponsor Bipar Sciences, which is developing iniparib with its new parent company. Dr. Carey reported no conflicts. Dr. Sharpless reported financial relationships with G-Zero Therapeutics, consultancy for Wyeth, and royalties from Merck.

Adding the investigational PARP inhibitor iniparib to the chemotherapy doublet gemcitabine/carboplatin significantly extended survival in metastatic triple-negative breast cancer in a phase II study involving 123 women.

Progression-free survival increased from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin to 5.9 months with chemotherapy plus iniparib.

Women who received the combination regimen lived nearly 5 months longer – a median of 12.3 months vs. 7.7 months for those receiving chemotherapy alone, Dr. Joyce O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas, and her associates reported (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMoa1011418]).

The primary efficacy end point of rate of clinical benefit, a measure of complete or partial response or stable disease for at least 6 months, was 34% in the chemotherapy arm vs. 56% in the iniparib arm.

Iniparib also significantly improved the overall response rate from 32% to 52%, suggesting that it may overcome the intrinsic drug resistance of some triple-negative breast cancers, the investigators reported. No standard-of-care therapy currently exists for patients with triple-negative breast cancer, a subgroup that represents 10%-15% of all breast cancer cases.

Iniparib inhibits poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), a key regulator of the DNA repair pathway, thereby enhancing the cytotoxic effects of chemotherapy.

If the phase II results are confirmed in a larger, ongoing phase III trial involving 500 women, PARP inhibition could be a rational approach to treating triple-negative breast cancer and the first therapy showing a survival advantage over chemotherapy alone, Dr. Lisa A. Carey and Dr. Norman E. Sharpless wrote in an accompanying editorial (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMe1012546]).

Although the results warrant excitement, the editorialists also urged caution. They pointed out that the cohort was small, the end points were investigator assessed, the chemotherapy regimen is unconventional, and there were imbalances in important prognostic factors favoring the iniparib group. It was also unclear whether the benefit of iniparib accrued to all triple-negative tumors equally or whether responders are mostly BRCA-positive patients, a smaller subset of triple-negative breast cancer.

"Caveats notwithstanding, these are exciting results presaging improved therapy for an underserved subgroup of patients with breast cancer and, we hope, heralding a new approach of ‘setting cancers up for the next blow’ by combining cytotoxic chemotherapy with agents directly targeting the DNA-damage response," wrote Dr. Carey and Dr. Sharpless, both with the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.

The study enrolled 123 women with estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative breast cancer and a median of three metastatic sites; they had received no more than two prior cytotoxic regimens for metastatic disease. In all, 62 women were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (area under the curve [AUC] = 2) IV on days 1 and 8 every 3 weeks and 61 women received the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11. Twenty women initially received iniparib at a dose of 4.0 mg/kg IV, but the study protocol was amended in 2008 to reflect emerging phase I safety data.

During a formal presentation of the data at the 2010 congress of the European Society for Medical Oncology in Milan, concerns were raised over whether the control arm received an insufficient dose of carboplatin. Dr. O’Shaughnessy responded that they chose an AUC of 2 rather than 2.5 because they couldn’t administer carboplatin AUC 2.5 consistently.

[PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival]

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, she reported. The incidence of grade 3 or 4 adverse events was 81% in the chemotherapy-alone arm vs. 86% in the iniparib arm. Notably, patients in the iniparib arm completed more treatment cycles (seven) than those in the chemotherapy-alone arm (four). Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression within 30 days of treatment.

One of the important questions remaining from the open-label trial is whether the activity of iniparib results from PARP inhibition or an unknown mechanism, Dr. Carey and Dr. Sharpless wrote. They raised the question because other PARP inhibitors have not shown promising results outside of BRCA-associated breast cancer, iniparib produced reduced toxicity compared with other PARP inhibitors when combined with chemotherapy, and iniparib is a much less potent inhibitor of PARP1 than most other agents of this class, with approximately 0.1% the potency.

There are also outstanding questions as to whether PARP inhibitors can enhance the effects of chemotherapy administered to other breast cancer subtypes or other tumor types, which chemotherapy regimens best synergize with PARP inhibitors, and whether PARP inhibitors may exhibit as yet unknown "on-target" toxic effects such as the diet-induced obesity and insulin resistance seen in PARP1-deficient mice.

"In addition, the risk of secondary cancers from DNA-repair inhibition needs to be considered carefully if these agents are used for longer periods in healthier patients," Dr. Carey and Dr. Sharpless cautioned.

Dr. O’Shaughnessy reported receiving speaking and consulting fees from Sanofi-Aventis, which recently bought study sponsor Bipar Sciences. One coauthor reported receiving travel support from Sanofi-Aventis and another reported stock ownership. Several coauthors are employees with stock options in the study sponsor Bipar Sciences, which is developing iniparib with its new parent company. Dr. Carey reported no conflicts. Dr. Sharpless reported financial relationships with G-Zero Therapeutics, consultancy for Wyeth, and royalties from Merck.

Adding the investigational PARP inhibitor iniparib to the chemotherapy doublet gemcitabine/carboplatin significantly extended survival in metastatic triple-negative breast cancer in a phase II study involving 123 women.

Progression-free survival increased from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin to 5.9 months with chemotherapy plus iniparib.

Women who received the combination regimen lived nearly 5 months longer – a median of 12.3 months vs. 7.7 months for those receiving chemotherapy alone, Dr. Joyce O’Shaughnessy of the Baylor Sammons Cancer Center in Dallas, and her associates reported (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMoa1011418]).

The primary efficacy end point of rate of clinical benefit, a measure of complete or partial response or stable disease for at least 6 months, was 34% in the chemotherapy arm vs. 56% in the iniparib arm.

Iniparib also significantly improved the overall response rate from 32% to 52%, suggesting that it may overcome the intrinsic drug resistance of some triple-negative breast cancers, the investigators reported. No standard-of-care therapy currently exists for patients with triple-negative breast cancer, a subgroup that represents 10%-15% of all breast cancer cases.

Iniparib inhibits poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), a key regulator of the DNA repair pathway, thereby enhancing the cytotoxic effects of chemotherapy.

If the phase II results are confirmed in a larger, ongoing phase III trial involving 500 women, PARP inhibition could be a rational approach to treating triple-negative breast cancer and the first therapy showing a survival advantage over chemotherapy alone, Dr. Lisa A. Carey and Dr. Norman E. Sharpless wrote in an accompanying editorial (N. Engl. J. Med. 2011 Jan. 5 [doi: 10.1056/NEJMe1012546]).

Although the results warrant excitement, the editorialists also urged caution. They pointed out that the cohort was small, the end points were investigator assessed, the chemotherapy regimen is unconventional, and there were imbalances in important prognostic factors favoring the iniparib group. It was also unclear whether the benefit of iniparib accrued to all triple-negative tumors equally or whether responders are mostly BRCA-positive patients, a smaller subset of triple-negative breast cancer.

"Caveats notwithstanding, these are exciting results presaging improved therapy for an underserved subgroup of patients with breast cancer and, we hope, heralding a new approach of ‘setting cancers up for the next blow’ by combining cytotoxic chemotherapy with agents directly targeting the DNA-damage response," wrote Dr. Carey and Dr. Sharpless, both with the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill.

The study enrolled 123 women with estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative breast cancer and a median of three metastatic sites; they had received no more than two prior cytotoxic regimens for metastatic disease. In all, 62 women were randomized to gemcitabine 1,000 mg/m2 IV and carboplatin (area under the curve [AUC] = 2) IV on days 1 and 8 every 3 weeks and 61 women received the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11. Twenty women initially received iniparib at a dose of 4.0 mg/kg IV, but the study protocol was amended in 2008 to reflect emerging phase I safety data.

During a formal presentation of the data at the 2010 congress of the European Society for Medical Oncology in Milan, concerns were raised over whether the control arm received an insufficient dose of carboplatin. Dr. O’Shaughnessy responded that they chose an AUC of 2 rather than 2.5 because they couldn’t administer carboplatin AUC 2.5 consistently.

[PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival]

Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, she reported. The incidence of grade 3 or 4 adverse events was 81% in the chemotherapy-alone arm vs. 86% in the iniparib arm. Notably, patients in the iniparib arm completed more treatment cycles (seven) than those in the chemotherapy-alone arm (four). Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression within 30 days of treatment.

One of the important questions remaining from the open-label trial is whether the activity of iniparib results from PARP inhibition or an unknown mechanism, Dr. Carey and Dr. Sharpless wrote. They raised the question because other PARP inhibitors have not shown promising results outside of BRCA-associated breast cancer, iniparib produced reduced toxicity compared with other PARP inhibitors when combined with chemotherapy, and iniparib is a much less potent inhibitor of PARP1 than most other agents of this class, with approximately 0.1% the potency.

There are also outstanding questions as to whether PARP inhibitors can enhance the effects of chemotherapy administered to other breast cancer subtypes or other tumor types, which chemotherapy regimens best synergize with PARP inhibitors, and whether PARP inhibitors may exhibit as yet unknown "on-target" toxic effects such as the diet-induced obesity and insulin resistance seen in PARP1-deficient mice.

"In addition, the risk of secondary cancers from DNA-repair inhibition needs to be considered carefully if these agents are used for longer periods in healthier patients," Dr. Carey and Dr. Sharpless cautioned.

Dr. O’Shaughnessy reported receiving speaking and consulting fees from Sanofi-Aventis, which recently bought study sponsor Bipar Sciences. One coauthor reported receiving travel support from Sanofi-Aventis and another reported stock ownership. Several coauthors are employees with stock options in the study sponsor Bipar Sciences, which is developing iniparib with its new parent company. Dr. Carey reported no conflicts. Dr. Sharpless reported financial relationships with G-Zero Therapeutics, consultancy for Wyeth, and royalties from Merck.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.

Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.

The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.

When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)

There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.

At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.

Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.

"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.

"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."

Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.

Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.

Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.

FT. LAUDERDALE, FLA. — What do atypical antipsychotics, an analeptic, and targeted magnets have in common? They all might play a role in the treatment of anorexia nervosa.

"When you have a disorder that is so treatment resistant, it’s like metastatic breast cancer; you have to think outside the box for new interventions," Dr. Allan S. Kaplan said at a workshop on eating disorders at the annual meeting of the American College of Psychiatrists.

Current statistics indicate that 20% of patients diagnosed with anorexia are resistant to any intervention, and remain chronically ill and disabled. The needs of these patients have been largely neglected by the field, even though their numbers continue to grow as a result of the mortality gradually decreasing from 22% in older studies to about 8% to 10% today, said Dr. Kaplan, the Loretta Anne Rogers Chair in Eating Disorders and professor of psychiatry at the University of Toronto.

In his experience, many of these patients are now in their 40s and 50s, and have been ill for 20-30 years. Most suffer from significant medical complications, including renal failure, cardiac arrhythmias, and osteoporosis with resulting hip fractures that have left them wheelchair-bound.

"They are unbelievably disabled," he said. "They are more disabled on quality-of-life measurements than a comparative group of schizophrenics in the hospital.

"It’s a sobering experience to spend time with these patients."

One novel approach that might be useful is use of repetitive transcranial magnetic stimulation (rTMS), which has been shown to be effective in some patients with depression, schizophrenia, and obsessive-compulsive disorder. Current magnets stimulate superficial cortical areas of the brain, but Dr. Kaplan suggests that a better target might be the insula—a cerebral cortex structure located deep within the lateral fissure that plays a role in interoceptive awareness and motor control. His group recently completed an unpublished meta-analysis of neuroimaging studies in anorexia that provides evidence for overactivity in the insula.

The team members have subsequently contracted with an Israeli biotechnology firm to construct a patented magnet for rTMS that will specifically target the insula. They also plan to launch an open-label pilot trial of rTMS for anorexia shortly.

The approach is not without controversy, Dr. Kaplan acknowledged. Although the seizure rate with rTMS is very low in patients with depression, patients with anorexia are at an increased risk for seizures at a rate of about 10% in general.

"It’s a bit of a shot in the dark, but when you have no other effective treatment, you have to do that," he said.

Atypical antipsychotics have come under increased scrutiny for anorexia, but with limited success in the few small studies and case reports to date. A recent meta-analysis of 43 publications concluded that there is not enough evidence in anorexia to confirm that these medications increase weight (Eur. Eat. Disord. Rev. 2010 ;18:10-21).

Olanzapine is atypical antipsychotic that has been the most reported drug in the literature for treating anorexia and has been the subject of three small randomized controlled trials. Researchers in Ottawa showed that 10 weeks of olanzapine plus intensive day treatment resulted in faster weight gain and a greater decrease in obsessive symptoms than placebo in 34 patients with anorexia, but overall the same amount of weight gain (Am. J. Psychiatry 2008;165:1281-8).

Dr. Evelyn Attia from New York State Psychiatric Institute/Columbia University and Dr. Kaplan reported in a separate unpublished trial supported by a developmental grant from the National Institute of Mental Health in 2005 that patients gained a mean of almost 2 kilograms after 8 weeks of up to 10 mg olanzapine. Patients credited this weight gain not to an increase in hunger, but to being less anxious and consumed by thoughts of weight and shape. Importantly, there was absolutely no change in lipids, glucose, or insulin sensitivity, suggesting something might be different about the way the anorexic brain handles these drugs, Dr. Kaplan said.

The problem with olanzapine, however, is compliance, said Dr. Kaplan, noting that patients with eating disorders are well-informed of its side effect of stimulating weight gain. Aripiprazole has been found to be less likely to cause significant weight gain in schizophrenia patients and was indeed more acceptable in another small unpublished trial reported by Dr. Kaplan and his associates in 2005. Unfortunately, it had little impact on weight or measures of anxiety or depression in the eight patients in which it was tried, he said.

Positive results on both weight gain and cognition have been seen with ziprasidone and quetiapine, but their use has been limited by concerns about QT interval prolongation, which is already an issue for anorexics. Because of this concern, olanzapine was selected instead of ziprasidone as the study drug for a large multicenter anorexia trial that is planned, he said.

The rationale for using atypical antipsychotics in anorexia lies not just in their potential side effect of weight gain, but in their ability to ameliorate the core disturbances in cognition, affect regulation, and motor activity seen in patients with anorexia nervosa, Dr. Kaplan explained.

"Anorexia is often underestimated as being a disturbance of motor activity," he said. "Our patients are hyperactive in the face of increasing emaciation, which you don’t see in any other condition."

Finally, workshop attendee Dr. Charles Price reported an acute response in a single patient with anorexia given modafinil and followed for 6 months. In a counterintuitive finding, the drug did not have the weight loss aspects observed with other stimulants.

"Basically, it cured her anorexia; now it is an ‘N’ of one," said Dr. Price, who is in private practice in Reno, Nev.

"It’s still worth writing up as a case report," Dr. Kaplan said to the agreement of the audience.

Dr. Kaplan reported having no conflicts of interest. Dr. Attia reported having received research support from Pfizer and Eli Lilly.

FT. LAUDERDALE, FLA. — What do atypical antipsychotics, an analeptic, and targeted magnets have in common? They all might play a role in the treatment of anorexia nervosa.

"When you have a disorder that is so treatment resistant, it’s like metastatic breast cancer; you have to think outside the box for new interventions," Dr. Allan S. Kaplan said at a workshop on eating disorders at the annual meeting of the American College of Psychiatrists.

Current statistics indicate that 20% of patients diagnosed with anorexia are resistant to any intervention, and remain chronically ill and disabled. The needs of these patients have been largely neglected by the field, even though their numbers continue to grow as a result of the mortality gradually decreasing from 22% in older studies to about 8% to 10% today, said Dr. Kaplan, the Loretta Anne Rogers Chair in Eating Disorders and professor of psychiatry at the University of Toronto.

In his experience, many of these patients are now in their 40s and 50s, and have been ill for 20-30 years. Most suffer from significant medical complications, including renal failure, cardiac arrhythmias, and osteoporosis with resulting hip fractures that have left them wheelchair-bound.

"They are unbelievably disabled," he said. "They are more disabled on quality-of-life measurements than a comparative group of schizophrenics in the hospital.

"It’s a sobering experience to spend time with these patients."

One novel approach that might be useful is use of repetitive transcranial magnetic stimulation (rTMS), which has been shown to be effective in some patients with depression, schizophrenia, and obsessive-compulsive disorder. Current magnets stimulate superficial cortical areas of the brain, but Dr. Kaplan suggests that a better target might be the insula—a cerebral cortex structure located deep within the lateral fissure that plays a role in interoceptive awareness and motor control. His group recently completed an unpublished meta-analysis of neuroimaging studies in anorexia that provides evidence for overactivity in the insula.

The team members have subsequently contracted with an Israeli biotechnology firm to construct a patented magnet for rTMS that will specifically target the insula. They also plan to launch an open-label pilot trial of rTMS for anorexia shortly.

The approach is not without controversy, Dr. Kaplan acknowledged. Although the seizure rate with rTMS is very low in patients with depression, patients with anorexia are at an increased risk for seizures at a rate of about 10% in general.

"It’s a bit of a shot in the dark, but when you have no other effective treatment, you have to do that," he said.

Atypical antipsychotics have come under increased scrutiny for anorexia, but with limited success in the few small studies and case reports to date. A recent meta-analysis of 43 publications concluded that there is not enough evidence in anorexia to confirm that these medications increase weight (Eur. Eat. Disord. Rev. 2010 ;18:10-21).

Olanzapine is atypical antipsychotic that has been the most reported drug in the literature for treating anorexia and has been the subject of three small randomized controlled trials. Researchers in Ottawa showed that 10 weeks of olanzapine plus intensive day treatment resulted in faster weight gain and a greater decrease in obsessive symptoms than placebo in 34 patients with anorexia, but overall the same amount of weight gain (Am. J. Psychiatry 2008;165:1281-8).

Dr. Evelyn Attia from New York State Psychiatric Institute/Columbia University and Dr. Kaplan reported in a separate unpublished trial supported by a developmental grant from the National Institute of Mental Health in 2005 that patients gained a mean of almost 2 kilograms after 8 weeks of up to 10 mg olanzapine. Patients credited this weight gain not to an increase in hunger, but to being less anxious and consumed by thoughts of weight and shape. Importantly, there was absolutely no change in lipids, glucose, or insulin sensitivity, suggesting something might be different about the way the anorexic brain handles these drugs, Dr. Kaplan said.

The problem with olanzapine, however, is compliance, said Dr. Kaplan, noting that patients with eating disorders are well-informed of its side effect of stimulating weight gain. Aripiprazole has been found to be less likely to cause significant weight gain in schizophrenia patients and was indeed more acceptable in another small unpublished trial reported by Dr. Kaplan and his associates in 2005. Unfortunately, it had little impact on weight or measures of anxiety or depression in the eight patients in which it was tried, he said.

Positive results on both weight gain and cognition have been seen with ziprasidone and quetiapine, but their use has been limited by concerns about QT interval prolongation, which is already an issue for anorexics. Because of this concern, olanzapine was selected instead of ziprasidone as the study drug for a large multicenter anorexia trial that is planned, he said.

The rationale for using atypical antipsychotics in anorexia lies not just in their potential side effect of weight gain, but in their ability to ameliorate the core disturbances in cognition, affect regulation, and motor activity seen in patients with anorexia nervosa, Dr. Kaplan explained.

"Anorexia is often underestimated as being a disturbance of motor activity," he said. "Our patients are hyperactive in the face of increasing emaciation, which you don’t see in any other condition."

Finally, workshop attendee Dr. Charles Price reported an acute response in a single patient with anorexia given modafinil and followed for 6 months. In a counterintuitive finding, the drug did not have the weight loss aspects observed with other stimulants.

"Basically, it cured her anorexia; now it is an ‘N’ of one," said Dr. Price, who is in private practice in Reno, Nev.

"It’s still worth writing up as a case report," Dr. Kaplan said to the agreement of the audience.

Dr. Kaplan reported having no conflicts of interest. Dr. Attia reported having received research support from Pfizer and Eli Lilly.

FT. LAUDERDALE, FLA. — What do atypical antipsychotics, an analeptic, and targeted magnets have in common? They all might play a role in the treatment of anorexia nervosa.

"When you have a disorder that is so treatment resistant, it’s like metastatic breast cancer; you have to think outside the box for new interventions," Dr. Allan S. Kaplan said at a workshop on eating disorders at the annual meeting of the American College of Psychiatrists.

Current statistics indicate that 20% of patients diagnosed with anorexia are resistant to any intervention, and remain chronically ill and disabled. The needs of these patients have been largely neglected by the field, even though their numbers continue to grow as a result of the mortality gradually decreasing from 22% in older studies to about 8% to 10% today, said Dr. Kaplan, the Loretta Anne Rogers Chair in Eating Disorders and professor of psychiatry at the University of Toronto.

In his experience, many of these patients are now in their 40s and 50s, and have been ill for 20-30 years. Most suffer from significant medical complications, including renal failure, cardiac arrhythmias, and osteoporosis with resulting hip fractures that have left them wheelchair-bound.

"They are unbelievably disabled," he said. "They are more disabled on quality-of-life measurements than a comparative group of schizophrenics in the hospital.

"It’s a sobering experience to spend time with these patients."

One novel approach that might be useful is use of repetitive transcranial magnetic stimulation (rTMS), which has been shown to be effective in some patients with depression, schizophrenia, and obsessive-compulsive disorder. Current magnets stimulate superficial cortical areas of the brain, but Dr. Kaplan suggests that a better target might be the insula—a cerebral cortex structure located deep within the lateral fissure that plays a role in interoceptive awareness and motor control. His group recently completed an unpublished meta-analysis of neuroimaging studies in anorexia that provides evidence for overactivity in the insula.

The team members have subsequently contracted with an Israeli biotechnology firm to construct a patented magnet for rTMS that will specifically target the insula. They also plan to launch an open-label pilot trial of rTMS for anorexia shortly.

The approach is not without controversy, Dr. Kaplan acknowledged. Although the seizure rate with rTMS is very low in patients with depression, patients with anorexia are at an increased risk for seizures at a rate of about 10% in general.

"It’s a bit of a shot in the dark, but when you have no other effective treatment, you have to do that," he said.

Atypical antipsychotics have come under increased scrutiny for anorexia, but with limited success in the few small studies and case reports to date. A recent meta-analysis of 43 publications concluded that there is not enough evidence in anorexia to confirm that these medications increase weight (Eur. Eat. Disord. Rev. 2010 ;18:10-21).

Olanzapine is atypical antipsychotic that has been the most reported drug in the literature for treating anorexia and has been the subject of three small randomized controlled trials. Researchers in Ottawa showed that 10 weeks of olanzapine plus intensive day treatment resulted in faster weight gain and a greater decrease in obsessive symptoms than placebo in 34 patients with anorexia, but overall the same amount of weight gain (Am. J. Psychiatry 2008;165:1281-8).

Dr. Evelyn Attia from New York State Psychiatric Institute/Columbia University and Dr. Kaplan reported in a separate unpublished trial supported by a developmental grant from the National Institute of Mental Health in 2005 that patients gained a mean of almost 2 kilograms after 8 weeks of up to 10 mg olanzapine. Patients credited this weight gain not to an increase in hunger, but to being less anxious and consumed by thoughts of weight and shape. Importantly, there was absolutely no change in lipids, glucose, or insulin sensitivity, suggesting something might be different about the way the anorexic brain handles these drugs, Dr. Kaplan said.

The problem with olanzapine, however, is compliance, said Dr. Kaplan, noting that patients with eating disorders are well-informed of its side effect of stimulating weight gain. Aripiprazole has been found to be less likely to cause significant weight gain in schizophrenia patients and was indeed more acceptable in another small unpublished trial reported by Dr. Kaplan and his associates in 2005. Unfortunately, it had little impact on weight or measures of anxiety or depression in the eight patients in which it was tried, he said.

Positive results on both weight gain and cognition have been seen with ziprasidone and quetiapine, but their use has been limited by concerns about QT interval prolongation, which is already an issue for anorexics. Because of this concern, olanzapine was selected instead of ziprasidone as the study drug for a large multicenter anorexia trial that is planned, he said.

The rationale for using atypical antipsychotics in anorexia lies not just in their potential side effect of weight gain, but in their ability to ameliorate the core disturbances in cognition, affect regulation, and motor activity seen in patients with anorexia nervosa, Dr. Kaplan explained.

"Anorexia is often underestimated as being a disturbance of motor activity," he said. "Our patients are hyperactive in the face of increasing emaciation, which you don’t see in any other condition."

Finally, workshop attendee Dr. Charles Price reported an acute response in a single patient with anorexia given modafinil and followed for 6 months. In a counterintuitive finding, the drug did not have the weight loss aspects observed with other stimulants.

"Basically, it cured her anorexia; now it is an ‘N’ of one," said Dr. Price, who is in private practice in Reno, Nev.

"It’s still worth writing up as a case report," Dr. Kaplan said to the agreement of the audience.

Dr. Kaplan reported having no conflicts of interest. Dr. Attia reported having received research support from Pfizer and Eli Lilly.

CHICAGO – Patients with previously treated, advanced non–small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy.

These preliminary data suggest that "there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance," Dr. Robert Jotte said at the Chicago Multidisciplinary Symposium in Thoracic Oncology, where he presented the findings in a late-breaking oral abstract.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn’t clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.

Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG (Eastern Cooperative Oncology Group) performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said. The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO – Patients with previously treated, advanced non–small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy.

These preliminary data suggest that "there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance," Dr. Robert Jotte said at the Chicago Multidisciplinary Symposium in Thoracic Oncology, where he presented the findings in a late-breaking oral abstract.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn’t clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.

Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG (Eastern Cooperative Oncology Group) performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said. The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO – Patients with previously treated, advanced non–small cell lung cancer and high E-cadherin levels derived greater benefit when the investigational agent entinostat was added to erlotinib in a treatment strategy designed to overcome erlotinib resistance.

The data from a placebo-controlled, phase II trial are noteworthy because histone deacetylase inhibitors, such as entinostat, increase erlotinib sensitivity and prevent or delay resistance, which inevitably occurs in patients who are treated with erlotinib and other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

In addition, patients with elevated E-cadherin levels account for 40% of the overall NSCLC population, making it an attractive clinical biomarker for directing therapy.

These preliminary data suggest that "there may be a subpopulation of patients for which entinostat may have the ability to overcome erlotinib resistance," Dr. Robert Jotte said at the Chicago Multidisciplinary Symposium in Thoracic Oncology, where he presented the findings in a late-breaking oral abstract.

Among 132 unselected patients in the phase II ENCORE 401 trial, outcomes were comparable for oral entinostat plus erlotinib (Tarceva) vs. erlotinib plus placebo, with a nonsignificant median progression-free survival difference of just 0.4 months and a median overall survival difference of 2.2 months, he reported.

Among 26 patients who were identified as having high E-cadherin levels, however, entinostat significantly increased overall survival, from 5.4 months with placebo to 9.4 months (hazard ratio, 0.36; P = .03), said Dr. Jotte, director of thoracic oncology at the Rocky Mountain Cancer Centers in Denver.

In contrast, 40 patients with low E-cadherin expression who received placebo survived a median of 7.0 months, compared with 4.4 months with entinostat (P = .55; HR, 1.25).

Median progression-free survival in the exploratory biomarker analysis also trended in favor of high E-cadherin patients who received entinostat vs. placebo (3.7 months vs. 1.9 months), but the difference did not reach statistical significance (HR, 0.55; P = .19).

Median progression-free survival among low E-cadherin patients was similar at 1.7 months with entinostat vs. 1.9 months with placebo (HR, 1.36; P = .36), said Dr. Jotte.

Invited discussant Dr. Pasi Jänne of the Dana-Farber Cancer Institute in Boston, said that preclinical data showing that erlotinib and entinostat prevent the emergence of resistance in EGFR-mutant cell lines (Cell 2010;141:69-80) provide a rationale for combining these agents. What isn’t clear is whether entinostat would restore erlotinib sensitivity in cell lines with a KRAS mutation or EML4-ALK translocation.

Dr. Jänne also observed that the current data contradict two other preclinical studies and a subset analysis from the TRIBUTE trial demonstrating that high E-cadherin expression is associated with erlotinib sensitivity. In ENCORE 401, however, patients with high E-cadherin expression who were treated with erlotinib and placebo had a shorter median overall survival than did their counterparts with low E-cadherin expression (5.4 months vs. 7.0 months).

Discrepancies between these data and the phase II data need to be resolved before additional prospective trials of erlotinib/entinostat are undertaken, Dr. Jänne said.

Syndax Pharmaceuticals, which is developing entinostat, plans to evaluate the drug in combination with erlotinib in further randomized trials to be initiated in 2011 in selected NSCLC patients with high levels of E-cadherin, according to a statement by Syndax president and CEO Dr. Joanna Horobin.

During a press conference at the meeting, Dr. Fred Hirsch, a professor of medicine with the University of Colorado Cancer Center in Aurora, also cautioned that an accepted standardized classification of E-cadherin expression needs to be established.

In ENCORE 401, immunohistochemistry staining values of +3 or greater were defined as high E-cadherin expression, and 0, +1, and +2 were defined as low E-cadherin expression.

In all, 132 patients who had progressed after one or two prior chemotherapies for stage IIIB/IV NSCLC were randomized 1:1 to erlotinib (150 mg once daily for 28 day) plus entinostat (10 mg on days 1 and 15 for 28 days), or to erlotinib and placebo. The majority was male (66%), had an ECOG (Eastern Cooperative Oncology Group) performance status of 0/1 (86%), had a history of smoking (85%) and had adenocarcinoma histology (43%). Only 11 of 78 patients who were tested had KRAS-mutant tumors.

Entinostat/erlotinib was tolerable with no unexpected adverse events and a manageable safety profile among evaluated patients, Dr. Jotte said. The most common grade 3/4 adverse event in either arm was fatigue, occurring in 16% of 63 erlotinib/placebo patients and in 20% of 65 erlotinib/entinostat patients. Fatal adverse events occurred in 25.4% of erlotinib/placebo patients vs. 18.5% of erlotinib/entinostat patients, with 43% of patients in each arm discontinuing treatment because of adverse events.

The symposium was cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Syndax Pharmaceuticals sponsored ENCORE 401. Dr. Jotte and his coauthors disclosed no conflicts of interest. Dr. Jänne disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Roche, Gatekeeper Pharmaceuticals, and Genzyme.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A small study provides compelling data that both the genotype and phenotype of non-small cell lung cancers can transform as part of acquired resistance to tyrosine kinase inhibitors.

Repeat tumor biopsies revealed that the histologic diagnosis of the tumor shifted from adenocarcinoma to small cell lung cancer (SCLC) in 14% of 37 consecutive patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) and acquired tyrosine kinase inhibitor (TKI) resistance, Dr. Lecia Sequist said during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The original L858R mutation or E 19 deletion was retained in all cases but, in one patient, an additional PIK3CA mutation was observed only when the tumor shifted to SCLC.

Although other groups have documented sporadic case reports of transformation, Dr. Sequist called the 14% transformation rate remarkable. "I think this points to a broader conceptual model of acquired resistance, and we need to think very carefully about doing more repeat biopsies in patients," she said.

EGFR-mutant NSCLC is highly sensitive to EGFR TKI therapy, but acquired resistance develops at about 9-12 months due to T790M mutations in half of patients and MET amplification in 10% to 15%. Elucidating the remaining mechanisms of drug resistance is of great clinical and scientific significance, said Dr. Sequist of Massachusetts General Hospital Cancer Center, Boston.

Although re-biopsy is not common practice, invited discussant Dr. Mark Socinski said it should be on the clinicians’ radar because it can alter the therapeutic course of refractory disease and arguably the clinical benefit.

"I think the message here is to consider re-biopsy more often in selected patients until we have a better understanding of this one disease we call non–small lung cancer that we realize is an incredibly heterogenous disease," said Dr. Socinski, director of the multidisciplinary thoracic oncology program at the Lineberger Comprehensive Cancer Center at the University of North Carolina–Chapel Hill.

Among the five patients whose cancer transformed, two maintained a slow, indolent course after SCLC transformation, while three had a change around the time of their biopsy to an explosive growth pattern more clinically reminiscent of SCLC, Dr. Sequist said. Four patients were treated with SCLC-like chemotherapy regimens, and three responded with marked partial responses.

Longitudinal data from fluorescent in situ hybridization analysis for MET and EGFR gene copy number suggest that the resistant tumor is distinct from the original tumor and that MET amplification lies in a distinct subpopulation of the cell and is selected out under pressure from TKI therapy, she said.

Multiple biopsies over time also identified a waxing and waning of genotypic and phenotypic findings in response to selective pressure of TKI therapy. This pattern was most pronounced in a case that transformed from EGFR TKI-sensitive adenocarcinoma to resistant SCLC while on erlotinib (Tarceva) for more than one year, switched back to TKI-sensitive adenocarcinoma following treatment with chemotherapy and radiation and a 9- to 10-month break from erlotinib, and then after a very successful, but short-lived re-response to erlotinib, shifted back to SCLC a second time upon clinical resistance.

"It’s showing us that if you do repeat biopsies, it can direct patients towards clinical trials that they have a higher likelihood of benefiting from," Dr. Sequist said. "It’s a really a nice thing to be able to offer patients."

The population comprised 15 men and 22 women. All patients, median age 60 years, had clinically responded to either gefitinib (Iressa) or erlotinib, with a median of 18.4 months of initial EGFR TKI therapy (range 4-69 months). The majority, or 81%, remained on TKI at the time of repeat biopsy. Repeat biopsy showed T790m mutations in 49%, PIK3CA in 5%, MET amplification in 5%, and an unknown mechanism in 30%, reported Dr. Sequist at the symposium, cosponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, International Association for the Study of Lung Cancer, and University of Chicago.

Dr. Sequist and Dr. Socinski disclosed no relevant conflicts. Two coauthors have submitted a patent for genotyping methods.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.

CHICAGO – A subgroup analysis of the LUX-Lung 1 trial reveals that afatinib produces a more robust response in those lung cancer patients who are most likely to harbor EGFR mutations.

Median progression free survival increased significantly from 1 month with placebo to 4.4 months with afatinib in patients with a complete or partial response to prior erlotinib or gefitinib and/or at least 48 weeks of prior treatment with either of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (hazard ratio 0.28).

This subgroup also showed a trend in overall survival in favor of afatinib – 11.8 months vs. 11.2 months with placebo (HR 0.90).

The subgroup comprised 67% of patients in the phase III trial, Dr. Vincent Miller, lead author, reported during the plenary session at the Chicago Multidisciplinary Symposium in Thoracic Oncology. Previous studies have reported a strong connection between the clinical criteria used to define the subgroup and EGFR-mutation positivity.

LUX-Lung 1 compared afatinib 50 mg once-daily plus best supportive care with placebo plus best supportive care in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All study participants had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with erlotinib (Tarceva) or gefitinib (Iressa).

Initial results, presented earlier this year by Dr. Miller at the European Society for Medical Oncology (ESMO) meeting in Milan, showed that the addition of afatinib significantly improved progression-free survival from 1.1 month with placebo to 3.3 months, but failed to improve the primary end point of overall survival (11.96 months vs. 10.78 months).

[Read: Overall Survival Advantage Eludes Afatinib in NSCLC]

The long survival times were unprecedented and likely confounded by extensive subsequent treatment, explained Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York. This assertion is supported by an exploratory analysis in which median overall survival among patients with none or one subsequent systemic therapy was 7.2 months with placebo and 9.2 months with afatinib (HR 0.81), he said.

In all, 68% of the afatinib group and 79% of the placebo group went on to systemic therapy, with 28% and 44%, respectively, receiving at least two regimens.

Afatinib is an investigational irreversible inhibitor of the EGFR and human epidermal receptor 2 (HER2) tyrosine kinases. It has shown preclinical activity against EGFR T790M mutations, which are found in about half of patients who become resistant to erlotinib or gefitinib.

Irreversible inhibitors are potent against T790M mutations, but dose escalation of these agents is limited by diarrhea and rash, observed invited discussant Dr. Rogerio Lilenbaum, director of thoracic oncology at Mount Sinai Cancer Center in Miami Beach, Fla.

"It remains unclear, pending further molecular data, whether afatinib or other irreversible inhibitors will be effective against T790 tumors at tolerated doses," he said.

In all, 8% of LUX-Lung 1 patients discontinued afatinib due to a treatment-related adverse event, with 17% experiencing grade 3 diarrhea and 14% grade 3 rash. Serious treatment-related adverse events, including two deaths, were reported in 10% of patients.

Dr. Lilenbaum described afatinib as an active drug in the current setting and cited data from the phase II LUX-Lung 2 trial suggesting it is at least as active as erlotinib or gefitinib in patients with sensitizing EGFR mutations in first-line therapy (Yang, et al. Poster. ESMO 2010).

There are two ongoing first-line phase III trials, including LUX-Lung 3, of afatinib vs. chemotherapy in non–small cell lung cancer patients with EGFR mutations and a third trial comparing afatinib with cetuximab in the acquired-resistance setting. Results from the trials could be presented at the 2011 American Society of Clinical Oncology annual meeting, Dr. Miller said at the symposium, which was cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.

Dr. Miller disclosed consulting honoraria and other support from study sponsor Boehringer-Ingelheim, as well as financial support from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships, including employment with Boehringer-Ingelheim. Dr. Lilenbaum disclosed consulting for Genentech and stock options with YM BioSciences.