Patrice Wendling

A woman in Monrovia, Liberia, likely contracted the Ebola virus through sexual contact with a survivor whose semen tested positive 199 days after his Ebola onset, according to a Morbidity and Mortality Weekly Report early release (MMWR Morb. Mortal. Wkly. Rep. 2015 May 1;64:1-3).

It isn’t possible to “definitively ascribe” the woman’s infection to sexual contact, however. “The investigation identified only one epidemiologic link to Ebola: unprotected vaginal intercourse with a survivor,” the report from the Centers for Disease Control and Prevention stated.

Ebola virus is known to persist in seminal fluid following recovery, but the duration of viral shedding and the likelihood of transmission are unknown.

The virus has been isolated from semen as long as 82 days after symptom onset, and semen can be positive by reverse transcription-polymerase chain reaction (RT-PCR), indicating presence of viral RNA, up to 101 days after onset.

The Monrovian woman reported unprotected vaginal intercourse on March 7, 2015, with the male Ebola survivor and developed symptoms of headache, weakness, joint pain, and nausea on March 14.

A diagnosis of Ebola virus was confirmed March 20, 2015, 30 days after the most recent confirmed Ebola patient in Liberia. Ebola viral RNA sequenced from three patients in Liberia’s last known cluster of epidemiologically linked cases did not share mutations observed in the woman’s isolate, making it unlikely that she was infected from unrecognized, ongoing community transmission, authorities said.

Investigations of several other recent Ebola cases in West Africa also have suggested sexual transmission from survivors, but CDC officials said that they have not been confirmed.

“Based on information gathered in this investigation, CDC now recommends that contact with semen from male Ebola survivors should be avoided until more information regarding the duration and infectiousness of viral shedding in body fluids is known,” the report stated. “If male survivors have sex (oral, vaginal, or anal), a condom should be used correctly and consistently every time.”

Officials also recommended that used condoms be handled and disposed of safely to avoid contact with semen.

The male Ebola survivor was admitted to an Ebola treatment unit on Sept. 23, 2014, and had multiple family members with confirmed or suspected Ebola at that time. His first test by RT-PCR was indeterminate: positive on one assay with a cycle threshold of 40, indicating a low viral load, and negative on a second assay. A second RT-PCR test in October 2014 was negative.

Complete genome sequencing of viral RNA from his semen has not been possible because of the low level of detectable viral nucleic acid, but a partial sequence obtained so far closely matches the sequence from the Monrovian woman, CDC officials said.

The male Ebola survivor reported having unprotected vaginal intercourse with another woman around the same time as the Monrovian woman, but so far her blood has tested negative for Ebola.

RT-PCR testing of semen might be a useful tool for assessing and counseling male survivors on measures they should take to prevent Ebola transmission. The CDC and other public health partners are reviewing existing data to determine the validity and feasibility of potential recommendations.

The CDC and the World Health Organization have previously recommended abstinence or condom use for 3 months following recovery from Ebola virus infection.

“Sufficient supplies of condoms and counseling to promote their correct and consistent use should be provided as part of the response in Ebola-affected countries,” CDC officials suggested. “In addition, efforts should be undertaken to prevent the possibility of sexual transmission from stigmatizing survivors.”

[email protected]

On Twitter @pwendl

A woman in Monrovia, Liberia, likely contracted the Ebola virus through sexual contact with a survivor whose semen tested positive 199 days after his Ebola onset, according to a Morbidity and Mortality Weekly Report early release (MMWR Morb. Mortal. Wkly. Rep. 2015 May 1;64:1-3).

It isn’t possible to “definitively ascribe” the woman’s infection to sexual contact, however. “The investigation identified only one epidemiologic link to Ebola: unprotected vaginal intercourse with a survivor,” the report from the Centers for Disease Control and Prevention stated.

Ebola virus is known to persist in seminal fluid following recovery, but the duration of viral shedding and the likelihood of transmission are unknown.

The virus has been isolated from semen as long as 82 days after symptom onset, and semen can be positive by reverse transcription-polymerase chain reaction (RT-PCR), indicating presence of viral RNA, up to 101 days after onset.

The Monrovian woman reported unprotected vaginal intercourse on March 7, 2015, with the male Ebola survivor and developed symptoms of headache, weakness, joint pain, and nausea on March 14.

A diagnosis of Ebola virus was confirmed March 20, 2015, 30 days after the most recent confirmed Ebola patient in Liberia. Ebola viral RNA sequenced from three patients in Liberia’s last known cluster of epidemiologically linked cases did not share mutations observed in the woman’s isolate, making it unlikely that she was infected from unrecognized, ongoing community transmission, authorities said.

Investigations of several other recent Ebola cases in West Africa also have suggested sexual transmission from survivors, but CDC officials said that they have not been confirmed.

“Based on information gathered in this investigation, CDC now recommends that contact with semen from male Ebola survivors should be avoided until more information regarding the duration and infectiousness of viral shedding in body fluids is known,” the report stated. “If male survivors have sex (oral, vaginal, or anal), a condom should be used correctly and consistently every time.”

Officials also recommended that used condoms be handled and disposed of safely to avoid contact with semen.

The male Ebola survivor was admitted to an Ebola treatment unit on Sept. 23, 2014, and had multiple family members with confirmed or suspected Ebola at that time. His first test by RT-PCR was indeterminate: positive on one assay with a cycle threshold of 40, indicating a low viral load, and negative on a second assay. A second RT-PCR test in October 2014 was negative.

Complete genome sequencing of viral RNA from his semen has not been possible because of the low level of detectable viral nucleic acid, but a partial sequence obtained so far closely matches the sequence from the Monrovian woman, CDC officials said.

The male Ebola survivor reported having unprotected vaginal intercourse with another woman around the same time as the Monrovian woman, but so far her blood has tested negative for Ebola.

RT-PCR testing of semen might be a useful tool for assessing and counseling male survivors on measures they should take to prevent Ebola transmission. The CDC and other public health partners are reviewing existing data to determine the validity and feasibility of potential recommendations.

The CDC and the World Health Organization have previously recommended abstinence or condom use for 3 months following recovery from Ebola virus infection.

“Sufficient supplies of condoms and counseling to promote their correct and consistent use should be provided as part of the response in Ebola-affected countries,” CDC officials suggested. “In addition, efforts should be undertaken to prevent the possibility of sexual transmission from stigmatizing survivors.”

[email protected]

On Twitter @pwendl

A woman in Monrovia, Liberia, likely contracted the Ebola virus through sexual contact with a survivor whose semen tested positive 199 days after his Ebola onset, according to a Morbidity and Mortality Weekly Report early release (MMWR Morb. Mortal. Wkly. Rep. 2015 May 1;64:1-3).

It isn’t possible to “definitively ascribe” the woman’s infection to sexual contact, however. “The investigation identified only one epidemiologic link to Ebola: unprotected vaginal intercourse with a survivor,” the report from the Centers for Disease Control and Prevention stated.

Ebola virus is known to persist in seminal fluid following recovery, but the duration of viral shedding and the likelihood of transmission are unknown.

The virus has been isolated from semen as long as 82 days after symptom onset, and semen can be positive by reverse transcription-polymerase chain reaction (RT-PCR), indicating presence of viral RNA, up to 101 days after onset.

The Monrovian woman reported unprotected vaginal intercourse on March 7, 2015, with the male Ebola survivor and developed symptoms of headache, weakness, joint pain, and nausea on March 14.

A diagnosis of Ebola virus was confirmed March 20, 2015, 30 days after the most recent confirmed Ebola patient in Liberia. Ebola viral RNA sequenced from three patients in Liberia’s last known cluster of epidemiologically linked cases did not share mutations observed in the woman’s isolate, making it unlikely that she was infected from unrecognized, ongoing community transmission, authorities said.

Investigations of several other recent Ebola cases in West Africa also have suggested sexual transmission from survivors, but CDC officials said that they have not been confirmed.

“Based on information gathered in this investigation, CDC now recommends that contact with semen from male Ebola survivors should be avoided until more information regarding the duration and infectiousness of viral shedding in body fluids is known,” the report stated. “If male survivors have sex (oral, vaginal, or anal), a condom should be used correctly and consistently every time.”

Officials also recommended that used condoms be handled and disposed of safely to avoid contact with semen.

The male Ebola survivor was admitted to an Ebola treatment unit on Sept. 23, 2014, and had multiple family members with confirmed or suspected Ebola at that time. His first test by RT-PCR was indeterminate: positive on one assay with a cycle threshold of 40, indicating a low viral load, and negative on a second assay. A second RT-PCR test in October 2014 was negative.

Complete genome sequencing of viral RNA from his semen has not been possible because of the low level of detectable viral nucleic acid, but a partial sequence obtained so far closely matches the sequence from the Monrovian woman, CDC officials said.

The male Ebola survivor reported having unprotected vaginal intercourse with another woman around the same time as the Monrovian woman, but so far her blood has tested negative for Ebola.

RT-PCR testing of semen might be a useful tool for assessing and counseling male survivors on measures they should take to prevent Ebola transmission. The CDC and other public health partners are reviewing existing data to determine the validity and feasibility of potential recommendations.

The CDC and the World Health Organization have previously recommended abstinence or condom use for 3 months following recovery from Ebola virus infection.

“Sufficient supplies of condoms and counseling to promote their correct and consistent use should be provided as part of the response in Ebola-affected countries,” CDC officials suggested. “In addition, efforts should be undertaken to prevent the possibility of sexual transmission from stigmatizing survivors.”

[email protected]

On Twitter @pwendl

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

[email protected]

On Twitter @pwendl

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

[email protected]

On Twitter @pwendl

Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.

Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.

Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.

The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.

Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.

Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.

Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.

No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.

As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.

Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.

“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.

Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.

The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.

[email protected]

On Twitter @pwendl

A phase II study evaluating single-agent olaparib in metastatic, castration-resistant prostate cancer offers the first evidence that genetic testing could be used to select patients for treatment.

The overall response rate was 86.7% in a subgroup of men (14/16) identified as harboring genomic defects in DNA repair genes and 32.7% among all evaluable patients (16/49).

Median radiological progression-free survival was estimated at 13.2 months in men with mutations and 2.7 months in those without mutations (hazard ratio, 0.21; P < .001), Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Trust, London, reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We hope that this is a step towards molecular stratification of treatment for prostate cancer. We are a year behind breast cancer or colorectal cancer investigators,” he said during a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly ADP-ribose polymerase) inhibitor ,was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

Most of the genomic aberrations in patients with prostate cancer occurred in BRCA2 and ATM, although biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Research presented at the meeting suggests that BRCA2 is present in about 12% of prostate tumors and ATM in about 7%, Dr. Mateo told reporters.

The first phase of the study, referred to as TOPARP-A, enrolled 50 men from 7 U.K. centers who had metastatic, castration-resistant prostate cancer after 1-2 lines of taxane chemotherapy and a circulating tumor cell (CTC) count of at least 5 cells/7.5 mL of blood at screening. All patients had received prior docetaxel (Taxotere), 58% cabazitaxel (Jevtana), 96% abiraterone (Zytiga), 28% enzalutamide (Xtandi), and 26% palliative radiotherapy. The median baseline prostate specific antigen (PSA) was 349.5 mcg/L and median age was 67.5 years.

Patients received olaparib 400 mg twice daily continuously in a 28-day cycle. Response rate, the study’s primary endpoint, was defined as objective response by RECIST 1.1 and/or PSA decline of at least 50% and/or CTC count decline from at least 5 cells to less than 5 cells/7.5 mL blood. One patient was not evaluable for response.

Genomic defects in DNA repair genes, somatic and germline, were identified via next-generation sequencing and other studies of fresh tumor samples, taken before and while on olaparib.

Among the 16 unselected patients with responses, 6 had radiological responses and 11 had biochemical responses. Four of these responses have lasted more than 1 year, Dr. Mateo said.

Among those with genomic testing results, seven patients had a BRCA2 alteration and all responded to olaparib. Four of the five men with ATM truncating mutations responded.

PTEN loss and ERG rearrangements were not associated with response, he said.

The biomarker panel had a high specificity of 94% and sensitivity of 87.5%.

Consistent with previous olaparib studies, the most common grade 3 or higher adverse events were anemia (20%) and fatigue (12%), with 13% of patients requiring a dose reduction.

The next phase of the study, TOPARP-B, will validate the biomarker panel by enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A, said Dr. Mateo, noting that samples can be turned around in 7-10 days.

Press briefing moderator Dr. William Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said newer drugs such as abiraterone and enzalutamide have given clinicians more mileage in treating castration-resistant prostate cancer by better targeting the androgen-receptor, but that the current results with olaparib will likely prompt more drug development off the androgen receptor.

The Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the U.K. National Institute for Health Research Biomedical Research Center funded the study. Dr. Mateo disclosed no financial conflicts. Two coauthors reported serving as advisors to AstraZeneca

[email protected]

On Twitter @pwendl

A phase II study evaluating single-agent olaparib in metastatic, castration-resistant prostate cancer offers the first evidence that genetic testing could be used to select patients for treatment.

The overall response rate was 86.7% in a subgroup of men (14/16) identified as harboring genomic defects in DNA repair genes and 32.7% among all evaluable patients (16/49).

Median radiological progression-free survival was estimated at 13.2 months in men with mutations and 2.7 months in those without mutations (hazard ratio, 0.21; P < .001), Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Trust, London, reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We hope that this is a step towards molecular stratification of treatment for prostate cancer. We are a year behind breast cancer or colorectal cancer investigators,” he said during a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly ADP-ribose polymerase) inhibitor ,was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

Most of the genomic aberrations in patients with prostate cancer occurred in BRCA2 and ATM, although biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Research presented at the meeting suggests that BRCA2 is present in about 12% of prostate tumors and ATM in about 7%, Dr. Mateo told reporters.

The first phase of the study, referred to as TOPARP-A, enrolled 50 men from 7 U.K. centers who had metastatic, castration-resistant prostate cancer after 1-2 lines of taxane chemotherapy and a circulating tumor cell (CTC) count of at least 5 cells/7.5 mL of blood at screening. All patients had received prior docetaxel (Taxotere), 58% cabazitaxel (Jevtana), 96% abiraterone (Zytiga), 28% enzalutamide (Xtandi), and 26% palliative radiotherapy. The median baseline prostate specific antigen (PSA) was 349.5 mcg/L and median age was 67.5 years.

Patients received olaparib 400 mg twice daily continuously in a 28-day cycle. Response rate, the study’s primary endpoint, was defined as objective response by RECIST 1.1 and/or PSA decline of at least 50% and/or CTC count decline from at least 5 cells to less than 5 cells/7.5 mL blood. One patient was not evaluable for response.

Genomic defects in DNA repair genes, somatic and germline, were identified via next-generation sequencing and other studies of fresh tumor samples, taken before and while on olaparib.

Among the 16 unselected patients with responses, 6 had radiological responses and 11 had biochemical responses. Four of these responses have lasted more than 1 year, Dr. Mateo said.

Among those with genomic testing results, seven patients had a BRCA2 alteration and all responded to olaparib. Four of the five men with ATM truncating mutations responded.

PTEN loss and ERG rearrangements were not associated with response, he said.

The biomarker panel had a high specificity of 94% and sensitivity of 87.5%.

Consistent with previous olaparib studies, the most common grade 3 or higher adverse events were anemia (20%) and fatigue (12%), with 13% of patients requiring a dose reduction.

The next phase of the study, TOPARP-B, will validate the biomarker panel by enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A, said Dr. Mateo, noting that samples can be turned around in 7-10 days.

Press briefing moderator Dr. William Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said newer drugs such as abiraterone and enzalutamide have given clinicians more mileage in treating castration-resistant prostate cancer by better targeting the androgen-receptor, but that the current results with olaparib will likely prompt more drug development off the androgen receptor.

The Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the U.K. National Institute for Health Research Biomedical Research Center funded the study. Dr. Mateo disclosed no financial conflicts. Two coauthors reported serving as advisors to AstraZeneca

[email protected]

On Twitter @pwendl

A phase II study evaluating single-agent olaparib in metastatic, castration-resistant prostate cancer offers the first evidence that genetic testing could be used to select patients for treatment.

The overall response rate was 86.7% in a subgroup of men (14/16) identified as harboring genomic defects in DNA repair genes and 32.7% among all evaluable patients (16/49).

Median radiological progression-free survival was estimated at 13.2 months in men with mutations and 2.7 months in those without mutations (hazard ratio, 0.21; P < .001), Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Trust, London, reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We hope that this is a step towards molecular stratification of treatment for prostate cancer. We are a year behind breast cancer or colorectal cancer investigators,” he said during a press briefing at the meeting.

Olaparib (Lynparza), a PARP (poly ADP-ribose polymerase) inhibitor ,was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.

Most of the genomic aberrations in patients with prostate cancer occurred in BRCA2 and ATM, although biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Research presented at the meeting suggests that BRCA2 is present in about 12% of prostate tumors and ATM in about 7%, Dr. Mateo told reporters.

The first phase of the study, referred to as TOPARP-A, enrolled 50 men from 7 U.K. centers who had metastatic, castration-resistant prostate cancer after 1-2 lines of taxane chemotherapy and a circulating tumor cell (CTC) count of at least 5 cells/7.5 mL of blood at screening. All patients had received prior docetaxel (Taxotere), 58% cabazitaxel (Jevtana), 96% abiraterone (Zytiga), 28% enzalutamide (Xtandi), and 26% palliative radiotherapy. The median baseline prostate specific antigen (PSA) was 349.5 mcg/L and median age was 67.5 years.

Patients received olaparib 400 mg twice daily continuously in a 28-day cycle. Response rate, the study’s primary endpoint, was defined as objective response by RECIST 1.1 and/or PSA decline of at least 50% and/or CTC count decline from at least 5 cells to less than 5 cells/7.5 mL blood. One patient was not evaluable for response.

Genomic defects in DNA repair genes, somatic and germline, were identified via next-generation sequencing and other studies of fresh tumor samples, taken before and while on olaparib.

Among the 16 unselected patients with responses, 6 had radiological responses and 11 had biochemical responses. Four of these responses have lasted more than 1 year, Dr. Mateo said.

Among those with genomic testing results, seven patients had a BRCA2 alteration and all responded to olaparib. Four of the five men with ATM truncating mutations responded.

PTEN loss and ERG rearrangements were not associated with response, he said.

The biomarker panel had a high specificity of 94% and sensitivity of 87.5%.

Consistent with previous olaparib studies, the most common grade 3 or higher adverse events were anemia (20%) and fatigue (12%), with 13% of patients requiring a dose reduction.

The next phase of the study, TOPARP-B, will validate the biomarker panel by enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A, said Dr. Mateo, noting that samples can be turned around in 7-10 days.

Press briefing moderator Dr. William Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said newer drugs such as abiraterone and enzalutamide have given clinicians more mileage in treating castration-resistant prostate cancer by better targeting the androgen-receptor, but that the current results with olaparib will likely prompt more drug development off the androgen receptor.

The Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the U.K. National Institute for Health Research Biomedical Research Center funded the study. Dr. Mateo disclosed no financial conflicts. Two coauthors reported serving as advisors to AstraZeneca

[email protected]

On Twitter @pwendl

Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.

The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.

For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.

About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.

Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.

After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).

“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.

Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.

Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.

“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”

Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.

In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.

The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.

Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.

There were no clear differences in efficacy and safety between dosing regimens, he said.

Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.

Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAF^V600E mutation in melanoma.

“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.

Dr. Garon responded that there are two important aspects to a biomarker.

“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”

[email protected]

On Twitter @pwendl

Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.

The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.

For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.

About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.

Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.

After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).

“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.

Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.

Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.

“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”

Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.

In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.

The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.

Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.

There were no clear differences in efficacy and safety between dosing regimens, he said.

Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.

Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAF^V600E mutation in melanoma.

“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.

Dr. Garon responded that there are two important aspects to a biomarker.

“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”

[email protected]

On Twitter @pwendl

Results from KEYNOTE-001 show that not only is the anti-PD-L1 antibody pembrolizumab clinically active in advanced non–small cell lung cancer, but that PD-L1 expression is a marker of response, as well.

The objective response rate was 45.2% for patients with programmed cell death ligand 1 (PD-L1) expression in at least half of their tumor cells, including 44% in previously treated patients and 50% in treatment-naive patients.

For patients with 1% to 49% and < 1% tumor PD-L1 expression, objective response rates were 16.5% and 10.7%, respectively, Dr. Edward Garon of the University of California, Los Angeles, reported at the annual meeting of the American Association for Cancer Research.

About a quarter of those screened had PD-L1 expression in at least half of their tumor cells.

Median progression-free survival (PFS) in this subgroup was 6.3 months vs. 3.3 months in patients with 1%-49% tumor PD-L1 and 2.3 months in those with < 1% PD-L1.

After a median follow-up of 10.9 months, median overall survival was not reached in patients with at least 50% tumor PD-L1 expression and was 8.8 months in both groups with lesser degrees of tumor PD-L1 expression, according to results simultaneously reported in the New England Journal of Medicine (2015 April 19 [doi:10.1056/NEJMoa1501824]).

“I think that with [these] data, we can now confidently say that in previously treated patients who have PD-L1 expression in at least half of their cells, pembrolizumab is associated with superior clinical outcomes, clearly, than what would be anticipated with cytotoxic chemotherapy,” Dr. Garon said during a press briefing.

Outcomes in patients with lesser tumor PD-L1 expression may also be better than what is seen with comparators, but complete data on that will require data from randomized studies, he added.

Press briefing moderator Dr. Suzanne Topalian, with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, pointed out that more than three-fourths of patients in the study had progressed on prior systemic therapies.

“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive I think in this particular treatment setting.”

Results from KEYNOTE-001 were drawn from 495 patients with advanced or metastatic non–small cell lung cancer, including 182 patients assigned to a training group in which the PD-L1 cutoff value was selected and 313 patients with measurable disease assigned to an independent biomarker validation group. PD-L1 status was assessed in tumor samples by a prototype immunohistochemistry assay using the 22C3 antibody clone (Merck). Patients were randomized to intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.

In the training group, 171 patients were previously treated and 11 were treatment naive, with 129 remaining after exclusions for cutoff selection. In the validation group, 223 patients were previously treated and 90 were treatment naive, with 204 biomarker evaluable patients remaining after exclusions.

The objective response rate among the entire 495 patients was 19.4%, including 18% in previously treated patients and 24.8% in treatment-naive patients, Dr. Garon said.

Median PFS was 3.7 months, 3.0 months, and 6.0 months and median overall survival 12 months, 9.3 months, and 16.2 months, respectively.

There were no clear differences in efficacy and safety between dosing regimens, he said.

Treatment-related adverse events occurred in 351 patients (71%), the most common being fatigue, pruritus, and decreased appetite. Grade 3 or higher events were reported in 47 patients (9.5%), the most common being dyspnea in 19, pneumonitis in 9 and decreased appetite in 5.

Based on the current data, Dr. Topalian asked how the proposed PD-L1 biomarker would be used in clinical practice. She noted that the situation is more clearcut with the kinase inhibitor class of drugs in which the biology tells us whether the drug is unlikely to work based on whether the patient has a particular mutation, like the BRAF^V600E mutation in melanoma.

“This kind of biomarker is a lot more blurry and you saw that even patients with lower levels of expression of this marker still have notable response rates,” Dr. Topalian said.

Dr. Garon responded that there are two important aspects to a biomarker.

“One is that when you select patients who are positive, you do a very good job of enriching for patients with good clinical outcome, and this data set I believe very well addresses that piece,” he said. “The other piece, which is a shortfall and in some respects a fortunate shortfall for someone who treats patients with lung cancer, is that we haven’t done as good a job as we would like with this biomarker of demonstrating the group of people who is not likely to benefit.”

[email protected]

On Twitter @pwendl

SAN DIEGO – Surgical experience puts transulnar access on a par with transradial access for percutaneous coronary procedures, the randomized AJULAR trial showed.

The primary composite outcome of major adverse cardiac events or major vascular events during hospitalization was 14.6% for transulnar access and 14.4% for transradial access, meeting the noninferiority criteria.

“If used as a default strategy, [transulnar access] is noninferior to the transradial approach when performed by an experienced operator,” study author Dr. Rajendra Gokhroo reported at the annual meeting of the American College of Cardiology.

The use of radial artery cannulation is growing in the United States as an approach for coronary access because of obvious safety advantages over femoral access, but has its own limitations such as frequent vasospasm, small caliber, and unsuitability as a graft for coronary artery bypass grafting after cannulation.

Transulnar access is used by some as an alternative, but was found inferior to transradial access in the AURA of ARTEMIS study because of significantly more large hematomas and a high crossover rate in the transulnar group (Circ. Cardiovasc. Interv. 2013;6:252-261).

However, the study used inexperienced ulnar operators and attempted to cannulate even nearly absent ulnar arteries, said Dr. Gokhroo, a pioneer in ulnar intervention at Jawaharlal Nehru Medical College, Ajmer, India, and president of the Indian Society of Cardiology. Based on their observations, the risk of such events is threefold higher during the first 50 procedures, but is no longer statistically significant after 51-100 operations or after 100 operations.

For the prospective, single-center AJULAR (Ajmer Ulnar Artery) trial, all operators were required to have a minimum experience of 50 transulnar cannulations, and cannulation was attempted only if the ulnar artery was easily palpable and the anatomy favorable.

“Excessive calcification, tortuosity, and low-volume pulse were the additional features where the ulnar was avoided; otherwise no other patient characteristics or demographic features compelled us to avoid ulnar access,” Dr. Gokhroo said in an interview.

Inability to palpate the radial artery was also an exclusion criterion.

A total of 2,532 patients scheduled to undergo elective coronary angiography and ad hoc percutaneous transluminal coronary angioplasty were evenly randomized to transulnar access or transradial access. The mean age for the 1,270 ulnar patients was 67 years and 63 years for the 1,262 radial patients.

There were no significant differences in an intention-to-treat analysis between the transulnar and transradial groups with respect to the individual components of the primary outcome: major adverse cardiac events (2.9% vs. 3.2%), large hematoma (1% vs. 0.9%), or occlusion (6.1% vs. 6.6%), Dr. Gokhroo reported.

The secondary endpoints of crossover rate (4.4% vs. 3.8%) and vessel spasm (6.9% vs. 8.7%) were also similar.

“Our study definitely says that ulnar access is as good as radial access,” he said.

An analysis of 48 transradial crossover events revealed that, had ulnar cannulation been considered, the need for crossover to femoral artery access would have been reduced from 38 patients to 2 patients, with the remaining 10 patients accessed via the contralateral radial artery.

“If you have expertise in ulnar cannulation, 75% of femoral artery cannulations can be avoided,” Dr. Gokhroo said. “Transulnar cannulation is also an easy, safe, and comfortable procedure.”

Dr. Gokhroo and his associates said they had no relevant financial disclosures.

[email protected]

SAN DIEGO – Surgical experience puts transulnar access on a par with transradial access for percutaneous coronary procedures, the randomized AJULAR trial showed.

The primary composite outcome of major adverse cardiac events or major vascular events during hospitalization was 14.6% for transulnar access and 14.4% for transradial access, meeting the noninferiority criteria.

“If used as a default strategy, [transulnar access] is noninferior to the transradial approach when performed by an experienced operator,” study author Dr. Rajendra Gokhroo reported at the annual meeting of the American College of Cardiology.

The use of radial artery cannulation is growing in the United States as an approach for coronary access because of obvious safety advantages over femoral access, but has its own limitations such as frequent vasospasm, small caliber, and unsuitability as a graft for coronary artery bypass grafting after cannulation.

Transulnar access is used by some as an alternative, but was found inferior to transradial access in the AURA of ARTEMIS study because of significantly more large hematomas and a high crossover rate in the transulnar group (Circ. Cardiovasc. Interv. 2013;6:252-261).

However, the study used inexperienced ulnar operators and attempted to cannulate even nearly absent ulnar arteries, said Dr. Gokhroo, a pioneer in ulnar intervention at Jawaharlal Nehru Medical College, Ajmer, India, and president of the Indian Society of Cardiology. Based on their observations, the risk of such events is threefold higher during the first 50 procedures, but is no longer statistically significant after 51-100 operations or after 100 operations.

For the prospective, single-center AJULAR (Ajmer Ulnar Artery) trial, all operators were required to have a minimum experience of 50 transulnar cannulations, and cannulation was attempted only if the ulnar artery was easily palpable and the anatomy favorable.

“Excessive calcification, tortuosity, and low-volume pulse were the additional features where the ulnar was avoided; otherwise no other patient characteristics or demographic features compelled us to avoid ulnar access,” Dr. Gokhroo said in an interview.

Inability to palpate the radial artery was also an exclusion criterion.

A total of 2,532 patients scheduled to undergo elective coronary angiography and ad hoc percutaneous transluminal coronary angioplasty were evenly randomized to transulnar access or transradial access. The mean age for the 1,270 ulnar patients was 67 years and 63 years for the 1,262 radial patients.

There were no significant differences in an intention-to-treat analysis between the transulnar and transradial groups with respect to the individual components of the primary outcome: major adverse cardiac events (2.9% vs. 3.2%), large hematoma (1% vs. 0.9%), or occlusion (6.1% vs. 6.6%), Dr. Gokhroo reported.

The secondary endpoints of crossover rate (4.4% vs. 3.8%) and vessel spasm (6.9% vs. 8.7%) were also similar.

“Our study definitely says that ulnar access is as good as radial access,” he said.

An analysis of 48 transradial crossover events revealed that, had ulnar cannulation been considered, the need for crossover to femoral artery access would have been reduced from 38 patients to 2 patients, with the remaining 10 patients accessed via the contralateral radial artery.

“If you have expertise in ulnar cannulation, 75% of femoral artery cannulations can be avoided,” Dr. Gokhroo said. “Transulnar cannulation is also an easy, safe, and comfortable procedure.”

Dr. Gokhroo and his associates said they had no relevant financial disclosures.

[email protected]

SAN DIEGO – Surgical experience puts transulnar access on a par with transradial access for percutaneous coronary procedures, the randomized AJULAR trial showed.

The primary composite outcome of major adverse cardiac events or major vascular events during hospitalization was 14.6% for transulnar access and 14.4% for transradial access, meeting the noninferiority criteria.

“If used as a default strategy, [transulnar access] is noninferior to the transradial approach when performed by an experienced operator,” study author Dr. Rajendra Gokhroo reported at the annual meeting of the American College of Cardiology.

The use of radial artery cannulation is growing in the United States as an approach for coronary access because of obvious safety advantages over femoral access, but has its own limitations such as frequent vasospasm, small caliber, and unsuitability as a graft for coronary artery bypass grafting after cannulation.

Transulnar access is used by some as an alternative, but was found inferior to transradial access in the AURA of ARTEMIS study because of significantly more large hematomas and a high crossover rate in the transulnar group (Circ. Cardiovasc. Interv. 2013;6:252-261).

However, the study used inexperienced ulnar operators and attempted to cannulate even nearly absent ulnar arteries, said Dr. Gokhroo, a pioneer in ulnar intervention at Jawaharlal Nehru Medical College, Ajmer, India, and president of the Indian Society of Cardiology. Based on their observations, the risk of such events is threefold higher during the first 50 procedures, but is no longer statistically significant after 51-100 operations or after 100 operations.

For the prospective, single-center AJULAR (Ajmer Ulnar Artery) trial, all operators were required to have a minimum experience of 50 transulnar cannulations, and cannulation was attempted only if the ulnar artery was easily palpable and the anatomy favorable.

“Excessive calcification, tortuosity, and low-volume pulse were the additional features where the ulnar was avoided; otherwise no other patient characteristics or demographic features compelled us to avoid ulnar access,” Dr. Gokhroo said in an interview.

Inability to palpate the radial artery was also an exclusion criterion.

A total of 2,532 patients scheduled to undergo elective coronary angiography and ad hoc percutaneous transluminal coronary angioplasty were evenly randomized to transulnar access or transradial access. The mean age for the 1,270 ulnar patients was 67 years and 63 years for the 1,262 radial patients.

There were no significant differences in an intention-to-treat analysis between the transulnar and transradial groups with respect to the individual components of the primary outcome: major adverse cardiac events (2.9% vs. 3.2%), large hematoma (1% vs. 0.9%), or occlusion (6.1% vs. 6.6%), Dr. Gokhroo reported.

The secondary endpoints of crossover rate (4.4% vs. 3.8%) and vessel spasm (6.9% vs. 8.7%) were also similar.

“Our study definitely says that ulnar access is as good as radial access,” he said.

An analysis of 48 transradial crossover events revealed that, had ulnar cannulation been considered, the need for crossover to femoral artery access would have been reduced from 38 patients to 2 patients, with the remaining 10 patients accessed via the contralateral radial artery.

“If you have expertise in ulnar cannulation, 75% of femoral artery cannulations can be avoided,” Dr. Gokhroo said. “Transulnar cannulation is also an easy, safe, and comfortable procedure.”

Dr. Gokhroo and his associates said they had no relevant financial disclosures.

[email protected]

The name is still evolving, but the idea of a more patient-centered cesarean delivery is beginning to take root in American hospitals.

At Cedars-Sinai Medical Center, where roughly 35% of the 6,500 deliveries each year are by cesarean, an obstetrics-gynecology “customization of care” task force is working to standardize what is being referred to nationally as gentle or natural cesareans, as well as family- or patient-centered cesarean delivery.

Central to the approach is parent involvement, keeping mothers and infants together, and transferring the baby onto the mother’s chest for early skin-to-skin contact after delivery.

“When they find out they have the option to do skin-to-skin, it relieves a lot of the anxiety, especially if the C-section is unplanned,” said Dr. Paola Aghajanian, director of labor and delivery and the Maternal-Fetal Care Unit at the Los Angeles–based hospital.

During a traditional cesarean, it’s at least 30 minutes and in most cases up to 60 minutes before the mother can hold her baby. But with a gentle cesarean, Apgar testing is performed on the mother’s chest, while warm blankets are used to maintain the infant’s temperature.

At Cedars-Sinai, they are working to reduce maternal sedation and eliminate extraneous conversations in the operating room. The hospital is also in the process of ordering clear surgical drapes so that mothers and their partners can watch the birth, Dr. Aghajanian said. The use of clear drapes has been popularized by Dr. William Camann, director of obstetric anesthesia at Brigham and Women’s Hospital in Boston, who said the idea came to him after watching open heart surgery at another hospital where the drapes were used to enhance coordination and communication between anesthesiologists and cardiothoracic surgeons.

Courtesy Brigham and Women&#039;s Hospital

The clear drapes have been met with tremendous approval, particularly from mothers, and reduce the potential risk for infection, though it is already very low, said Dr. Camann, an early adopter of what the Brigham calls “gentle cesareans.”

Over the last 4 years they’ve made other adjustments, including moving ECG leads from the chest to a more lateral position, shifting monitors so mothers can have more mobility to interact with or breastfeed the baby, and liberalizing policies so a second support person or doula can be present.

There’s more traffic and sharing of the “real estate” at the head of the bed for surgeons and anesthesiologists and a different rhythm in baby care for pediatricians and nurses, Dr. Camann said, but the changes don’t require more space or add to the cost of the procedure.

“It’s more of a change in attitude, thinking a little bit outside the box,” he said. “A phrase I often use is ‘When you enter a cesarean delivery, turn off your surgical mentality.’ Even though it’s still an operating room, and it’s still a surgery, there are some different things that we can do that really just have to do with the attitude of everyone in the room, basically re-engineering the way we think about some of the traditional practices that go along in an operating room.”

Shifting those long-standing practices requires buy-in from around the hospital and multiple simulations to ensure everyone in the room understands their new role, family physician Dr. Susanna Magee, another early adopter of the approach and director of maternal child health at Memorial Hospital of Rhode Island in Pawtucket.

“This is absolutely a paradigm shift,” she said. “This is different from other operations, and it’s a difficult thing for surgeons, anesthesiologists, or nurses to get their heads around.”

The hospital recently published its experience with 144 “gentle cesarean births” from 2009 to 2013, and has seen no increase in complications, operating room times, or infection rates (J. Am. Board Fam. Med. 2014;27:690-3).

Beginning in 2011, they implemented gentle cesarean even in nonscheduled or urgent cesareans, recognizing the potential for false-positive fetal monitoring and the probability of a healthy infant even in cases of a persistent category II fetal heart tracing, Dr. Magee said.

Courtesy Brigham and Women&#039;s Hospital

Immediate skin-to-skin contact after cesarean is now the standard of care at the hospital and has prompted some women who knew they would require a cesarean delivery to transfer care to the Rhode Island hospital, according to Dr. Magee. Gentle cesareans have also been an selling point for the Brigham, Dr. Camann said.

“I suspect there will be some marketing from hospitals who are looking to say we can offer this, but my suspicion is hospitals would be in a better position to market that their cesarean section rates are at or below the national average,” said Dr. Wanda Filer, president-elect of the American Academy of Family Physicians. “The gentle C-section in and of itself is not going to be their competitive advantage. It would be interesting to see if they choose that because I think there could be upsides, but also opportunities for backlash.”

Sources interviewed for this article were all quick to point out that they are not advocating increasing the number of cesarean deliveries, but instead trying to enrich the experience for women who are already candidates for an operative birth.

“Some people have said you’re actually making cesareans so pleasant that you might change the cesarean section rate, maybe encourage people to have a cesarean, and I want to directly address that by saying it is simply not the case at all,” Dr. Camann said. “A cesarean should be done only if there are appropriate medical indications, nothing to do with the whole concept we are discussing here. But if there are appropriate medical indications for a cesarean, we can do certain things to make it a better experience.”

The new approach reflects the move toward more patient-centered care across all specialties and rising demand over the past decade for more natural birth processes, both Dr. Aghajanian and Dr. Magee observed.

“It was truly patients that brought it to our attention, and I think that’s important. It’s a patient-centered technique,” Dr. Magee said, adding that the highest compliment came from a mother who remarked, “I know you did surgery on me, but this was a birth.”

Some recent media reports have cast the approach as a major shift in cesarean delivery, but there’s nothing radical about it, according to ob.gyn. Dr. Jeff Livingston and certified nurse-midwife Ms. Rachel Zimmer, both with MacArthur Medical Center in Irving, Texas.

“We’re making minor adjustments with the patient and her family’s interests at heart, always doing it safely, but making it a more personalized and individualized experience,” he said.

For many patients, the most appreciable difference about their “family-centered cesarean” is that they get to actively participate and plan their birth, just as they would with a vaginal birth, Ms. Zimmer said.

For Dr. Livingston, the biggest change is pausing after the baby’s head enters the abdominal field to allow external compression from the uterus to help expel lung liquids, a technique described in an early report on “the natural cesarean” by obstetricians in the United Kingdom and Australia (BJOG 2008;115:1037-42).

An opaque surgical drape is lowered and the mother’s head elevated by the anesthesiologist to let parents watch the birth, but not all patients choose to do so, he said.

Overall awareness of family-centered cesareans is low among new mothers, and they are performed upon request, not as the standard of care, Dr. Livingston noted.

And the trend is being seen outside large urban centers, as well. In Peoria, Ill., Dr. Michael Leonardi of OSF Saint Francis Medical Center, said patients at his hospital are requesting family-centered cesareans. At the same time, the hospital continues to get referrals for the management of placenta accreta from women who’ve had too many cesareans, reflecting the need to have the “bigger conversation” with patients about what they and the hospital can do to safely avoid the primary cesarean and interventions that increase cesarean risk, such as induction of labor with an unfavorable cervix, he said.

“A piece to patient-centered care is not me telling the patient what to do and being paternalistic, but making sure people have the information they need, in a way that makes sense to them, so they can make an informed decision,” Dr. Leonardi said.

[email protected]

The name is still evolving, but the idea of a more patient-centered cesarean delivery is beginning to take root in American hospitals.

At Cedars-Sinai Medical Center, where roughly 35% of the 6,500 deliveries each year are by cesarean, an obstetrics-gynecology “customization of care” task force is working to standardize what is being referred to nationally as gentle or natural cesareans, as well as family- or patient-centered cesarean delivery.

Central to the approach is parent involvement, keeping mothers and infants together, and transferring the baby onto the mother’s chest for early skin-to-skin contact after delivery.

“When they find out they have the option to do skin-to-skin, it relieves a lot of the anxiety, especially if the C-section is unplanned,” said Dr. Paola Aghajanian, director of labor and delivery and the Maternal-Fetal Care Unit at the Los Angeles–based hospital.

During a traditional cesarean, it’s at least 30 minutes and in most cases up to 60 minutes before the mother can hold her baby. But with a gentle cesarean, Apgar testing is performed on the mother’s chest, while warm blankets are used to maintain the infant’s temperature.

At Cedars-Sinai, they are working to reduce maternal sedation and eliminate extraneous conversations in the operating room. The hospital is also in the process of ordering clear surgical drapes so that mothers and their partners can watch the birth, Dr. Aghajanian said. The use of clear drapes has been popularized by Dr. William Camann, director of obstetric anesthesia at Brigham and Women’s Hospital in Boston, who said the idea came to him after watching open heart surgery at another hospital where the drapes were used to enhance coordination and communication between anesthesiologists and cardiothoracic surgeons.

Courtesy Brigham and Women&#039;s Hospital

The clear drapes have been met with tremendous approval, particularly from mothers, and reduce the potential risk for infection, though it is already very low, said Dr. Camann, an early adopter of what the Brigham calls “gentle cesareans.”

Over the last 4 years they’ve made other adjustments, including moving ECG leads from the chest to a more lateral position, shifting monitors so mothers can have more mobility to interact with or breastfeed the baby, and liberalizing policies so a second support person or doula can be present.

There’s more traffic and sharing of the “real estate” at the head of the bed for surgeons and anesthesiologists and a different rhythm in baby care for pediatricians and nurses, Dr. Camann said, but the changes don’t require more space or add to the cost of the procedure.

“It’s more of a change in attitude, thinking a little bit outside the box,” he said. “A phrase I often use is ‘When you enter a cesarean delivery, turn off your surgical mentality.’ Even though it’s still an operating room, and it’s still a surgery, there are some different things that we can do that really just have to do with the attitude of everyone in the room, basically re-engineering the way we think about some of the traditional practices that go along in an operating room.”

Shifting those long-standing practices requires buy-in from around the hospital and multiple simulations to ensure everyone in the room understands their new role, family physician Dr. Susanna Magee, another early adopter of the approach and director of maternal child health at Memorial Hospital of Rhode Island in Pawtucket.

“This is absolutely a paradigm shift,” she said. “This is different from other operations, and it’s a difficult thing for surgeons, anesthesiologists, or nurses to get their heads around.”

The hospital recently published its experience with 144 “gentle cesarean births” from 2009 to 2013, and has seen no increase in complications, operating room times, or infection rates (J. Am. Board Fam. Med. 2014;27:690-3).

Beginning in 2011, they implemented gentle cesarean even in nonscheduled or urgent cesareans, recognizing the potential for false-positive fetal monitoring and the probability of a healthy infant even in cases of a persistent category II fetal heart tracing, Dr. Magee said.

Courtesy Brigham and Women&#039;s Hospital

Immediate skin-to-skin contact after cesarean is now the standard of care at the hospital and has prompted some women who knew they would require a cesarean delivery to transfer care to the Rhode Island hospital, according to Dr. Magee. Gentle cesareans have also been an selling point for the Brigham, Dr. Camann said.

“I suspect there will be some marketing from hospitals who are looking to say we can offer this, but my suspicion is hospitals would be in a better position to market that their cesarean section rates are at or below the national average,” said Dr. Wanda Filer, president-elect of the American Academy of Family Physicians. “The gentle C-section in and of itself is not going to be their competitive advantage. It would be interesting to see if they choose that because I think there could be upsides, but also opportunities for backlash.”

Sources interviewed for this article were all quick to point out that they are not advocating increasing the number of cesarean deliveries, but instead trying to enrich the experience for women who are already candidates for an operative birth.

“Some people have said you’re actually making cesareans so pleasant that you might change the cesarean section rate, maybe encourage people to have a cesarean, and I want to directly address that by saying it is simply not the case at all,” Dr. Camann said. “A cesarean should be done only if there are appropriate medical indications, nothing to do with the whole concept we are discussing here. But if there are appropriate medical indications for a cesarean, we can do certain things to make it a better experience.”

The new approach reflects the move toward more patient-centered care across all specialties and rising demand over the past decade for more natural birth processes, both Dr. Aghajanian and Dr. Magee observed.

“It was truly patients that brought it to our attention, and I think that’s important. It’s a patient-centered technique,” Dr. Magee said, adding that the highest compliment came from a mother who remarked, “I know you did surgery on me, but this was a birth.”

Some recent media reports have cast the approach as a major shift in cesarean delivery, but there’s nothing radical about it, according to ob.gyn. Dr. Jeff Livingston and certified nurse-midwife Ms. Rachel Zimmer, both with MacArthur Medical Center in Irving, Texas.

“We’re making minor adjustments with the patient and her family’s interests at heart, always doing it safely, but making it a more personalized and individualized experience,” he said.

For many patients, the most appreciable difference about their “family-centered cesarean” is that they get to actively participate and plan their birth, just as they would with a vaginal birth, Ms. Zimmer said.

For Dr. Livingston, the biggest change is pausing after the baby’s head enters the abdominal field to allow external compression from the uterus to help expel lung liquids, a technique described in an early report on “the natural cesarean” by obstetricians in the United Kingdom and Australia (BJOG 2008;115:1037-42).

An opaque surgical drape is lowered and the mother’s head elevated by the anesthesiologist to let parents watch the birth, but not all patients choose to do so, he said.

Overall awareness of family-centered cesareans is low among new mothers, and they are performed upon request, not as the standard of care, Dr. Livingston noted.

And the trend is being seen outside large urban centers, as well. In Peoria, Ill., Dr. Michael Leonardi of OSF Saint Francis Medical Center, said patients at his hospital are requesting family-centered cesareans. At the same time, the hospital continues to get referrals for the management of placenta accreta from women who’ve had too many cesareans, reflecting the need to have the “bigger conversation” with patients about what they and the hospital can do to safely avoid the primary cesarean and interventions that increase cesarean risk, such as induction of labor with an unfavorable cervix, he said.

“A piece to patient-centered care is not me telling the patient what to do and being paternalistic, but making sure people have the information they need, in a way that makes sense to them, so they can make an informed decision,” Dr. Leonardi said.

[email protected]

The name is still evolving, but the idea of a more patient-centered cesarean delivery is beginning to take root in American hospitals.

At Cedars-Sinai Medical Center, where roughly 35% of the 6,500 deliveries each year are by cesarean, an obstetrics-gynecology “customization of care” task force is working to standardize what is being referred to nationally as gentle or natural cesareans, as well as family- or patient-centered cesarean delivery.

Central to the approach is parent involvement, keeping mothers and infants together, and transferring the baby onto the mother’s chest for early skin-to-skin contact after delivery.

“When they find out they have the option to do skin-to-skin, it relieves a lot of the anxiety, especially if the C-section is unplanned,” said Dr. Paola Aghajanian, director of labor and delivery and the Maternal-Fetal Care Unit at the Los Angeles–based hospital.

During a traditional cesarean, it’s at least 30 minutes and in most cases up to 60 minutes before the mother can hold her baby. But with a gentle cesarean, Apgar testing is performed on the mother’s chest, while warm blankets are used to maintain the infant’s temperature.

At Cedars-Sinai, they are working to reduce maternal sedation and eliminate extraneous conversations in the operating room. The hospital is also in the process of ordering clear surgical drapes so that mothers and their partners can watch the birth, Dr. Aghajanian said. The use of clear drapes has been popularized by Dr. William Camann, director of obstetric anesthesia at Brigham and Women’s Hospital in Boston, who said the idea came to him after watching open heart surgery at another hospital where the drapes were used to enhance coordination and communication between anesthesiologists and cardiothoracic surgeons.

Courtesy Brigham and Women&#039;s Hospital

The clear drapes have been met with tremendous approval, particularly from mothers, and reduce the potential risk for infection, though it is already very low, said Dr. Camann, an early adopter of what the Brigham calls “gentle cesareans.”

Over the last 4 years they’ve made other adjustments, including moving ECG leads from the chest to a more lateral position, shifting monitors so mothers can have more mobility to interact with or breastfeed the baby, and liberalizing policies so a second support person or doula can be present.

There’s more traffic and sharing of the “real estate” at the head of the bed for surgeons and anesthesiologists and a different rhythm in baby care for pediatricians and nurses, Dr. Camann said, but the changes don’t require more space or add to the cost of the procedure.

“It’s more of a change in attitude, thinking a little bit outside the box,” he said. “A phrase I often use is ‘When you enter a cesarean delivery, turn off your surgical mentality.’ Even though it’s still an operating room, and it’s still a surgery, there are some different things that we can do that really just have to do with the attitude of everyone in the room, basically re-engineering the way we think about some of the traditional practices that go along in an operating room.”

Shifting those long-standing practices requires buy-in from around the hospital and multiple simulations to ensure everyone in the room understands their new role, family physician Dr. Susanna Magee, another early adopter of the approach and director of maternal child health at Memorial Hospital of Rhode Island in Pawtucket.

“This is absolutely a paradigm shift,” she said. “This is different from other operations, and it’s a difficult thing for surgeons, anesthesiologists, or nurses to get their heads around.”

The hospital recently published its experience with 144 “gentle cesarean births” from 2009 to 2013, and has seen no increase in complications, operating room times, or infection rates (J. Am. Board Fam. Med. 2014;27:690-3).

Beginning in 2011, they implemented gentle cesarean even in nonscheduled or urgent cesareans, recognizing the potential for false-positive fetal monitoring and the probability of a healthy infant even in cases of a persistent category II fetal heart tracing, Dr. Magee said.

Courtesy Brigham and Women&#039;s Hospital

Immediate skin-to-skin contact after cesarean is now the standard of care at the hospital and has prompted some women who knew they would require a cesarean delivery to transfer care to the Rhode Island hospital, according to Dr. Magee. Gentle cesareans have also been an selling point for the Brigham, Dr. Camann said.

“I suspect there will be some marketing from hospitals who are looking to say we can offer this, but my suspicion is hospitals would be in a better position to market that their cesarean section rates are at or below the national average,” said Dr. Wanda Filer, president-elect of the American Academy of Family Physicians. “The gentle C-section in and of itself is not going to be their competitive advantage. It would be interesting to see if they choose that because I think there could be upsides, but also opportunities for backlash.”

Sources interviewed for this article were all quick to point out that they are not advocating increasing the number of cesarean deliveries, but instead trying to enrich the experience for women who are already candidates for an operative birth.

“Some people have said you’re actually making cesareans so pleasant that you might change the cesarean section rate, maybe encourage people to have a cesarean, and I want to directly address that by saying it is simply not the case at all,” Dr. Camann said. “A cesarean should be done only if there are appropriate medical indications, nothing to do with the whole concept we are discussing here. But if there are appropriate medical indications for a cesarean, we can do certain things to make it a better experience.”

The new approach reflects the move toward more patient-centered care across all specialties and rising demand over the past decade for more natural birth processes, both Dr. Aghajanian and Dr. Magee observed.

“It was truly patients that brought it to our attention, and I think that’s important. It’s a patient-centered technique,” Dr. Magee said, adding that the highest compliment came from a mother who remarked, “I know you did surgery on me, but this was a birth.”

Some recent media reports have cast the approach as a major shift in cesarean delivery, but there’s nothing radical about it, according to ob.gyn. Dr. Jeff Livingston and certified nurse-midwife Ms. Rachel Zimmer, both with MacArthur Medical Center in Irving, Texas.

“We’re making minor adjustments with the patient and her family’s interests at heart, always doing it safely, but making it a more personalized and individualized experience,” he said.

For many patients, the most appreciable difference about their “family-centered cesarean” is that they get to actively participate and plan their birth, just as they would with a vaginal birth, Ms. Zimmer said.

For Dr. Livingston, the biggest change is pausing after the baby’s head enters the abdominal field to allow external compression from the uterus to help expel lung liquids, a technique described in an early report on “the natural cesarean” by obstetricians in the United Kingdom and Australia (BJOG 2008;115:1037-42).

An opaque surgical drape is lowered and the mother’s head elevated by the anesthesiologist to let parents watch the birth, but not all patients choose to do so, he said.

Overall awareness of family-centered cesareans is low among new mothers, and they are performed upon request, not as the standard of care, Dr. Livingston noted.

And the trend is being seen outside large urban centers, as well. In Peoria, Ill., Dr. Michael Leonardi of OSF Saint Francis Medical Center, said patients at his hospital are requesting family-centered cesareans. At the same time, the hospital continues to get referrals for the management of placenta accreta from women who’ve had too many cesareans, reflecting the need to have the “bigger conversation” with patients about what they and the hospital can do to safely avoid the primary cesarean and interventions that increase cesarean risk, such as induction of labor with an unfavorable cervix, he said.

“A piece to patient-centered care is not me telling the patient what to do and being paternalistic, but making sure people have the information they need, in a way that makes sense to them, so they can make an informed decision,” Dr. Leonardi said.

[email protected]

A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.

Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.

The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.

© 2015 AACR/Todd Buchanan

To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.

A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.

An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.

The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).

The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.

Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.

Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.

The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.

The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.

“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”

That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.

A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.

It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.

[email protected]

On Twitter @pwendl

A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.

Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.

The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.

© 2015 AACR/Todd Buchanan

To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.

A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.

An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.

The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).

The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.

Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.

Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.

The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.

The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.

“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”

That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.

A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.

It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.

[email protected]

On Twitter @pwendl

A detailed survival analysis questions the rationale behind use of the diabetes drug metformin to improve pancreatic cancer survival.

Several epidemiologic studies have shown that metformin use reduces cancer mortality, leading the diabetes drug to be included in the treatment arm of 20 open clinical trials in recalcitrant cancers, Dr. Roongruedee Chaiteerakij reported at the annual meeting of the American Association for Cancer Research.

The problem is that the epidemiologic studies commonly classified metformin use as simply “ever or never,” which may have introduced unintended biases.

© 2015 AACR/Todd Buchanan

To address these potential biases, Dr. Chaiteerakij and her colleagues at the Mayo Clinic in Rochester, Minn., analyzed 1,360 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and diabetes between 2000 and 2011 in the database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. More than half (59%) were male; the average age was 67 years.

A total of 380 patients were excluded for surgically induced diabetes, unknown diabetes duration, and PDAC diagnosis more than 90 days prior to the first Mayo visit. This left 980 patients in the final cohort.

An initial analysis using the ever vs. never classification suggested that metformin use was associated with marginally improved survival in patients with PDAC (median 9.9 months ever use vs. 8.9 months never use; unadjusted hazard ratio, 0.9; P = .08), Dr. Chaiteerakij said.

The association was most significant in locally advanced PDAC patients (10.2 months ever use vs. 8.1 months never use; unadjusted HR 0.7; P = .006).

The investigators then performed a subanalysis of locally advanced PDAC patients, this time stratified by timing of metformin initiation: never used (reference group), started more than 1 year before PDAC diagnosis, started within 1 year before PDAC diagnosis, started less than 30 days post PDAC diagnosis, and started more than 30 days post PDAC diagnosis.

Median survival was 8.1, 10.1, and 9.9 months in the first three groups, increasing to 11.4 months and 13.7 months in the two groups that started metformin after PDAC diagnosis, Dr. Chaiteerakij reported.

Hazard ratios for the four metformin groups were 0.7, 0.6, 0.9, and 0.5, after adjustment for age, sex, disease stage, body mass index, and diagnosis year.

The increased survival in patients who started metformin after PDAC diagnosis demonstrates the inherent survival bias in ever/never classification because these patients had lived long enough to receive the drug, she said.

The ever/never classification is commonly used because it can be difficult to extract detailed information on drug use, dose, or timing from retrospective medical records, she noted in a press briefing.

“Epidemiologic studies of medication exposure and cancer survival warrant very careful and detailed data collection and analysis to minimize biases,” Dr. Chaiteerakij concluded. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.”

That said, 11 pancreatic cancer trials are currently listed on www.clinicaltrials.gov, she told reporters.

A simple search of the site for “cancer and metformin” yields no fewer than 230 trials.

It isn’t possible to say at this time whether the Mayo results are applicable to other nonrecalcitrant cancers, Dr. Chaiteerakij said.

[email protected]

On Twitter @pwendl

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

[email protected]

On Twitter @pwendl

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

[email protected]

On Twitter @pwendl

Metastatic triple-negative breast cancer appears to be the latest hard-to-treat cancer to yield to the juggernaut that is now anti-PD-L1 immunotherapy.

MPDL3280L, an investigational monoclonal antibody against programmed death ligand 1 (PD-L1), posted an overall response rate of 19% among 21 evaluable patients in a phase Ia trial (95% confidence interval, 5-42).

© 2015 AACR/Todd Buchanan

This included two complete responses in patients with high PD-L1 expression and two partial responses. Three of the four responses are ongoing, Dr. Leisha Emens reported at the annual meeting of the American Association for Cancer Research.

“I think it very well could be the first targeted therapy that bears out in a larger trial,” she said during a press briefing. “These data are still early, and we need to enroll and treat a lot more patients with this agent, but I think it has great, great promise for this particular breast cancer subtype.”

There is great unmet need for new treatments in triple-negative breast cancer (TNBC) because it has a worse prognosis than other breast cancer subtypes do, and the only approved treatment option in the United States is chemotherapy.

TNBC is a good candidate for immunotherapy, particularly PD-L1 targeted therapies, because it has a higher mutation rate than do other breast cancer subtypes. This produces neoantigens that can be recognized as foreign by the immune system and be more effective targets for an immune response, Dr. Emens of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, explained.

TNBC also has higher PD-L1 expression levels, which can inhibit T-cell antitumor responses, and more tumor-infiltrating lymphocytes, which can facilitate a immune response and are associated with improved outcomes when present in high numbers.

MPDL3280A is designed to inhibit the binding of PD-L1 to programmed death receptor 1 (PD-1) and B7.1, which can restore antitumor T-cell activity and enhance T-cell priming, she said.

The checkpoint inhibitor received breakthrough therapy designation for metastatic bladder cancer in 2014 and a second designation in non–small cell lung cancer in February.

The ongoing phase Ia trial enrolled 54 women with metastatic TNBC and an ECOG performance status of 0 or 1. This included 21 patients initially selected for high PD-L1 expression levels (at least 5%) on their immune cells and 33 all-comers. MPDL3280A intravenous infusions were given every 3 weeks at doses of 15 mg/kg, 20 mg/kg, or 1,200 mg. Efficacy was evaluated in the 21 patients and safety in all 54 patients.

At 24 weeks, progression-free survival was 27% (95% CI, 7-47), Dr. Emens said.The median duration of response (range, 18-56+ weeks) has not been reached.

Three patients with progressive disease experienced pseudoprogression, where the target lesion shrank, but new lesions developed. Pseudoprogression, a feature of checkpoint inhibition that also has been seen with ipilimumab (Yervoy), is new for many physicians to manage and requires the patient’s entire clinical picture be taken into account, Dr. Emens said.

“An important component of the phenomenon of pseudoprogression is that if you see evidence of new lesions on a scan and the patient’s doing clinically well, you continue to treat and then reevaluate subsequent to that,” she said. “If there’s progression at that point, then potentially you consider changing the therapy or just following the patient more closely. Another potential option to help sort through that is to try and obtain tissue from one of those lesions to get some idea of what is happening, if it’s a phenomenon of the inflammatory response or a response to the therapy.”

Dr. Emens detailed one such case in which three target lesions decreased in size from baseline on 9- and 20-month follow-up scans, but newly enlarged axillary nodes that appeared inflammatory or necrotic developed near the third target lesion at 9 months. The patient remained on therapy and is doing well today, with further shrinkage of the target lesion and regression of the axillary nodes at 20 months.

MPDL3280A was generally well tolerated, with fatigue, nausea, fever, decreased appetite, and asthenia being the most common adverse events, Dr. Emens said. In all, 11% of patients experienced grade 3 treatment-related events. Two deaths, assessed as drug related by the investigator, are under investigation.

Press briefing moderator Louis M. Winer, director of the Georgetown Lombardi Comprehensive Cancer Center, commented that it wasn’t that long ago that phase I investigators were pleased if they saw even a hint of activity that would justify moving forward to phase II. The activity signals with the checkpoint inhibitors, however, are “unequivocal” and the implications for the future treatment of people with triple negative breast cancer are “very, very exciting,” according to Dr. Winer.

Earlier in the meeting, stellar results with the checkpoint inhibitor pembrolizumab from the KEYNOTE-006 trial upended the treatment paradigm for advanced melanoma. Pembrolizumab has been evaluated in TNBC and the safety profile and responses are similar to those with MPDL3280A, Dr. Emens said.

A global phase III trial evaluating MPDL3280A in combination with paclitaxel (Abraxane) as first-line therapy for metastatic TNBC is preparing to launch.

[email protected]

On Twitter @pwendl

Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.

Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.

Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.

Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.

Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.

The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.

Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.

© 2015 AACR/Todd Buchanan

Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.

KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.

Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.

At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.

The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.

At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.

The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.

There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.

At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.

Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).

When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.

“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”

The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.

[email protected]

Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.

Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.

Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.

Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.

Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.

The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.

Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.

© 2015 AACR/Todd Buchanan

Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.

KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.

Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.

At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.

The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.

At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.

The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.

There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.

At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.

Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).

When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.

“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”

The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.

[email protected]

Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYNOTE-006 trial.

Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.

Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.

© 2015 AACR/Todd Buchanan

“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.

Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.

Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian, director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.

The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.

Results of the KEYSTONE-006 trial, simultaneously published on line (N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.

© 2015 AACR/Todd Buchanan

Lead investigator Dr. Caroline Robert, head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.

KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.

Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.

At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.

The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.

At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.

The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.

There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.

At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.

Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).

When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.

“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”

The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.

[email protected]