User login
Toxicity high for SBRT in centrally-located lung tumors
VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.
The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.
“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).
“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.
“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.
A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.
Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.
The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.
After a follow-up of 18.6 months, 31 (42%) patients had died.
The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).
Bleeding often occurred without warning and had an acute onset and toll.
Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.
SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.
Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.
“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?
“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”
The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.
VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.
The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.
“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).
“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.
“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.
A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.
Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.
The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.
After a follow-up of 18.6 months, 31 (42%) patients had died.
The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).
Bleeding often occurred without warning and had an acute onset and toll.
Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.
SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.
Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.
“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?
“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”
The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.
VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.
The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.
“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).
“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.
“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.
A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.
Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.
The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.
After a follow-up of 18.6 months, 31 (42%) patients had died.
The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).
Bleeding often occurred without warning and had an acute onset and toll.
Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.
SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.
Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.
“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?
“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”
The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.
AT WCLC 2016
Key clinical point: Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.
Major finding: There was a high rate of grade 3, 4, and 5 toxicities, including six cases of grade 5 bleeding.
Data source: The phase II non-randomized HILUS trial of 74 patients with centrally-located lung tumors treated with SBRT.
Disclosures: The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.
c-Myc could be key to alisertib potential in small-cell lung cancer
VIENNA – The investigational agent alisertib plus paclitaxel improved progression-free survival (PFS), compared with paclitaxel plus placebo, in a randomized, double-blind, phase II study of patients with relapsed or refractory small-cell lung cancer (SCLC).
The median PFS was 3.32 months with alisertib/paclitaxel and 2.17 months with paclitaxel/placebo, giving an overall 30% improvement with the combination (hazard ratio, 0.71; 95% confidence interval, 0.509-0.985; P = .038).
“c-Myc protein expression showed a strong association with improved PFS, despite the small number of evaluable patients,” study investigator Taofeek Owonikoko, MD, of Emory University, Atlanta, said at the World Conference on Lung Cancer.
Amplification and overexpression of c-Myc is a strong oncogenic driver in many cancers, he explained. Around 18%-31% of SCLCs overexpress the protein, and it is often found in patients with chemorefractory disease, he said.
In the study, longer PFS was achieved in patients treated with alisertib/paclitaxel than in those given placebo/paclitaxel if they were c-Myc positive (4.64 vs. 2.27 months; HR, 0.29). Conversely, patients who were c-Myc negative had a shorter PFS with the combination (3.32 vs. 5.16 months; HR, 11.8).
“A prospective study is needed to further validate the predictive value of c-Myc in the clinic,” Dr. Owonikoko said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Alisertib is an aurora A kinase inhibitor that has already been shown to have antitumor activity in patients with solid tumors, including those with SCLC (Lancet Oncol. 2015;16[4]:395-405).
The current phase II study was designed to evaluate the efficacy and safety of alisertib in combination with paclitaxel, compared with placebo plus paclitaxel, in a larger population of patients with SCLC who had relapsed within 6 months or did not respond to standard first-line, platinum-based chemotherapy.
Treatment was given in 28-day cycles, with patients randomized to the combination receiving alisertib at an oral, 40-mg, twice-daily dose on days 1-3, 8-10, and 15-17 and paclitaxel administered intravenously at a dose of 60 mg/m2 IV on days 1, 8, 15. Patients randomized to the control arm received a matched placebo plus paclitaxel given on the same days but at a dose of 80 mg/m2.
Overall, 178 patients were randomized, with a mean age of 62 years, and just over half (57%) were men.
Numerically higher objective response rates (22% vs. 18%), disease control rates (77 vs. 67%), and overall survival (6.87 vs. 5.58 months) also were seen with the combination over paclitaxel alone, although they did not achieve statistical significance.
Additional toxicities were observed with the combination treatment versus paclitaxel. Many of these were to be expected, Dr. Owonikoko said. Almost all (99% vs. 96%) of patients reported some type of adverse event, of which 75% and 51% were grade 3 or higher, respectively. Common any-grade adverse effects were diarrhea (59% vs. 20%), neutropenia (49% vs. 8%), anemia (44% vs. 20%), and fatigue (44% vs. 33%).
These toxicities, however, did not appear to affect patients’ quality of life, Dr. Owonikoko said, as comparable changes in quality-of-life scores using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument were observed. There was even an indication that patients taking alisertib/paclitaxel might have improved lung-related symptoms, such as shortness of breath and worsening cough.
The treatment of SCLC, particularly in the second-line setting, remains challenging, observed the invited discussant for the trial Jens Benn Sørensen, MD, of the Finsen Centre at Rigshospitalet, Copenhagen.
“There have been no major improvements in the last decade and there are no targeted agents approved for use,” Dr. Sørensen said. Although that is not for lack of trying, he qualified.
When first-line therapies fail, the guideline-recommended option is to put patients back on platinum-based chemotherapy if they were sensitive to such chemotherapy. If not, then topotecan is often an appropriate, reasonably tolerated option.
“The clinical relevance of second-line paclitaxel/alisertib in all comers is questionable,” he said. The PFS improvement of 1.2 months in this phase II study seems “mostly at the same level” when comparing trials of second-line, single-agent topotecan.
“However, the use of c-Myc as a predictor for efficacy seems very promising and should clearly be explored,” Dr. Sørensen noted.
He also suggested that it might be interesting to look into the combination of topotecan and alisertib versus topotecan alone in c-Myc-positive patients.
The study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Dr. Owonikoko disclosed consulting for Takeda and several other pharmaceutical companies. Dr. Sørensen did not have disclosures.
VIENNA – The investigational agent alisertib plus paclitaxel improved progression-free survival (PFS), compared with paclitaxel plus placebo, in a randomized, double-blind, phase II study of patients with relapsed or refractory small-cell lung cancer (SCLC).
The median PFS was 3.32 months with alisertib/paclitaxel and 2.17 months with paclitaxel/placebo, giving an overall 30% improvement with the combination (hazard ratio, 0.71; 95% confidence interval, 0.509-0.985; P = .038).
“c-Myc protein expression showed a strong association with improved PFS, despite the small number of evaluable patients,” study investigator Taofeek Owonikoko, MD, of Emory University, Atlanta, said at the World Conference on Lung Cancer.
Amplification and overexpression of c-Myc is a strong oncogenic driver in many cancers, he explained. Around 18%-31% of SCLCs overexpress the protein, and it is often found in patients with chemorefractory disease, he said.
In the study, longer PFS was achieved in patients treated with alisertib/paclitaxel than in those given placebo/paclitaxel if they were c-Myc positive (4.64 vs. 2.27 months; HR, 0.29). Conversely, patients who were c-Myc negative had a shorter PFS with the combination (3.32 vs. 5.16 months; HR, 11.8).
“A prospective study is needed to further validate the predictive value of c-Myc in the clinic,” Dr. Owonikoko said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Alisertib is an aurora A kinase inhibitor that has already been shown to have antitumor activity in patients with solid tumors, including those with SCLC (Lancet Oncol. 2015;16[4]:395-405).
The current phase II study was designed to evaluate the efficacy and safety of alisertib in combination with paclitaxel, compared with placebo plus paclitaxel, in a larger population of patients with SCLC who had relapsed within 6 months or did not respond to standard first-line, platinum-based chemotherapy.
Treatment was given in 28-day cycles, with patients randomized to the combination receiving alisertib at an oral, 40-mg, twice-daily dose on days 1-3, 8-10, and 15-17 and paclitaxel administered intravenously at a dose of 60 mg/m2 IV on days 1, 8, 15. Patients randomized to the control arm received a matched placebo plus paclitaxel given on the same days but at a dose of 80 mg/m2.
Overall, 178 patients were randomized, with a mean age of 62 years, and just over half (57%) were men.
Numerically higher objective response rates (22% vs. 18%), disease control rates (77 vs. 67%), and overall survival (6.87 vs. 5.58 months) also were seen with the combination over paclitaxel alone, although they did not achieve statistical significance.
Additional toxicities were observed with the combination treatment versus paclitaxel. Many of these were to be expected, Dr. Owonikoko said. Almost all (99% vs. 96%) of patients reported some type of adverse event, of which 75% and 51% were grade 3 or higher, respectively. Common any-grade adverse effects were diarrhea (59% vs. 20%), neutropenia (49% vs. 8%), anemia (44% vs. 20%), and fatigue (44% vs. 33%).
These toxicities, however, did not appear to affect patients’ quality of life, Dr. Owonikoko said, as comparable changes in quality-of-life scores using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument were observed. There was even an indication that patients taking alisertib/paclitaxel might have improved lung-related symptoms, such as shortness of breath and worsening cough.
The treatment of SCLC, particularly in the second-line setting, remains challenging, observed the invited discussant for the trial Jens Benn Sørensen, MD, of the Finsen Centre at Rigshospitalet, Copenhagen.
“There have been no major improvements in the last decade and there are no targeted agents approved for use,” Dr. Sørensen said. Although that is not for lack of trying, he qualified.
When first-line therapies fail, the guideline-recommended option is to put patients back on platinum-based chemotherapy if they were sensitive to such chemotherapy. If not, then topotecan is often an appropriate, reasonably tolerated option.
“The clinical relevance of second-line paclitaxel/alisertib in all comers is questionable,” he said. The PFS improvement of 1.2 months in this phase II study seems “mostly at the same level” when comparing trials of second-line, single-agent topotecan.
“However, the use of c-Myc as a predictor for efficacy seems very promising and should clearly be explored,” Dr. Sørensen noted.
He also suggested that it might be interesting to look into the combination of topotecan and alisertib versus topotecan alone in c-Myc-positive patients.
The study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Dr. Owonikoko disclosed consulting for Takeda and several other pharmaceutical companies. Dr. Sørensen did not have disclosures.
VIENNA – The investigational agent alisertib plus paclitaxel improved progression-free survival (PFS), compared with paclitaxel plus placebo, in a randomized, double-blind, phase II study of patients with relapsed or refractory small-cell lung cancer (SCLC).
The median PFS was 3.32 months with alisertib/paclitaxel and 2.17 months with paclitaxel/placebo, giving an overall 30% improvement with the combination (hazard ratio, 0.71; 95% confidence interval, 0.509-0.985; P = .038).
“c-Myc protein expression showed a strong association with improved PFS, despite the small number of evaluable patients,” study investigator Taofeek Owonikoko, MD, of Emory University, Atlanta, said at the World Conference on Lung Cancer.
Amplification and overexpression of c-Myc is a strong oncogenic driver in many cancers, he explained. Around 18%-31% of SCLCs overexpress the protein, and it is often found in patients with chemorefractory disease, he said.
In the study, longer PFS was achieved in patients treated with alisertib/paclitaxel than in those given placebo/paclitaxel if they were c-Myc positive (4.64 vs. 2.27 months; HR, 0.29). Conversely, patients who were c-Myc negative had a shorter PFS with the combination (3.32 vs. 5.16 months; HR, 11.8).
“A prospective study is needed to further validate the predictive value of c-Myc in the clinic,” Dr. Owonikoko said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
Alisertib is an aurora A kinase inhibitor that has already been shown to have antitumor activity in patients with solid tumors, including those with SCLC (Lancet Oncol. 2015;16[4]:395-405).
The current phase II study was designed to evaluate the efficacy and safety of alisertib in combination with paclitaxel, compared with placebo plus paclitaxel, in a larger population of patients with SCLC who had relapsed within 6 months or did not respond to standard first-line, platinum-based chemotherapy.
Treatment was given in 28-day cycles, with patients randomized to the combination receiving alisertib at an oral, 40-mg, twice-daily dose on days 1-3, 8-10, and 15-17 and paclitaxel administered intravenously at a dose of 60 mg/m2 IV on days 1, 8, 15. Patients randomized to the control arm received a matched placebo plus paclitaxel given on the same days but at a dose of 80 mg/m2.
Overall, 178 patients were randomized, with a mean age of 62 years, and just over half (57%) were men.
Numerically higher objective response rates (22% vs. 18%), disease control rates (77 vs. 67%), and overall survival (6.87 vs. 5.58 months) also were seen with the combination over paclitaxel alone, although they did not achieve statistical significance.
Additional toxicities were observed with the combination treatment versus paclitaxel. Many of these were to be expected, Dr. Owonikoko said. Almost all (99% vs. 96%) of patients reported some type of adverse event, of which 75% and 51% were grade 3 or higher, respectively. Common any-grade adverse effects were diarrhea (59% vs. 20%), neutropenia (49% vs. 8%), anemia (44% vs. 20%), and fatigue (44% vs. 33%).
These toxicities, however, did not appear to affect patients’ quality of life, Dr. Owonikoko said, as comparable changes in quality-of-life scores using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument were observed. There was even an indication that patients taking alisertib/paclitaxel might have improved lung-related symptoms, such as shortness of breath and worsening cough.
The treatment of SCLC, particularly in the second-line setting, remains challenging, observed the invited discussant for the trial Jens Benn Sørensen, MD, of the Finsen Centre at Rigshospitalet, Copenhagen.
“There have been no major improvements in the last decade and there are no targeted agents approved for use,” Dr. Sørensen said. Although that is not for lack of trying, he qualified.
When first-line therapies fail, the guideline-recommended option is to put patients back on platinum-based chemotherapy if they were sensitive to such chemotherapy. If not, then topotecan is often an appropriate, reasonably tolerated option.
“The clinical relevance of second-line paclitaxel/alisertib in all comers is questionable,” he said. The PFS improvement of 1.2 months in this phase II study seems “mostly at the same level” when comparing trials of second-line, single-agent topotecan.
“However, the use of c-Myc as a predictor for efficacy seems very promising and should clearly be explored,” Dr. Sørensen noted.
He also suggested that it might be interesting to look into the combination of topotecan and alisertib versus topotecan alone in c-Myc-positive patients.
The study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Dr. Owonikoko disclosed consulting for Takeda and several other pharmaceutical companies. Dr. Sørensen did not have disclosures.
AT WCLC 2016
Key clinical point: Alisertib/paclitaxel is an investigational combination that was tested for the treatment of relapsed or refractory small-cell lung cancer (SCLC).
Major finding: Improved progression-free survival was seen with the combination versus paclitaxel alone (3.2 vs. 2.17 months, P less than .038).
Data source: Randomized, double-blind, multicenter, phase II study of alisertib/paclitaxel versus placebo/paclitaxel in 178 patients with relapsed or refractory SCLC.
Disclosures: The study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Dr. Owonikoko disclosed consulting for Takeda and several other pharmaceutical companies. Dr. Sørensen had no conflicts of interest to disclose.
Pembrolizumab proves promising for treating advanced SCLC
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
VIENNA – One third of patients with extensive-stage small-cell lung cancer (SCLC) treated with the checkpoint inhibitor pembrolizumab achieved an objective response, according to updated data from the KEYNOTE-28 trial.
Of the 24 patients with advanced SCLC who received pembrolizumab in the multicohort phase Ib study, one had a complete response, seven had a partial response, and one further patient had stable disease for 6 or more months, giving a clinical benefit rate of 33.3% (95% CI, 15.6-53.3%).
“Pembrolizumab demonstrated meaningful antitumor activity in previously treated patients with PD-L1-positive small-cell lung cancer,” said presenting study author Patrick A. Ott, MD, PhD, of the Dana-Faber Cancer Institute in Boston.
“Responses were durable, with a median duration of response of 19.4 months,” Dr. Ott said at the World Conference on Cancer, which is sponsored by the International Association for the Study of Lung Cancer. About 40% of patients exhibited a decrease in tumor size, he added.
Treatment with pembrolizumab was associated with a progression-free survival (PFS) of 1.2 months, with a range of 1.7-5.9 months. The 6- and 12-month PFS rates were 28.6% and 23.8%, respectively.
The median overall survival (OS) was 9.7 months, ranging from 4.1 months to an upper limit that has not yet been reached. The respective 6- and 12-month OS rates were 66.0% and 37.7%.
“The safety experience was consistent with previous experience for pembrolizumab in other tumor types, and was identical with longer follow-up” Dr. Ott said.
Over a median follow-up duration of 9.8 months, treatment-related adverse events occurred in two-thirds of patients, with arthralgia, asthenia, and rash reported by four (16.7%) patients each, and diarrhea and fatigue by three (12.5%) patients each. There were no cases of pneumonitis.
The mean age of patients recruited into the KEYNOTE-28 trial was 60.5 years; more than half of the patients (58%) were male. Five (20.8%) had stable brain metastases, and 95.8% had small cell histology.
All recruited patients had received prior standard-of-care chemotherapy with cisplatin or carboplatin plus etoposide, 45.8% had received irinotecan or topotecan, and 29.2% had been treated with a taxane. In addition, one patient had received prior radiotherapy, one had been given an investigational tyrosine kinase inhibitor therapy, and another had received another, unspecified, investigational treatment.
After enrollment, all patients were treated with pembrolizumab at an intravenous dose of 10 mg/kg every 2 weeks. Response was assessed every 8 weeks for the first 6 months and then annually, with patients continuing to respond continuing to be treated for up to 2 years or until progression or unacceptable toxicity.
There are two ongoing, phase II trials with pembrolizumab in patients with advanced SCLC. One is looking at maintenance therapy with pembrolizumab after combination chemotherapy and is sponsored by the Barbara Ann Karmanos Cancer Institute in collaboration with the National Cancer Institute (NCT02359019). The other, the REACTION trial sponsored by the European Organisation for Research and Treatment of Cancer, is looking at the use of pembrolizumab together with etoposide and platinum chemotherapy in previously untreated patients (NCT02580994).
Merck funded the KEYNOTE-28 study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
AT WCLC 2016
Key clinical point: Pembrolizumab has antitumor activity in patients with advanced small-cell lung cancer.
Major finding: The objective response rate was 33.3% (95% CI 15.6-55.3%), including one complete and seven partial responses.
Data source: Phase Ib, nonrandomized, multicohort trial of 24 heavily pretreated patients with extensive-disease small-cell lung cancer.
Disclosures: Merck funded the study. Dr. Ott disclosed ties with Bristol-Myers Squibb, Merck, ArmoBiosciences, AstraZeneca/MedImmune, Celldex, Genentech, Alexion, and CytomX.
VIDEO: Pivotal results nail osimertinib’s role in NSCLC
VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.
During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
The AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) trial enrolled 419 patients at 126 international sites during 2014 and 2015. The trial’s primary endpoint was investigator-assessed progression-free survival, which occurred after a median of 10.1 months with osimertinib and 4.4 months with standard chemotherapy, a statistically significant 70% relative risk reduction (P less than .001) in the hazard for death or progressive disease. The drug was as effective for patients with central nervous system metastases as it was for the other patients, which Dr. Papadimitrakopoulou attributed to osimertinib’s good penetration across the blood-brain barrier. The drug’s overall performance in AURA3 was completely consistent with the results of earlier studies that led to its U.S. approval.
Despite that approval, routine testing for T790M mutations and routine prescribing of osimertinib to positive patients “has not fully penetrated U.S. practice,” Dr. Papadimitrakopoulou said, but she hoped that these new confirmatory data will now firmly establish it as standard of care for the tested population.
Osimertinib is now under testing as first-line TKI treatment for EGFR-positive NSCLC regardless of the tumor’s T790M status. It’s going head to head with two first-generation EGFR TKIs, gefitinib and erlotinib, in the FLAURA trial, which should have reportable results in 2017. “We are very encouraged by the AURA3 data that osimertinib could beat the first-generation TKIs” for first-line treatment, she said.
AURA3 was sponsored by AstraZeneca, which markets osimertinib (Tagrisso). Dr. Papadimitrakopoulou is a consultant to, and has received research support from, AstraZeneca and several other companies.
[email protected]
On Twitter @mitchelzoler
Osimertinib overcomes the T790M mutation, which is the cause of about half of the non–small-cell lung cancers that are EGFR positive and develop resistance to a first- or-second generation tyrosine kinase inhibitor. The AURA3 results officially make osimertinib the standard of care for these patients.
Osimertinib’s performance in AURA3 was consistent with what it did in the earlier studies, producing an overall response rate of about 60%-70% and extending progression-free survival out to a median of 10-11 months.
Tetsuya Mitsudomi, MD, is professor of thoracic surgery at Kindai University in Osaka-Sayama, Japan. He has been a consultant to, and has received honoraria and research support from, AstraZeneca and several other companies. He was principal investigator for AURA2, one of the phase II studies of osimertinib. He made these comments as designated discussant for AURA3.
Osimertinib overcomes the T790M mutation, which is the cause of about half of the non–small-cell lung cancers that are EGFR positive and develop resistance to a first- or-second generation tyrosine kinase inhibitor. The AURA3 results officially make osimertinib the standard of care for these patients.
Osimertinib’s performance in AURA3 was consistent with what it did in the earlier studies, producing an overall response rate of about 60%-70% and extending progression-free survival out to a median of 10-11 months.
Tetsuya Mitsudomi, MD, is professor of thoracic surgery at Kindai University in Osaka-Sayama, Japan. He has been a consultant to, and has received honoraria and research support from, AstraZeneca and several other companies. He was principal investigator for AURA2, one of the phase II studies of osimertinib. He made these comments as designated discussant for AURA3.
Osimertinib overcomes the T790M mutation, which is the cause of about half of the non–small-cell lung cancers that are EGFR positive and develop resistance to a first- or-second generation tyrosine kinase inhibitor. The AURA3 results officially make osimertinib the standard of care for these patients.
Osimertinib’s performance in AURA3 was consistent with what it did in the earlier studies, producing an overall response rate of about 60%-70% and extending progression-free survival out to a median of 10-11 months.
Tetsuya Mitsudomi, MD, is professor of thoracic surgery at Kindai University in Osaka-Sayama, Japan. He has been a consultant to, and has received honoraria and research support from, AstraZeneca and several other companies. He was principal investigator for AURA2, one of the phase II studies of osimertinib. He made these comments as designated discussant for AURA3.
VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.
During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
The AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) trial enrolled 419 patients at 126 international sites during 2014 and 2015. The trial’s primary endpoint was investigator-assessed progression-free survival, which occurred after a median of 10.1 months with osimertinib and 4.4 months with standard chemotherapy, a statistically significant 70% relative risk reduction (P less than .001) in the hazard for death or progressive disease. The drug was as effective for patients with central nervous system metastases as it was for the other patients, which Dr. Papadimitrakopoulou attributed to osimertinib’s good penetration across the blood-brain barrier. The drug’s overall performance in AURA3 was completely consistent with the results of earlier studies that led to its U.S. approval.
Despite that approval, routine testing for T790M mutations and routine prescribing of osimertinib to positive patients “has not fully penetrated U.S. practice,” Dr. Papadimitrakopoulou said, but she hoped that these new confirmatory data will now firmly establish it as standard of care for the tested population.
Osimertinib is now under testing as first-line TKI treatment for EGFR-positive NSCLC regardless of the tumor’s T790M status. It’s going head to head with two first-generation EGFR TKIs, gefitinib and erlotinib, in the FLAURA trial, which should have reportable results in 2017. “We are very encouraged by the AURA3 data that osimertinib could beat the first-generation TKIs” for first-line treatment, she said.
AURA3 was sponsored by AstraZeneca, which markets osimertinib (Tagrisso). Dr. Papadimitrakopoulou is a consultant to, and has received research support from, AstraZeneca and several other companies.
[email protected]
On Twitter @mitchelzoler
VIENNA – Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that received U.S. marketing approval in November 2015 as second-line treatment for selected patients with non–small-cell lung cancer based on phase II trial data, now has the pivotal-trial results that completely justify that action.
During a median follow-up of just over 8 months, patients who had progressed on their first-line EGFR tyrosine kinase inhibitor (TKI) and carried the T790M mutation and switched to osimertinib (Tagrisso) had “overwhelmingly” better response rates and progression-free survival, compared with patients put on standard-of-care chemotherapy in a multicenter randomized trial involving 419 patients, Vassiliki A. Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.
The AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3) trial enrolled 419 patients at 126 international sites during 2014 and 2015. The trial’s primary endpoint was investigator-assessed progression-free survival, which occurred after a median of 10.1 months with osimertinib and 4.4 months with standard chemotherapy, a statistically significant 70% relative risk reduction (P less than .001) in the hazard for death or progressive disease. The drug was as effective for patients with central nervous system metastases as it was for the other patients, which Dr. Papadimitrakopoulou attributed to osimertinib’s good penetration across the blood-brain barrier. The drug’s overall performance in AURA3 was completely consistent with the results of earlier studies that led to its U.S. approval.
Despite that approval, routine testing for T790M mutations and routine prescribing of osimertinib to positive patients “has not fully penetrated U.S. practice,” Dr. Papadimitrakopoulou said, but she hoped that these new confirmatory data will now firmly establish it as standard of care for the tested population.
Osimertinib is now under testing as first-line TKI treatment for EGFR-positive NSCLC regardless of the tumor’s T790M status. It’s going head to head with two first-generation EGFR TKIs, gefitinib and erlotinib, in the FLAURA trial, which should have reportable results in 2017. “We are very encouraged by the AURA3 data that osimertinib could beat the first-generation TKIs” for first-line treatment, she said.
AURA3 was sponsored by AstraZeneca, which markets osimertinib (Tagrisso). Dr. Papadimitrakopoulou is a consultant to, and has received research support from, AstraZeneca and several other companies.
[email protected]
On Twitter @mitchelzoler
Key clinical point:
Major finding: Progression-free survival averaged 10.1 months with osimertinib and 4.4 months in patients on standard chemotherapy.
Data source: AURA3, which randomized 419 patients at 126 international centers.
Disclosures: AURA3 was sponsored by AstraZeneca, which markets osimertinib (Tagrisso). Dr. Papadimitrakopoulou is a consultant to, and has received research support from, AstraZeneca and several other companies.
‘Vanishing’ role forecast for whole-brain irradiation for NSCLC metastases
VIENNA – Icotinib proved significantly more effective and less toxic than standard therapy with whole-brain irradiation and chemotherapy in patients with multiple brain metastases from epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer in the phase III BRAIN trial.
“With favorable objective response and disease control rates, icotinib was superior to whole-brain irradiation with chemotherapy, and therefore icotinib should be used as first-line therapy for advanced EGFR-mutant non–small cell lung cancers with brain metastases,” Yi-long Wu, MD, said in presenting the BRAIN results at the World Congress on Lung Cancer.
Patients with brain metastases are often excluded from participation in clinical trials because their prognosis is so poor. BRAIN is the first phase III trial to report results comparing an EGFR tyrosine kinase inhibitor (TKI) – icotinib – to whole-brain irradiation (WBI) plus chemotherapy, regarded in National Comprehensive Cancer Network guidelines as standard therapy in the setting of brain metastases from NSCLC, noted Dr. Wu of the Guangdong Lung Cancer Institute in Guangzhou, China.
BRAIN was a multicenter Chinese trial in which investigators randomized 158 patients with three or more brain metastases from EGFR-mutated NSCLC to oral icotinib at 125 mg t.i.d. or to WBI with four to six cycles of concurrent or sequential platinum-based chemotherapy.
Icotinib outperformed standard therapy with WBI plus chemotherapy on multiple efficacy endpoints. Median intracranial progression-free survival was 10 months with icotinib, compared with only 4.8 months in patients on WBI with chemotherapy. At 6 months, 72% of patients assigned to icotinib remained free of intracranial disease progression, compared with just 48% of controls on WBI and chemotherapy. Six-month overall PFS, intracranial as well as extracranial, was 6.8 months with icotinib and 3.4 months in the WBI group. The intracranial and overall objective response rates were 67% and 55%, respectively, with icotinib, compared with 41% and 11% with WBI.
In addition, the EGFR TKI had a significantly better safety profile: grade 3 or worse toxicities occurred in just 8% of the icotinib group, compared with 26% of controls on standard therapy, Dr. Wu reported at the meeting sponsored by the International Association for the Study of Lung Cancer.
There was, however, no significant difference between the two study arms in overall survival: 18 months with icotinib, 20.5 months with standard therapy, noted Dr. Wu, who is president of the Chinese Society of Clinical Oncology.
Discussant Jacek Jassem, MD, said “This is potentially, and likely, a practice-changing study.” He added that he’s looking forward to planned future presentation of neurotoxicity and quality of life data from BRAIN. Those important endpoints are also incorporated in the ongoing phase III trials of gefitinib and erlotinib, EGFR TKIs which are far more readily accessible at present to physicians outside the Far East.
“Whole-brain radiotherapy for brain metastases from EGFR-mutated non–small cell lung cancer is a vanishing approach. The remaining role in this setting is as salvage in cases of symptomatic primary or secondary resistance to EGFR TKIs,” said Dr. Jassem, head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.
By way of background, he noted that 10%-15% of patients already have brain metastases at the time of diagnosis of NSCLC, and 40% develop them eventually. EGFR-mutated primary tumors are particularly likely to metastasize to the brain.
Remaining questions in the wake of the BRAIN trial include the efficacy of gefitinib and erlotinib versus WBI plus chemotherapy, as well as the broader question of the efficacy of EGFR TKIs in non-Asian patients with brain metastases.
“Most of the studies of EGFR TKIs have been in East Asian populations. These agents are particularly active in East Asians. There’s a question as to whether the BRAIN results can be applied to other populations,” Dr. Jassem said.
The BRAIN study was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu reported serving as a consultant to AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi. Dr. Jassem reported having no financial conflicts of interest.
VIENNA – Icotinib proved significantly more effective and less toxic than standard therapy with whole-brain irradiation and chemotherapy in patients with multiple brain metastases from epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer in the phase III BRAIN trial.
“With favorable objective response and disease control rates, icotinib was superior to whole-brain irradiation with chemotherapy, and therefore icotinib should be used as first-line therapy for advanced EGFR-mutant non–small cell lung cancers with brain metastases,” Yi-long Wu, MD, said in presenting the BRAIN results at the World Congress on Lung Cancer.
Patients with brain metastases are often excluded from participation in clinical trials because their prognosis is so poor. BRAIN is the first phase III trial to report results comparing an EGFR tyrosine kinase inhibitor (TKI) – icotinib – to whole-brain irradiation (WBI) plus chemotherapy, regarded in National Comprehensive Cancer Network guidelines as standard therapy in the setting of brain metastases from NSCLC, noted Dr. Wu of the Guangdong Lung Cancer Institute in Guangzhou, China.
BRAIN was a multicenter Chinese trial in which investigators randomized 158 patients with three or more brain metastases from EGFR-mutated NSCLC to oral icotinib at 125 mg t.i.d. or to WBI with four to six cycles of concurrent or sequential platinum-based chemotherapy.
Icotinib outperformed standard therapy with WBI plus chemotherapy on multiple efficacy endpoints. Median intracranial progression-free survival was 10 months with icotinib, compared with only 4.8 months in patients on WBI with chemotherapy. At 6 months, 72% of patients assigned to icotinib remained free of intracranial disease progression, compared with just 48% of controls on WBI and chemotherapy. Six-month overall PFS, intracranial as well as extracranial, was 6.8 months with icotinib and 3.4 months in the WBI group. The intracranial and overall objective response rates were 67% and 55%, respectively, with icotinib, compared with 41% and 11% with WBI.
In addition, the EGFR TKI had a significantly better safety profile: grade 3 or worse toxicities occurred in just 8% of the icotinib group, compared with 26% of controls on standard therapy, Dr. Wu reported at the meeting sponsored by the International Association for the Study of Lung Cancer.
There was, however, no significant difference between the two study arms in overall survival: 18 months with icotinib, 20.5 months with standard therapy, noted Dr. Wu, who is president of the Chinese Society of Clinical Oncology.
Discussant Jacek Jassem, MD, said “This is potentially, and likely, a practice-changing study.” He added that he’s looking forward to planned future presentation of neurotoxicity and quality of life data from BRAIN. Those important endpoints are also incorporated in the ongoing phase III trials of gefitinib and erlotinib, EGFR TKIs which are far more readily accessible at present to physicians outside the Far East.
“Whole-brain radiotherapy for brain metastases from EGFR-mutated non–small cell lung cancer is a vanishing approach. The remaining role in this setting is as salvage in cases of symptomatic primary or secondary resistance to EGFR TKIs,” said Dr. Jassem, head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.
By way of background, he noted that 10%-15% of patients already have brain metastases at the time of diagnosis of NSCLC, and 40% develop them eventually. EGFR-mutated primary tumors are particularly likely to metastasize to the brain.
Remaining questions in the wake of the BRAIN trial include the efficacy of gefitinib and erlotinib versus WBI plus chemotherapy, as well as the broader question of the efficacy of EGFR TKIs in non-Asian patients with brain metastases.
“Most of the studies of EGFR TKIs have been in East Asian populations. These agents are particularly active in East Asians. There’s a question as to whether the BRAIN results can be applied to other populations,” Dr. Jassem said.
The BRAIN study was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu reported serving as a consultant to AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi. Dr. Jassem reported having no financial conflicts of interest.
VIENNA – Icotinib proved significantly more effective and less toxic than standard therapy with whole-brain irradiation and chemotherapy in patients with multiple brain metastases from epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer in the phase III BRAIN trial.
“With favorable objective response and disease control rates, icotinib was superior to whole-brain irradiation with chemotherapy, and therefore icotinib should be used as first-line therapy for advanced EGFR-mutant non–small cell lung cancers with brain metastases,” Yi-long Wu, MD, said in presenting the BRAIN results at the World Congress on Lung Cancer.
Patients with brain metastases are often excluded from participation in clinical trials because their prognosis is so poor. BRAIN is the first phase III trial to report results comparing an EGFR tyrosine kinase inhibitor (TKI) – icotinib – to whole-brain irradiation (WBI) plus chemotherapy, regarded in National Comprehensive Cancer Network guidelines as standard therapy in the setting of brain metastases from NSCLC, noted Dr. Wu of the Guangdong Lung Cancer Institute in Guangzhou, China.
BRAIN was a multicenter Chinese trial in which investigators randomized 158 patients with three or more brain metastases from EGFR-mutated NSCLC to oral icotinib at 125 mg t.i.d. or to WBI with four to six cycles of concurrent or sequential platinum-based chemotherapy.
Icotinib outperformed standard therapy with WBI plus chemotherapy on multiple efficacy endpoints. Median intracranial progression-free survival was 10 months with icotinib, compared with only 4.8 months in patients on WBI with chemotherapy. At 6 months, 72% of patients assigned to icotinib remained free of intracranial disease progression, compared with just 48% of controls on WBI and chemotherapy. Six-month overall PFS, intracranial as well as extracranial, was 6.8 months with icotinib and 3.4 months in the WBI group. The intracranial and overall objective response rates were 67% and 55%, respectively, with icotinib, compared with 41% and 11% with WBI.
In addition, the EGFR TKI had a significantly better safety profile: grade 3 or worse toxicities occurred in just 8% of the icotinib group, compared with 26% of controls on standard therapy, Dr. Wu reported at the meeting sponsored by the International Association for the Study of Lung Cancer.
There was, however, no significant difference between the two study arms in overall survival: 18 months with icotinib, 20.5 months with standard therapy, noted Dr. Wu, who is president of the Chinese Society of Clinical Oncology.
Discussant Jacek Jassem, MD, said “This is potentially, and likely, a practice-changing study.” He added that he’s looking forward to planned future presentation of neurotoxicity and quality of life data from BRAIN. Those important endpoints are also incorporated in the ongoing phase III trials of gefitinib and erlotinib, EGFR TKIs which are far more readily accessible at present to physicians outside the Far East.
“Whole-brain radiotherapy for brain metastases from EGFR-mutated non–small cell lung cancer is a vanishing approach. The remaining role in this setting is as salvage in cases of symptomatic primary or secondary resistance to EGFR TKIs,” said Dr. Jassem, head of the department of oncology and radiotherapy at the Medical University of Gdansk, Poland.
By way of background, he noted that 10%-15% of patients already have brain metastases at the time of diagnosis of NSCLC, and 40% develop them eventually. EGFR-mutated primary tumors are particularly likely to metastasize to the brain.
Remaining questions in the wake of the BRAIN trial include the efficacy of gefitinib and erlotinib versus WBI plus chemotherapy, as well as the broader question of the efficacy of EGFR TKIs in non-Asian patients with brain metastases.
“Most of the studies of EGFR TKIs have been in East Asian populations. These agents are particularly active in East Asians. There’s a question as to whether the BRAIN results can be applied to other populations,” Dr. Jassem said.
The BRAIN study was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu reported serving as a consultant to AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi. Dr. Jassem reported having no financial conflicts of interest.
AT WCLC 2016
Key clinical point:
Major finding: Median intracranial progression-free survival in patients with multiple brain metastases from EGFR-mutated NSCLC was 10 months in those randomized to icotinib, compared with 4.8 months with standard-of-care whole-brain irradiation plus chemotherapy.
Data source: This phase III multicenter Chinese trial included 158 patients with multiple brain metastases from EGFR-mutated NSCLC.
Disclosures: The BRAIN study was sponsored by the Guangdong Association of Clinical Trials. The presenter reported serving as a consultant to AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi.
Ganetespib fails to hit mark in phase III NSCLC trial
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
VIENNA – The addition of ganetespib to docetaxel for the treatment of advanced non–small cell lung cancer (NSCLC) did not live up to its earlier promise of improved efficacy over docetaxel alone in a phase III study.
Interim results of the GALAXY-2 study, which led to the trial’s termination for futility, showed that there was no difference in the primary endpoint of overall survival (OS). The median OS was a respective 10.9 months and 10.5 months for the combination of ganetespib plus docetaxel versus docetaxel alone (hazard ratio, 1.111, 95% confidence interval, 0.899-1.372, P = .03293).
The combination had looked promising in the phase II GALAXY-1 study (Ann Oncol. 2015;26:1741-8), with a trend towards improved PFS and OS, with patients diagnosed with advanced disease perhaps gaining the most benefit.
“The addition of ganetespib to docetaxel did not result in improved efficacy for the salvage therapy of patients with advanced-stage lung adenocarcinoma,” Rathi Pillai, MD, said at the World Conference on Lung Cancer.
“Based on these findings, further development of Hsp [heat shock protein] 90 inhibitors in lung cancer should be limited to patients with driver mutations with relevant client proteins,” added Dr. Pillai of the Winship Cancer Institute at Emory University in Atlanta.
In GALAXY-2, 672 patients were randomized, 1:1, to receive docetaxel (75 mg/m2 on day 1) with ganetespib (150 mg/m2 on days 1 and 15) or a placebo every 3 weeks. The median number of cycles received was five in the combination arm and four in the docetaxel-only arm. All patients had advanced non–small cell lung adenocarcinoma diagnosed at least 6 months prior to enrollment and had received only one prior treatment regimen.
Response rates were similar between the two groups, with 13.7% and 16% of ganetespib/docetaxel– and docetaxel/placebo–treated patients achieving a partial response (P = .448) and 56.1% and 50.1%, respectively, having stable disease (P = .123).
Almost two-thirds (65%) of patients given ganetespib/docetaxel reported any grade 3-4 adverse event versus 54% of patients given docetaxel/placebo. The most frequent treatment-emergent grade 3-4 adverse event was neutropenia, occurring in 34.6% ad 29.5% of patients in each arm (P = .1807), with only diarrhea (46.2% vs. 14.6%; P less than .0001) and weight loss (11.3% vs. 5.2%; P = .0044) occurring more frequently in the combination than the docetaxel-only arm.
Ganetespib is a second-generation Hsp90 inhibitor and the rationale for using Hsp90 inhibitors as cancer therapy remains sound, Dr. Gandara maintained. One of the issues is finding a biomarker to predict the benefit for these drugs in a clinical setting, he said. In the phase II GALAXY-1 trial it was noted that patients diagnosed with advanced disease more than 6 months prior to study entry fared better than those with more recent diagnosis if they were treated with ganetespib/docetaxel than docetaxel alone. Patients with elevated levels of lactate dehydrogenase (eLDH) also seemed to do better than those with normal LDH levels if they were treated with the combination.
These two subpopulations were specifically looked at the in the phase III study, but again no differences in OS or PFS were observed, nor were differences observed in any of the other subgroups analyzed, which included EGFR- and ALK-negative patients, by response rate or progression because of new metastatic lesions.
“Were these the right surrogates to use as predictive biomarkers for heat shock protein inhibition? Of course, in retrospect, it is easy to say that they were not,” Dr. Gandara said.
“Is there still an opportunity for this class of drugs to make a meaningful impact in NSCLC? In my own opinion I think the answer is yes, but not in this broad page approach and not with these potential surrogates as were used in GALAXY-2,” he said at the meeting sponsored by the International Association for the Study of Lung Cancer.
The study was sponsored by Synta Pharmaceuticals, which became part of Madrigal Pharmaceuticals in June 2016. Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
AT WCLC 2016
Key clinical point: Adding ganetespib to docetaxel did not improve the survival of the patients studied versus docetaxel alone.
Major finding: Median overall survival was 10.9 months for ganetespib/docetaxel and 10.5 months for docetaxel alone (HR, 1.111; 95% CI, 0.899-1.372; P = .03293).
Data source: International, randomized, phase III, open-label GALAXY-2 study of docetaxel with or without ganetespib in 672 patients with advanced non–small cell lung adenocarcinoma.
Disclosures: The study was sponsored by Synta Pharmaceuticals (Madrigal Pharmaceuticals since June 2016). Dr. Pillai reported having no financial disclosures. Dr. Gandara disclosed that he had received research grants from several pharmaceutical companies.
Nivolumab plus ipilimumab shines as first-line in advanced NSCLC
VIENNA – The combination of nivolumab and ipilimumab as first-line therapy in patients with advanced non–small cell lung cancer (NSCLC) doubled median progression-free survival time compared with nivolumab monotherapy in updated results from the CheckMate 012 trial, Scott N. Gettinger, MD, reported at the World Congress on Lung Cancer.
This doubling of progression-free survival (PFS) applied to all comers regardless of whether or not their tumor expressed programmed death-ligand 1 (PD-L1). In those patients with any degree of PD-L1 expression – even if just 1% of tumor cells stained positive – combination therapy didn’t just double median PFS, it tripled it, compared with nivolumab alone, added Dr. Gettinger of the Yale Cancer Center in New Haven, Conn.
CheckMate 012 is a phase I study of nivolumab as first-line therapy for advanced NSCLC with numerous treatment arms. Dr. Gettinger presented updated results for 52 patients who received intravenous nivolumab monotherapy at a dose of 3 mg/kg every 2 weeks, 36 patients on nivolumab plus intravenous ipilimumab at 1 mg/kg every 12 weeks, and 39 who received nivolumab plus ipilimumab every 6 weeks. None of the participants had prior chemotherapy for their advanced stage IIIb or IV NSCLC.
Median PFS in the overall study population was 3.6 months with nivolumab monotherapy and 8.0 months with combination therapy. In the roughly 70% of participants who had any degree of tumor PD-L1 expression, median PFS was 3.5 months with monotherapy, compared with 12.7 months in the combined dual therapy arms. And, in the roughly one-quarter of patients whose tumor showed at least 50% PD-L1 expression, median PFS rose to 8.3 months with nivolumab monotherapy and hasn’t yet been reached in patients on combination therapy.
The 1-year overall survival rate in patients on nivolumab monotherapy was 73% in all treated patients, 69% in those with any detectable tumor PD-L1 expression, and 83% in patients with at least 50% PD-L1 expression. In patients on combination therapy, the corresponding figures were higher at 76%, 87%, and 100%.
The clearly enhanced efficacy achieved with the combination of nivolumab plus ipilimumab was accomplished with only a modest increase in toxicity compared with nivolumab alone. At a median follow-up of 22 months in the nivolumab monotherapy group and 16 months for combination therapy, the rate of any treatment-related adverse event leading to study withdrawal was 12% with monotherapy and 18% with combination therapy.
The combination of nivolumab (Opdivo), a PD-L1 immune checkpoint inhibitor, and ipilimumab (Yervoy), a cytotoxic T-lymphocyte–associated protein 4 immune checkpoint inhibitor, is biologically attractive: “The ipilimumab primes the immune system by inducing tumor infiltration of effector T cells while depleting the number of myeloid-derived suppressor cells and suppressive regulatory T cells within the tumor microenvironment,” Dr. Gettinger explained.
Nivolumab is approved for treatment of advanced NSCLC that has progressed despite platinum-based chemotherapy. Of the various toxicities associated with the drug, only dermatologic and GI adverse events occurred more frequently with combination therapy than nivolumab alone.
There were five complete responses in the nivolumab monotherapy group and six with combination therapy. Of note, four of these complete responses occurred in patients without any measurable tumor PD-L1 expression.
Based upon these encouraging results from CheckMate 012, a phase III randomized clinical trial of nivolumab as first-line therapy in patients with advanced NSCLC is underway. In the CheckMate 227 trial, patients with any detectable PD-L1 expression are randomized to nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks, nivolumab monotherapy at 240 mg every 2 weeks, or standard platinum-based chemotherapy. Patients with no PD-L1 expression in their tumor are assigned to the nivolumab/ipilimumab combination, or nivolumab at 360 mg every 3 weeks plus chemotherapy, or chemotherapy alone.
“I think we should be cautious despite the excitement about the combination,” argued Dr. Garon, director of thoracic oncology at the University of California, Los Angeles.
He noted that various iterations of the large CheckMate 012 phase I program have been presented repeatedly at major meetings, and the shifting data have raised concerns in his mind about possible patient selection bias stemming from the study design.
“From my perspective, until we see randomized data that can control for these biases, I will remain hopeful but not yet extremely confident that this combination will be the new frontline therapy for metastatic non–small cell lung cancer,” Dr. Garon said.
Dr. Gettinger reported serving as a consultant to Bristol-Myers Squibb, which markets nivolumab.
Dr. Garon reported that his institution receives funding from Bristol-Myers Squibb as well as AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, Mirati, Merck, Pfizer, and Novartis.
VIENNA – The combination of nivolumab and ipilimumab as first-line therapy in patients with advanced non–small cell lung cancer (NSCLC) doubled median progression-free survival time compared with nivolumab monotherapy in updated results from the CheckMate 012 trial, Scott N. Gettinger, MD, reported at the World Congress on Lung Cancer.
This doubling of progression-free survival (PFS) applied to all comers regardless of whether or not their tumor expressed programmed death-ligand 1 (PD-L1). In those patients with any degree of PD-L1 expression – even if just 1% of tumor cells stained positive – combination therapy didn’t just double median PFS, it tripled it, compared with nivolumab alone, added Dr. Gettinger of the Yale Cancer Center in New Haven, Conn.
CheckMate 012 is a phase I study of nivolumab as first-line therapy for advanced NSCLC with numerous treatment arms. Dr. Gettinger presented updated results for 52 patients who received intravenous nivolumab monotherapy at a dose of 3 mg/kg every 2 weeks, 36 patients on nivolumab plus intravenous ipilimumab at 1 mg/kg every 12 weeks, and 39 who received nivolumab plus ipilimumab every 6 weeks. None of the participants had prior chemotherapy for their advanced stage IIIb or IV NSCLC.
Median PFS in the overall study population was 3.6 months with nivolumab monotherapy and 8.0 months with combination therapy. In the roughly 70% of participants who had any degree of tumor PD-L1 expression, median PFS was 3.5 months with monotherapy, compared with 12.7 months in the combined dual therapy arms. And, in the roughly one-quarter of patients whose tumor showed at least 50% PD-L1 expression, median PFS rose to 8.3 months with nivolumab monotherapy and hasn’t yet been reached in patients on combination therapy.
The 1-year overall survival rate in patients on nivolumab monotherapy was 73% in all treated patients, 69% in those with any detectable tumor PD-L1 expression, and 83% in patients with at least 50% PD-L1 expression. In patients on combination therapy, the corresponding figures were higher at 76%, 87%, and 100%.
The clearly enhanced efficacy achieved with the combination of nivolumab plus ipilimumab was accomplished with only a modest increase in toxicity compared with nivolumab alone. At a median follow-up of 22 months in the nivolumab monotherapy group and 16 months for combination therapy, the rate of any treatment-related adverse event leading to study withdrawal was 12% with monotherapy and 18% with combination therapy.
The combination of nivolumab (Opdivo), a PD-L1 immune checkpoint inhibitor, and ipilimumab (Yervoy), a cytotoxic T-lymphocyte–associated protein 4 immune checkpoint inhibitor, is biologically attractive: “The ipilimumab primes the immune system by inducing tumor infiltration of effector T cells while depleting the number of myeloid-derived suppressor cells and suppressive regulatory T cells within the tumor microenvironment,” Dr. Gettinger explained.
Nivolumab is approved for treatment of advanced NSCLC that has progressed despite platinum-based chemotherapy. Of the various toxicities associated with the drug, only dermatologic and GI adverse events occurred more frequently with combination therapy than nivolumab alone.
There were five complete responses in the nivolumab monotherapy group and six with combination therapy. Of note, four of these complete responses occurred in patients without any measurable tumor PD-L1 expression.
Based upon these encouraging results from CheckMate 012, a phase III randomized clinical trial of nivolumab as first-line therapy in patients with advanced NSCLC is underway. In the CheckMate 227 trial, patients with any detectable PD-L1 expression are randomized to nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks, nivolumab monotherapy at 240 mg every 2 weeks, or standard platinum-based chemotherapy. Patients with no PD-L1 expression in their tumor are assigned to the nivolumab/ipilimumab combination, or nivolumab at 360 mg every 3 weeks plus chemotherapy, or chemotherapy alone.
“I think we should be cautious despite the excitement about the combination,” argued Dr. Garon, director of thoracic oncology at the University of California, Los Angeles.
He noted that various iterations of the large CheckMate 012 phase I program have been presented repeatedly at major meetings, and the shifting data have raised concerns in his mind about possible patient selection bias stemming from the study design.
“From my perspective, until we see randomized data that can control for these biases, I will remain hopeful but not yet extremely confident that this combination will be the new frontline therapy for metastatic non–small cell lung cancer,” Dr. Garon said.
Dr. Gettinger reported serving as a consultant to Bristol-Myers Squibb, which markets nivolumab.
Dr. Garon reported that his institution receives funding from Bristol-Myers Squibb as well as AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, Mirati, Merck, Pfizer, and Novartis.
VIENNA – The combination of nivolumab and ipilimumab as first-line therapy in patients with advanced non–small cell lung cancer (NSCLC) doubled median progression-free survival time compared with nivolumab monotherapy in updated results from the CheckMate 012 trial, Scott N. Gettinger, MD, reported at the World Congress on Lung Cancer.
This doubling of progression-free survival (PFS) applied to all comers regardless of whether or not their tumor expressed programmed death-ligand 1 (PD-L1). In those patients with any degree of PD-L1 expression – even if just 1% of tumor cells stained positive – combination therapy didn’t just double median PFS, it tripled it, compared with nivolumab alone, added Dr. Gettinger of the Yale Cancer Center in New Haven, Conn.
CheckMate 012 is a phase I study of nivolumab as first-line therapy for advanced NSCLC with numerous treatment arms. Dr. Gettinger presented updated results for 52 patients who received intravenous nivolumab monotherapy at a dose of 3 mg/kg every 2 weeks, 36 patients on nivolumab plus intravenous ipilimumab at 1 mg/kg every 12 weeks, and 39 who received nivolumab plus ipilimumab every 6 weeks. None of the participants had prior chemotherapy for their advanced stage IIIb or IV NSCLC.
Median PFS in the overall study population was 3.6 months with nivolumab monotherapy and 8.0 months with combination therapy. In the roughly 70% of participants who had any degree of tumor PD-L1 expression, median PFS was 3.5 months with monotherapy, compared with 12.7 months in the combined dual therapy arms. And, in the roughly one-quarter of patients whose tumor showed at least 50% PD-L1 expression, median PFS rose to 8.3 months with nivolumab monotherapy and hasn’t yet been reached in patients on combination therapy.
The 1-year overall survival rate in patients on nivolumab monotherapy was 73% in all treated patients, 69% in those with any detectable tumor PD-L1 expression, and 83% in patients with at least 50% PD-L1 expression. In patients on combination therapy, the corresponding figures were higher at 76%, 87%, and 100%.
The clearly enhanced efficacy achieved with the combination of nivolumab plus ipilimumab was accomplished with only a modest increase in toxicity compared with nivolumab alone. At a median follow-up of 22 months in the nivolumab monotherapy group and 16 months for combination therapy, the rate of any treatment-related adverse event leading to study withdrawal was 12% with monotherapy and 18% with combination therapy.
The combination of nivolumab (Opdivo), a PD-L1 immune checkpoint inhibitor, and ipilimumab (Yervoy), a cytotoxic T-lymphocyte–associated protein 4 immune checkpoint inhibitor, is biologically attractive: “The ipilimumab primes the immune system by inducing tumor infiltration of effector T cells while depleting the number of myeloid-derived suppressor cells and suppressive regulatory T cells within the tumor microenvironment,” Dr. Gettinger explained.
Nivolumab is approved for treatment of advanced NSCLC that has progressed despite platinum-based chemotherapy. Of the various toxicities associated with the drug, only dermatologic and GI adverse events occurred more frequently with combination therapy than nivolumab alone.
There were five complete responses in the nivolumab monotherapy group and six with combination therapy. Of note, four of these complete responses occurred in patients without any measurable tumor PD-L1 expression.
Based upon these encouraging results from CheckMate 012, a phase III randomized clinical trial of nivolumab as first-line therapy in patients with advanced NSCLC is underway. In the CheckMate 227 trial, patients with any detectable PD-L1 expression are randomized to nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks, nivolumab monotherapy at 240 mg every 2 weeks, or standard platinum-based chemotherapy. Patients with no PD-L1 expression in their tumor are assigned to the nivolumab/ipilimumab combination, or nivolumab at 360 mg every 3 weeks plus chemotherapy, or chemotherapy alone.
“I think we should be cautious despite the excitement about the combination,” argued Dr. Garon, director of thoracic oncology at the University of California, Los Angeles.
He noted that various iterations of the large CheckMate 012 phase I program have been presented repeatedly at major meetings, and the shifting data have raised concerns in his mind about possible patient selection bias stemming from the study design.
“From my perspective, until we see randomized data that can control for these biases, I will remain hopeful but not yet extremely confident that this combination will be the new frontline therapy for metastatic non–small cell lung cancer,” Dr. Garon said.
Dr. Gettinger reported serving as a consultant to Bristol-Myers Squibb, which markets nivolumab.
Dr. Garon reported that his institution receives funding from Bristol-Myers Squibb as well as AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, Mirati, Merck, Pfizer, and Novartis.
AT WCLC 2016
Key clinical point: A combination of two immunotherapy agents with different mechanisms of action produced impressive efficacy and acceptable toxicities as first-line therapy in patients with chemotherapy-naive advanced non–small cell lung cancer.
Major finding: in patients with any detectable tumor PD-L1 expression.
Data source: This analysis from a larger phase I study included 127 patients with no prior chemotherapy for advanced NSCLC.
Disclosures: The study presenter is a consultant to Bristol-Myers Squibb, which sponsored the CheckMate 012 trial.
GOLD: Base COPD treatment on symptoms, exacerbation risk
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has uncoupled spirometry results from the ABCD treatment algorithm; this move marks the organization’s first announcing of major COPD guidance since 2011.
Spirometry now stands apart from GOLD’s ABCD symptom/exacerbation risk score with its own grade, with possibilities ranging from 1 to 4. A forced expiratory volume in 1 second (FEV1) of 80% or more of the predicted value rates a 1; the score degrades to 4 with an FEV1 below 30%.
“In previous GOLD documents, recommendations for management of COPD were based solely on spirometric category. However, there is considerable evidence that the level of FEV1 is a poor descriptor of disease status, and, for this reason, the management of stable COPD based on … disease impact (determined mainly by symptom burden and activity limitation) and future risk of disease progression (especially of exacerbations) is recommended. ... ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations,” GOLD said.
The clear focus on symptoms and exacerbations is “the major accomplishment” of the new report, which has been downloaded more than 45,000 times since it’s release, a testament to GOLD’s importance to clinicians trying to help COPD patients.
“We are trying to do a better job of personalizing treatment,” said GOLD board member Gerard Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia.
The change “allows you to plan treatment based on symptoms [even] if you don’t have immediate access to spirometry, and then refine treatment once you have spirometry results. It also allows you to escalate and deescalate treatment because you are not boxed into a letter grade group” forced by spirometry. “You can also take a better look at pharmacologic versus nonpharmacologic therapy” when deciding what to do, he said.
In short, “we think it gives more freedom” to manage patients based on what seems best, Dr. Criner said.
GOLD included an example of how the new assessment can help. “Consider two patients,” it said, both with an FEV1 less than 30% and a COPD Assessment Test result of 18, but one with no exacerbations in the past year and the other with three. Both would have scored a GOLD D in the old system, and been treated similarly.
“However, with the new proposed scheme, the subject with three exacerbations ... would be labeled GOLD [spirometry] grade 4, group D,” and their treatment would focus on exacerbations. The no-exacerbation patient would be classified as GOLD grade 4, group B. Treatment would focus on symptoms. Drugs are still an option, but also lung volume reduction and lung transplant, GOLD said. Spirometry, in other words, is less important than how the patient is doing.
The group incorporated “every major study up to the first week of November” in the new report, Dr. Criner said, so there’s more to consider.
For instance, it’s clear now that patients benefit from home oxygen if they are severely hypoxemic while sitting on the couch watching TV, but not if they desaturate only when they get up and walk around, or come into the clinic to exercise. “We did not” know that in 2011, he said.
GOLD also recommended pulmonary rehabilitation and palliative care when indicated, as well as ongoing evaluation to make sure patients are able to use their inhalers, a major problem in COPD.
GOLD said that group A patients - those with few symptoms and low exacerbation risk - should be offered a bronchodilator. Initial therapy for group B - more symptoms, but low exacerbation risk - and group C - higher exacerbation risk but fewer symptoms - “should consist of a single long-acting bronchodilator. There is no evidence to recommend one class of long-acting bronchodilator over another.”
For group D - highly symptomatic with frequent exacerbations - “we recommend starting therapy with a [long-acting beta-2 agonist]/[long-acting antimuscarinic antagonist] combination,” the group said.
There was no industry involvement in GOLD’s report, but numerous authors and board members had pharmaceutical company ties, and GOLD’s treatment advice relies on drug company studies. Dr. Criner reported personal payments from Holaria, and research funding and other nonpersonal payments from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Johnson and Johnson, and others.
As health care moves toward individualized care plans for patients, the updated GOLD recommendations enhance the possibility of personalized COPD treatment. This means more symptom-focused treatment for patients and, as Dr. Criner points out, more freedom for providers to manage patients based on what seems best.
As health care moves toward individualized care plans for patients, the updated GOLD recommendations enhance the possibility of personalized COPD treatment. This means more symptom-focused treatment for patients and, as Dr. Criner points out, more freedom for providers to manage patients based on what seems best.
As health care moves toward individualized care plans for patients, the updated GOLD recommendations enhance the possibility of personalized COPD treatment. This means more symptom-focused treatment for patients and, as Dr. Criner points out, more freedom for providers to manage patients based on what seems best.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has uncoupled spirometry results from the ABCD treatment algorithm; this move marks the organization’s first announcing of major COPD guidance since 2011.
Spirometry now stands apart from GOLD’s ABCD symptom/exacerbation risk score with its own grade, with possibilities ranging from 1 to 4. A forced expiratory volume in 1 second (FEV1) of 80% or more of the predicted value rates a 1; the score degrades to 4 with an FEV1 below 30%.
“In previous GOLD documents, recommendations for management of COPD were based solely on spirometric category. However, there is considerable evidence that the level of FEV1 is a poor descriptor of disease status, and, for this reason, the management of stable COPD based on … disease impact (determined mainly by symptom burden and activity limitation) and future risk of disease progression (especially of exacerbations) is recommended. ... ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations,” GOLD said.
The clear focus on symptoms and exacerbations is “the major accomplishment” of the new report, which has been downloaded more than 45,000 times since it’s release, a testament to GOLD’s importance to clinicians trying to help COPD patients.
“We are trying to do a better job of personalizing treatment,” said GOLD board member Gerard Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia.
The change “allows you to plan treatment based on symptoms [even] if you don’t have immediate access to spirometry, and then refine treatment once you have spirometry results. It also allows you to escalate and deescalate treatment because you are not boxed into a letter grade group” forced by spirometry. “You can also take a better look at pharmacologic versus nonpharmacologic therapy” when deciding what to do, he said.
In short, “we think it gives more freedom” to manage patients based on what seems best, Dr. Criner said.
GOLD included an example of how the new assessment can help. “Consider two patients,” it said, both with an FEV1 less than 30% and a COPD Assessment Test result of 18, but one with no exacerbations in the past year and the other with three. Both would have scored a GOLD D in the old system, and been treated similarly.
“However, with the new proposed scheme, the subject with three exacerbations ... would be labeled GOLD [spirometry] grade 4, group D,” and their treatment would focus on exacerbations. The no-exacerbation patient would be classified as GOLD grade 4, group B. Treatment would focus on symptoms. Drugs are still an option, but also lung volume reduction and lung transplant, GOLD said. Spirometry, in other words, is less important than how the patient is doing.
The group incorporated “every major study up to the first week of November” in the new report, Dr. Criner said, so there’s more to consider.
For instance, it’s clear now that patients benefit from home oxygen if they are severely hypoxemic while sitting on the couch watching TV, but not if they desaturate only when they get up and walk around, or come into the clinic to exercise. “We did not” know that in 2011, he said.
GOLD also recommended pulmonary rehabilitation and palliative care when indicated, as well as ongoing evaluation to make sure patients are able to use their inhalers, a major problem in COPD.
GOLD said that group A patients - those with few symptoms and low exacerbation risk - should be offered a bronchodilator. Initial therapy for group B - more symptoms, but low exacerbation risk - and group C - higher exacerbation risk but fewer symptoms - “should consist of a single long-acting bronchodilator. There is no evidence to recommend one class of long-acting bronchodilator over another.”
For group D - highly symptomatic with frequent exacerbations - “we recommend starting therapy with a [long-acting beta-2 agonist]/[long-acting antimuscarinic antagonist] combination,” the group said.
There was no industry involvement in GOLD’s report, but numerous authors and board members had pharmaceutical company ties, and GOLD’s treatment advice relies on drug company studies. Dr. Criner reported personal payments from Holaria, and research funding and other nonpersonal payments from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Johnson and Johnson, and others.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has uncoupled spirometry results from the ABCD treatment algorithm; this move marks the organization’s first announcing of major COPD guidance since 2011.
Spirometry now stands apart from GOLD’s ABCD symptom/exacerbation risk score with its own grade, with possibilities ranging from 1 to 4. A forced expiratory volume in 1 second (FEV1) of 80% or more of the predicted value rates a 1; the score degrades to 4 with an FEV1 below 30%.
“In previous GOLD documents, recommendations for management of COPD were based solely on spirometric category. However, there is considerable evidence that the level of FEV1 is a poor descriptor of disease status, and, for this reason, the management of stable COPD based on … disease impact (determined mainly by symptom burden and activity limitation) and future risk of disease progression (especially of exacerbations) is recommended. ... ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations,” GOLD said.
The clear focus on symptoms and exacerbations is “the major accomplishment” of the new report, which has been downloaded more than 45,000 times since it’s release, a testament to GOLD’s importance to clinicians trying to help COPD patients.
“We are trying to do a better job of personalizing treatment,” said GOLD board member Gerard Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia.
The change “allows you to plan treatment based on symptoms [even] if you don’t have immediate access to spirometry, and then refine treatment once you have spirometry results. It also allows you to escalate and deescalate treatment because you are not boxed into a letter grade group” forced by spirometry. “You can also take a better look at pharmacologic versus nonpharmacologic therapy” when deciding what to do, he said.
In short, “we think it gives more freedom” to manage patients based on what seems best, Dr. Criner said.
GOLD included an example of how the new assessment can help. “Consider two patients,” it said, both with an FEV1 less than 30% and a COPD Assessment Test result of 18, but one with no exacerbations in the past year and the other with three. Both would have scored a GOLD D in the old system, and been treated similarly.
“However, with the new proposed scheme, the subject with three exacerbations ... would be labeled GOLD [spirometry] grade 4, group D,” and their treatment would focus on exacerbations. The no-exacerbation patient would be classified as GOLD grade 4, group B. Treatment would focus on symptoms. Drugs are still an option, but also lung volume reduction and lung transplant, GOLD said. Spirometry, in other words, is less important than how the patient is doing.
The group incorporated “every major study up to the first week of November” in the new report, Dr. Criner said, so there’s more to consider.
For instance, it’s clear now that patients benefit from home oxygen if they are severely hypoxemic while sitting on the couch watching TV, but not if they desaturate only when they get up and walk around, or come into the clinic to exercise. “We did not” know that in 2011, he said.
GOLD also recommended pulmonary rehabilitation and palliative care when indicated, as well as ongoing evaluation to make sure patients are able to use their inhalers, a major problem in COPD.
GOLD said that group A patients - those with few symptoms and low exacerbation risk - should be offered a bronchodilator. Initial therapy for group B - more symptoms, but low exacerbation risk - and group C - higher exacerbation risk but fewer symptoms - “should consist of a single long-acting bronchodilator. There is no evidence to recommend one class of long-acting bronchodilator over another.”
For group D - highly symptomatic with frequent exacerbations - “we recommend starting therapy with a [long-acting beta-2 agonist]/[long-acting antimuscarinic antagonist] combination,” the group said.
There was no industry involvement in GOLD’s report, but numerous authors and board members had pharmaceutical company ties, and GOLD’s treatment advice relies on drug company studies. Dr. Criner reported personal payments from Holaria, and research funding and other nonpersonal payments from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Johnson and Johnson, and others.
In lung cancer screening, patient education works
A counseling and shared decision-making visit improved patient knowledge of the eligibility criteria, benefits, and potential risks of lung cancer screening via a low-radiation chest CT scan.
The Center for Medicare & Medicaid Services has added the type of visit addressed in this study to Medicare’s preventive services benefits for individuals meeting certain criteria, but no previous study had looked at how the implementation of such a visit impacted a patient’s knowledge and understanding.
The researchers noted significant improvement in all questions before and after a counseling session (P = .03 to P less than .0001). Those improvements lessened at 1 month, but were still higher than precounseling scores.
The percentages of participants who knew the age criteria for lung cancer screening before counseling, immediately after counseling, and 1 month after counseling, for example, were 8.8% (11 patients), 59.2% (74 patients), and 21.4% (24 patients), respectively. The percentage of participants able to identify at least one of the potential hazards of screening increased by a similar amount immediately after receiving counseling, as did the percentage of participants able to identify the age criteria for lung cancer screening immediately after receiving counseling. The percentages of patients able to identify at least one of the potential hazards of screening were 38.4% before counseling and 90.4% immediately after receiving counseling. One month following counseling, the percentage of patients with such knowledge remained fairly high, dropping to 78.6%.
“Showing the value of these visits is very important to encourage policymakers and payers to continue to support the counseling and shared decision-making visit,” Peter J. Mazzone, MD, MPH, who led the study, said in an interview.
These types of conversations are important because of the uncertainties surrounding lung cancer screening, which leads to about a 20% reduction in mortality risk. That translates to the need to screen about 250 people to save 1 life. “I think the public sometimes doesn’t realize that the effectiveness of some of these preventive screenings may not be as large as they think they are,” said David Grossman, vice chair of the US Preventive Services Task Force and a senior investigator at the Group Health Research Institute, Seattle, who was not involved in the study.
The researchers developed a centralized counseling and shared decision-making visit that included a narrated slide show and individualized risk assessment. They approached 423 consecutive patients who had been identified by their primary care provider or a specialist as potential candidates for screening. Of those 423 patients, 125 agreed to participate in the study (Chest. 2016 Nov 1. doi: 10.1016/j.chest.2016.10.027).
The session delivered expected improvements in patient knowledge, but there were some surprises. “The starting point of knowledge was perhaps less than we would have anticipated, and the gains, though very substantial, weren’t perfect,” said Dr. Mazzone, who is also director of the lung cancer screening program at the Cleveland Clinic.
The drop in knowledge at 1 month suggests that the information needs to be reinforced, possibly each time patients come in for an annual screening visit, Dr. Mazzone added.
Counseling sessions can also help convince patients to quit smoking, if tobacco use is a concern. “It’s not appropriate to screen for lung cancer without making a commitment to try to quit,” said Dr. Grossman.
No funding source was disclosed. Dr. Mazzone and Dr. Grossman reported having no financial disclosures.
A counseling and shared decision-making visit improved patient knowledge of the eligibility criteria, benefits, and potential risks of lung cancer screening via a low-radiation chest CT scan.
The Center for Medicare & Medicaid Services has added the type of visit addressed in this study to Medicare’s preventive services benefits for individuals meeting certain criteria, but no previous study had looked at how the implementation of such a visit impacted a patient’s knowledge and understanding.
The researchers noted significant improvement in all questions before and after a counseling session (P = .03 to P less than .0001). Those improvements lessened at 1 month, but were still higher than precounseling scores.
The percentages of participants who knew the age criteria for lung cancer screening before counseling, immediately after counseling, and 1 month after counseling, for example, were 8.8% (11 patients), 59.2% (74 patients), and 21.4% (24 patients), respectively. The percentage of participants able to identify at least one of the potential hazards of screening increased by a similar amount immediately after receiving counseling, as did the percentage of participants able to identify the age criteria for lung cancer screening immediately after receiving counseling. The percentages of patients able to identify at least one of the potential hazards of screening were 38.4% before counseling and 90.4% immediately after receiving counseling. One month following counseling, the percentage of patients with such knowledge remained fairly high, dropping to 78.6%.
“Showing the value of these visits is very important to encourage policymakers and payers to continue to support the counseling and shared decision-making visit,” Peter J. Mazzone, MD, MPH, who led the study, said in an interview.
These types of conversations are important because of the uncertainties surrounding lung cancer screening, which leads to about a 20% reduction in mortality risk. That translates to the need to screen about 250 people to save 1 life. “I think the public sometimes doesn’t realize that the effectiveness of some of these preventive screenings may not be as large as they think they are,” said David Grossman, vice chair of the US Preventive Services Task Force and a senior investigator at the Group Health Research Institute, Seattle, who was not involved in the study.
The researchers developed a centralized counseling and shared decision-making visit that included a narrated slide show and individualized risk assessment. They approached 423 consecutive patients who had been identified by their primary care provider or a specialist as potential candidates for screening. Of those 423 patients, 125 agreed to participate in the study (Chest. 2016 Nov 1. doi: 10.1016/j.chest.2016.10.027).
The session delivered expected improvements in patient knowledge, but there were some surprises. “The starting point of knowledge was perhaps less than we would have anticipated, and the gains, though very substantial, weren’t perfect,” said Dr. Mazzone, who is also director of the lung cancer screening program at the Cleveland Clinic.
The drop in knowledge at 1 month suggests that the information needs to be reinforced, possibly each time patients come in for an annual screening visit, Dr. Mazzone added.
Counseling sessions can also help convince patients to quit smoking, if tobacco use is a concern. “It’s not appropriate to screen for lung cancer without making a commitment to try to quit,” said Dr. Grossman.
No funding source was disclosed. Dr. Mazzone and Dr. Grossman reported having no financial disclosures.
A counseling and shared decision-making visit improved patient knowledge of the eligibility criteria, benefits, and potential risks of lung cancer screening via a low-radiation chest CT scan.
The Center for Medicare & Medicaid Services has added the type of visit addressed in this study to Medicare’s preventive services benefits for individuals meeting certain criteria, but no previous study had looked at how the implementation of such a visit impacted a patient’s knowledge and understanding.
The researchers noted significant improvement in all questions before and after a counseling session (P = .03 to P less than .0001). Those improvements lessened at 1 month, but were still higher than precounseling scores.
The percentages of participants who knew the age criteria for lung cancer screening before counseling, immediately after counseling, and 1 month after counseling, for example, were 8.8% (11 patients), 59.2% (74 patients), and 21.4% (24 patients), respectively. The percentage of participants able to identify at least one of the potential hazards of screening increased by a similar amount immediately after receiving counseling, as did the percentage of participants able to identify the age criteria for lung cancer screening immediately after receiving counseling. The percentages of patients able to identify at least one of the potential hazards of screening were 38.4% before counseling and 90.4% immediately after receiving counseling. One month following counseling, the percentage of patients with such knowledge remained fairly high, dropping to 78.6%.
“Showing the value of these visits is very important to encourage policymakers and payers to continue to support the counseling and shared decision-making visit,” Peter J. Mazzone, MD, MPH, who led the study, said in an interview.
These types of conversations are important because of the uncertainties surrounding lung cancer screening, which leads to about a 20% reduction in mortality risk. That translates to the need to screen about 250 people to save 1 life. “I think the public sometimes doesn’t realize that the effectiveness of some of these preventive screenings may not be as large as they think they are,” said David Grossman, vice chair of the US Preventive Services Task Force and a senior investigator at the Group Health Research Institute, Seattle, who was not involved in the study.
The researchers developed a centralized counseling and shared decision-making visit that included a narrated slide show and individualized risk assessment. They approached 423 consecutive patients who had been identified by their primary care provider or a specialist as potential candidates for screening. Of those 423 patients, 125 agreed to participate in the study (Chest. 2016 Nov 1. doi: 10.1016/j.chest.2016.10.027).
The session delivered expected improvements in patient knowledge, but there were some surprises. “The starting point of knowledge was perhaps less than we would have anticipated, and the gains, though very substantial, weren’t perfect,” said Dr. Mazzone, who is also director of the lung cancer screening program at the Cleveland Clinic.
The drop in knowledge at 1 month suggests that the information needs to be reinforced, possibly each time patients come in for an annual screening visit, Dr. Mazzone added.
Counseling sessions can also help convince patients to quit smoking, if tobacco use is a concern. “It’s not appropriate to screen for lung cancer without making a commitment to try to quit,” said Dr. Grossman.
No funding source was disclosed. Dr. Mazzone and Dr. Grossman reported having no financial disclosures.
FROM CHEST
Key clinical point:
Major finding: Failure to identify potential harm dropped from 61.6% to 21.4%.
Data source: Prospective study of 125 patients.
Disclosures: No funding source was disclosed. Dr. Mazzone and Dr. Grossman reported having no financial disclosures.
Can bioprosthetics work for large airway defects?
Large and complex airway defects that primary repair cannot fully close require alternative surgical approaches and techniques that are far more difficult to perform, but bioprosthetic materials may be an option to repair large tracheal and bronchial defects that has achieved good results, without postoperative death or defect recurrence, in a small cohort of patients at Massachusetts General Hospital, in Boston.
Brooks Udelsman, MD, and his coauthors reported their results of bioprosthetic repair of central airway defects in eight patients in the Journal of Thoracic and Cardiovascular Surgery (2016 Nov;152:1388-97). “Although our results are derived from a limited number of heterogeneous patients, they suggest that closure of noncircumferential large airway defects with bioprosthetic materials is feasible, safe and reliable,” Dr. Udelsman said. He previously reported the results at the annual meeting of the American Association for Thoracic Surgery, May 14-18, 2016, in Baltimore.
These complex defects typically exceed 5 cm and can involve communication with the esophagus. For repair of smaller defects, surgeons can use a more conventional approach that involves neck flexion, laryngeal release, airway mobilization, and hilar release, but in larger defects, these techniques increase the risk of too much tension on the anastomosis and dehiscence along with airway failure. Large and complex defects occur in patients who have had a previous airway operation or radiation exposure, requiring alternative strategies, the researchers wrote. “Patients in this rare category should be referred to a high-volume center for careful evaluation by a surgeon experienced in complex airway reconstruction before the decision to abandon primary repair is made,” he said. Among the advantages that bioprosthetic materials have over synthetic materials for airway defect repair are easier handling, minimal immunogenic response, and potential for tissue ingrowth, Dr. Udelsman and his coauthors said.
All eight patients in this study, who underwent repair from 2008 to 2015, had significant comorbidities, including previous surgery of the trachea, esophagus, or thyroid. The etiology of the airway defect included HIV-AIDS–associated esophagitis, malignancy, mesh erosion, and complications from extended intubation. Three patients had previous radiation therapy to the neck or chest. Five patients had defects localized to the membranous tracheal wall, two had defects of the mainstem bronchus or bronchus intermedius, and one patient had a defect of the anterior wall of the trachea.
Dr. Udelsman and his coauthors used both aortic homograft and acellular dermal matrix to repair large defects. Their experience confirmed previous reports of the formation of granulation tissue with aortic autografts, underscoring the importance of frequent bronchoscopy and debridement when necessary. And while previous reports have claimed human acellular dermis resists granulation formation, that wasn’t the case in this study. “The exact histologic basis of bioprosthetic incorporation and reepithelialization in these patients is still elusive and will require further study,” the researchers said.
This study also employed the controversial muscle buttress repair in six patients, which helped, at least theoretically, to secure the repairs when leaks occur, to separate suture lines when both the airway and esophagus were repaired and to support the bioprosthetic material to prevent tissue softening, Dr. Udelsman and his coauthors said.
Postoperative examinations confirmed that the operations successfully closed the airway defects in all eight patients. Long term, most resumed oral intake, but three did not for various reasons: one had a pharyngostomy; another had neurocognitive issues preoperatively; and a third with a tracheoesophageal fistula repair and cervical esophagostomy could resume oral intake but depended on tube feeds to meet caloric needs.
All patients developed granulation at the repair site, two of whom required further debridement and one who underwent balloon dilation. Pneumonia was the most common complication within 30 days of surgery, occurring in two patients. Three patients died within 120 days from metastatic disease, and a fourth patient progressed to end-stage AIDS 6 years after the operation and eventually died.
Dr. Udelsman and his coauthors reported having no financial disclosures.
In his invited commentary, Raja Flores, MD, of Mount Sinai Health System in New York said this study demonstrated “modest success” with bioprosthetic materials for repair of large airway deficits – the same level of success he ascribes to human studies of other surgical approaches to large airway deficits (J Thorac Cardiovasc Surg. 2016 Nov;152:1233-4).
But progress has been slow and animal studies of large airway deficit repair have been “wastefully repetitive” without any advances. “We must build on what these human studies have taught us and not continue unsuccessfully to reinvent the same malfunctioning [airways],” Dr. Flores said.
When surgeons encounter such patients, surgery isn’t necessary for their survival, Dr. Flores said. “T-tubes work just fine.” The goal is to improve their quality of life. “Unless we can provide a reliable, long-lasting solution, an unpredictable life-threatening experimental surgical intervention is not justified to treat a stable, functional patient,” he said.
And while Dr. Udelsman and his colleagues have shown “some progress” in their study, he cautioned surgeons to heed the words of a tracheal surgery pioneer Hermes Grillo, MD, at Boston’s Massachusetts General Hospital and Harvard Medical School: “Success has been announced episodically over the decades in each of these categories, but thus far no one replacement method has held for the long term in any safe and practicable manner.” Dr. Flores added: “This still holds true today.”
Dr. Flores reported having no financial disclosures.
In his invited commentary, Raja Flores, MD, of Mount Sinai Health System in New York said this study demonstrated “modest success” with bioprosthetic materials for repair of large airway deficits – the same level of success he ascribes to human studies of other surgical approaches to large airway deficits (J Thorac Cardiovasc Surg. 2016 Nov;152:1233-4).
But progress has been slow and animal studies of large airway deficit repair have been “wastefully repetitive” without any advances. “We must build on what these human studies have taught us and not continue unsuccessfully to reinvent the same malfunctioning [airways],” Dr. Flores said.
When surgeons encounter such patients, surgery isn’t necessary for their survival, Dr. Flores said. “T-tubes work just fine.” The goal is to improve their quality of life. “Unless we can provide a reliable, long-lasting solution, an unpredictable life-threatening experimental surgical intervention is not justified to treat a stable, functional patient,” he said.
And while Dr. Udelsman and his colleagues have shown “some progress” in their study, he cautioned surgeons to heed the words of a tracheal surgery pioneer Hermes Grillo, MD, at Boston’s Massachusetts General Hospital and Harvard Medical School: “Success has been announced episodically over the decades in each of these categories, but thus far no one replacement method has held for the long term in any safe and practicable manner.” Dr. Flores added: “This still holds true today.”
Dr. Flores reported having no financial disclosures.
In his invited commentary, Raja Flores, MD, of Mount Sinai Health System in New York said this study demonstrated “modest success” with bioprosthetic materials for repair of large airway deficits – the same level of success he ascribes to human studies of other surgical approaches to large airway deficits (J Thorac Cardiovasc Surg. 2016 Nov;152:1233-4).
But progress has been slow and animal studies of large airway deficit repair have been “wastefully repetitive” without any advances. “We must build on what these human studies have taught us and not continue unsuccessfully to reinvent the same malfunctioning [airways],” Dr. Flores said.
When surgeons encounter such patients, surgery isn’t necessary for their survival, Dr. Flores said. “T-tubes work just fine.” The goal is to improve their quality of life. “Unless we can provide a reliable, long-lasting solution, an unpredictable life-threatening experimental surgical intervention is not justified to treat a stable, functional patient,” he said.
And while Dr. Udelsman and his colleagues have shown “some progress” in their study, he cautioned surgeons to heed the words of a tracheal surgery pioneer Hermes Grillo, MD, at Boston’s Massachusetts General Hospital and Harvard Medical School: “Success has been announced episodically over the decades in each of these categories, but thus far no one replacement method has held for the long term in any safe and practicable manner.” Dr. Flores added: “This still holds true today.”
Dr. Flores reported having no financial disclosures.
Large and complex airway defects that primary repair cannot fully close require alternative surgical approaches and techniques that are far more difficult to perform, but bioprosthetic materials may be an option to repair large tracheal and bronchial defects that has achieved good results, without postoperative death or defect recurrence, in a small cohort of patients at Massachusetts General Hospital, in Boston.
Brooks Udelsman, MD, and his coauthors reported their results of bioprosthetic repair of central airway defects in eight patients in the Journal of Thoracic and Cardiovascular Surgery (2016 Nov;152:1388-97). “Although our results are derived from a limited number of heterogeneous patients, they suggest that closure of noncircumferential large airway defects with bioprosthetic materials is feasible, safe and reliable,” Dr. Udelsman said. He previously reported the results at the annual meeting of the American Association for Thoracic Surgery, May 14-18, 2016, in Baltimore.
These complex defects typically exceed 5 cm and can involve communication with the esophagus. For repair of smaller defects, surgeons can use a more conventional approach that involves neck flexion, laryngeal release, airway mobilization, and hilar release, but in larger defects, these techniques increase the risk of too much tension on the anastomosis and dehiscence along with airway failure. Large and complex defects occur in patients who have had a previous airway operation or radiation exposure, requiring alternative strategies, the researchers wrote. “Patients in this rare category should be referred to a high-volume center for careful evaluation by a surgeon experienced in complex airway reconstruction before the decision to abandon primary repair is made,” he said. Among the advantages that bioprosthetic materials have over synthetic materials for airway defect repair are easier handling, minimal immunogenic response, and potential for tissue ingrowth, Dr. Udelsman and his coauthors said.
All eight patients in this study, who underwent repair from 2008 to 2015, had significant comorbidities, including previous surgery of the trachea, esophagus, or thyroid. The etiology of the airway defect included HIV-AIDS–associated esophagitis, malignancy, mesh erosion, and complications from extended intubation. Three patients had previous radiation therapy to the neck or chest. Five patients had defects localized to the membranous tracheal wall, two had defects of the mainstem bronchus or bronchus intermedius, and one patient had a defect of the anterior wall of the trachea.
Dr. Udelsman and his coauthors used both aortic homograft and acellular dermal matrix to repair large defects. Their experience confirmed previous reports of the formation of granulation tissue with aortic autografts, underscoring the importance of frequent bronchoscopy and debridement when necessary. And while previous reports have claimed human acellular dermis resists granulation formation, that wasn’t the case in this study. “The exact histologic basis of bioprosthetic incorporation and reepithelialization in these patients is still elusive and will require further study,” the researchers said.
This study also employed the controversial muscle buttress repair in six patients, which helped, at least theoretically, to secure the repairs when leaks occur, to separate suture lines when both the airway and esophagus were repaired and to support the bioprosthetic material to prevent tissue softening, Dr. Udelsman and his coauthors said.
Postoperative examinations confirmed that the operations successfully closed the airway defects in all eight patients. Long term, most resumed oral intake, but three did not for various reasons: one had a pharyngostomy; another had neurocognitive issues preoperatively; and a third with a tracheoesophageal fistula repair and cervical esophagostomy could resume oral intake but depended on tube feeds to meet caloric needs.
All patients developed granulation at the repair site, two of whom required further debridement and one who underwent balloon dilation. Pneumonia was the most common complication within 30 days of surgery, occurring in two patients. Three patients died within 120 days from metastatic disease, and a fourth patient progressed to end-stage AIDS 6 years after the operation and eventually died.
Dr. Udelsman and his coauthors reported having no financial disclosures.
Large and complex airway defects that primary repair cannot fully close require alternative surgical approaches and techniques that are far more difficult to perform, but bioprosthetic materials may be an option to repair large tracheal and bronchial defects that has achieved good results, without postoperative death or defect recurrence, in a small cohort of patients at Massachusetts General Hospital, in Boston.
Brooks Udelsman, MD, and his coauthors reported their results of bioprosthetic repair of central airway defects in eight patients in the Journal of Thoracic and Cardiovascular Surgery (2016 Nov;152:1388-97). “Although our results are derived from a limited number of heterogeneous patients, they suggest that closure of noncircumferential large airway defects with bioprosthetic materials is feasible, safe and reliable,” Dr. Udelsman said. He previously reported the results at the annual meeting of the American Association for Thoracic Surgery, May 14-18, 2016, in Baltimore.
These complex defects typically exceed 5 cm and can involve communication with the esophagus. For repair of smaller defects, surgeons can use a more conventional approach that involves neck flexion, laryngeal release, airway mobilization, and hilar release, but in larger defects, these techniques increase the risk of too much tension on the anastomosis and dehiscence along with airway failure. Large and complex defects occur in patients who have had a previous airway operation or radiation exposure, requiring alternative strategies, the researchers wrote. “Patients in this rare category should be referred to a high-volume center for careful evaluation by a surgeon experienced in complex airway reconstruction before the decision to abandon primary repair is made,” he said. Among the advantages that bioprosthetic materials have over synthetic materials for airway defect repair are easier handling, minimal immunogenic response, and potential for tissue ingrowth, Dr. Udelsman and his coauthors said.
All eight patients in this study, who underwent repair from 2008 to 2015, had significant comorbidities, including previous surgery of the trachea, esophagus, or thyroid. The etiology of the airway defect included HIV-AIDS–associated esophagitis, malignancy, mesh erosion, and complications from extended intubation. Three patients had previous radiation therapy to the neck or chest. Five patients had defects localized to the membranous tracheal wall, two had defects of the mainstem bronchus or bronchus intermedius, and one patient had a defect of the anterior wall of the trachea.
Dr. Udelsman and his coauthors used both aortic homograft and acellular dermal matrix to repair large defects. Their experience confirmed previous reports of the formation of granulation tissue with aortic autografts, underscoring the importance of frequent bronchoscopy and debridement when necessary. And while previous reports have claimed human acellular dermis resists granulation formation, that wasn’t the case in this study. “The exact histologic basis of bioprosthetic incorporation and reepithelialization in these patients is still elusive and will require further study,” the researchers said.
This study also employed the controversial muscle buttress repair in six patients, which helped, at least theoretically, to secure the repairs when leaks occur, to separate suture lines when both the airway and esophagus were repaired and to support the bioprosthetic material to prevent tissue softening, Dr. Udelsman and his coauthors said.
Postoperative examinations confirmed that the operations successfully closed the airway defects in all eight patients. Long term, most resumed oral intake, but three did not for various reasons: one had a pharyngostomy; another had neurocognitive issues preoperatively; and a third with a tracheoesophageal fistula repair and cervical esophagostomy could resume oral intake but depended on tube feeds to meet caloric needs.
All patients developed granulation at the repair site, two of whom required further debridement and one who underwent balloon dilation. Pneumonia was the most common complication within 30 days of surgery, occurring in two patients. Three patients died within 120 days from metastatic disease, and a fourth patient progressed to end-stage AIDS 6 years after the operation and eventually died.
Dr. Udelsman and his coauthors reported having no financial disclosures.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: Bioprosthetic materials show progress for reconstruction of large airway defects.
Major finding: Airway defects were successfully closed in all patients, with no postoperative deaths or recurrence of airway defect.
Data source: Eight patients who underwent closure of complex central airway defects with bioprosthetic materials between 2008 and 2015.
Disclosures: Dr. Udelsman and coauthors reported having no relevant financial disclosures.