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Pembrolizumab ‘new standard of care’ in advanced PD-L1-rich NSCLC
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
AT ESMO 2016
Key clinical point: Pembrolizumab was superior to chemotherapy in stage IV NSCLC with PD-L1 expression of 50% or more.
Major finding: The hazard ratio for progression-free survival was 0.50 for pembrolizumab vs. platinum-based chemotherapy.
Data source: Randomized phase III trial in 305 patients with untreated stage IV NSCLC with 50% or more of tumor cells expressing PD-L1
Disclosures: The study was sponsored by Merck, Sharp & Dohme. Dr. Reck and Dr. Soria disclosed financial relationships (consulting/honoraria, research funding, etc.) with several companies, but not Merck.
OAK: Atezolizumab grows OS in advanced NSCLC
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
AT ESMO 2016
Key clinical point: Atezolizumab improved overall survival (OS), compared with docetaxel, in patients with advanced non–small-cell lung cancer.
Major finding: Median OS for patients assigned to atezolizumab was 13.8 months, compared with 9.6 months for patients assigned to docetaxel.
Data source: Prespecified analysis of a randomized phase III trial in 850 patients with metastatic or recurrent NSCLC after platinum-based chemotherapy.
Disclosures: The OAK trial was funded by F. Hoffman-La Roche. Dr. Barlesi disclosed consulting fees from that company and others. Dr, Rizvi disclosed consulting for Roche and other companies.
Pembrolizumab boosts response but not survival in small study of advanced NSCLC
COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.
After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
Dr. Langer presented results on one cohort in the KEYNOTE 021 trial, a phase II, randomized, open-label multicohort study looking at pembrolizumab in combination with chemotherapy or immunotherapy.
In this cohort, 123 patients with untreated stage IIIB or IV nonsquamous non–small cell lung cancer with no activating EGFR mutations or ALK translocations were randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 2 years plus carboplatin dosed to the area under the curve and infused at 5 mg/mL per min plus pemetrexed 500 mg/m2 every 3 weeks for four cycles, or to chemotherapy alone.
Following completion of the trial, patients randomized to chemotherapy could be switched over to pembrolizumab at the same dose and scheduled for up to 2 years.
As noted, for the primary endpoint of confirmed objective response rates, the rate in the pembrolizumab/chemo group was nearly double that of the chemo-alone group (55% vs. 29%, P = .0016).
Among 33 patients on the pembrolizumab/chemo combination and 18 on chemo alone who had clinical responses according to independent central review, the median time to response was 1.5 months vs. 2.7 months, respectively. The median duration of response had not been reached in either trial arm at the time of data cutoff, and 88% and 78% of patients, respectively, had ongoing treatment responses.
Progression-free survival, a secondary endpoint, was also significantly better with the combo, with a hazard ratio of 0.53 (P = .0102).
There was no difference in overall survival, however: 75% of patients on the combination were alive at 1 year, compared with 72% of the patients on chemo alone.
Grade 3 or greater treatment-related adverse events were seen in 39% of patients on pembrolizumab, compared with 26% of patients on chemotherapy.
The most common grade 3 or greater adverse events in the combination arm were anemia, decreased neutrophil count, acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis, and thrombocytopenia. In the chemotherapy-alone group, the most common grade 3 or greater events were anemia, decreased neutrophil count, pancytopenia, and thrombocytopenia.
There were three deaths, one from sepsis each in the pembrolizumab-treated group and chemotherapy alone group, and one from pancytopenia in the chemo alone group.
One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis, compared with two (3%) of 62 patients in the chemotherapy group.
Invited discussant Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, said that although the findings of the trial are “intriguing,” there were not enough patients to allow for drawing significant conclusions about the potential use of the combination in clinical practice.
COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.
After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
Dr. Langer presented results on one cohort in the KEYNOTE 021 trial, a phase II, randomized, open-label multicohort study looking at pembrolizumab in combination with chemotherapy or immunotherapy.
In this cohort, 123 patients with untreated stage IIIB or IV nonsquamous non–small cell lung cancer with no activating EGFR mutations or ALK translocations were randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 2 years plus carboplatin dosed to the area under the curve and infused at 5 mg/mL per min plus pemetrexed 500 mg/m2 every 3 weeks for four cycles, or to chemotherapy alone.
Following completion of the trial, patients randomized to chemotherapy could be switched over to pembrolizumab at the same dose and scheduled for up to 2 years.
As noted, for the primary endpoint of confirmed objective response rates, the rate in the pembrolizumab/chemo group was nearly double that of the chemo-alone group (55% vs. 29%, P = .0016).
Among 33 patients on the pembrolizumab/chemo combination and 18 on chemo alone who had clinical responses according to independent central review, the median time to response was 1.5 months vs. 2.7 months, respectively. The median duration of response had not been reached in either trial arm at the time of data cutoff, and 88% and 78% of patients, respectively, had ongoing treatment responses.
Progression-free survival, a secondary endpoint, was also significantly better with the combo, with a hazard ratio of 0.53 (P = .0102).
There was no difference in overall survival, however: 75% of patients on the combination were alive at 1 year, compared with 72% of the patients on chemo alone.
Grade 3 or greater treatment-related adverse events were seen in 39% of patients on pembrolizumab, compared with 26% of patients on chemotherapy.
The most common grade 3 or greater adverse events in the combination arm were anemia, decreased neutrophil count, acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis, and thrombocytopenia. In the chemotherapy-alone group, the most common grade 3 or greater events were anemia, decreased neutrophil count, pancytopenia, and thrombocytopenia.
There were three deaths, one from sepsis each in the pembrolizumab-treated group and chemotherapy alone group, and one from pancytopenia in the chemo alone group.
One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis, compared with two (3%) of 62 patients in the chemotherapy group.
Invited discussant Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, said that although the findings of the trial are “intriguing,” there were not enough patients to allow for drawing significant conclusions about the potential use of the combination in clinical practice.
COPENHAGEN – Adding the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) to a standard platinum-doublet chemotherapy regimen nearly doubled response rates among patients with previously untreated advanced nonsquamous non–small cell lung cancer, but did not result in an overall survival advantage, results of a phase II trial show.
After a median follow-up of 10.6 months, the objective response rate among patients randomized to receive carboplatin and pemetrexed plus pembrolizumab was 55%, compared with 29% for patients treated with the platinum doublet alone, reported Corey J. Langer, MD, from the Abramson Cancer Center of the University of Pennsylvania, Philadelphia.
Dr. Langer presented results on one cohort in the KEYNOTE 021 trial, a phase II, randomized, open-label multicohort study looking at pembrolizumab in combination with chemotherapy or immunotherapy.
In this cohort, 123 patients with untreated stage IIIB or IV nonsquamous non–small cell lung cancer with no activating EGFR mutations or ALK translocations were randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 2 years plus carboplatin dosed to the area under the curve and infused at 5 mg/mL per min plus pemetrexed 500 mg/m2 every 3 weeks for four cycles, or to chemotherapy alone.
Following completion of the trial, patients randomized to chemotherapy could be switched over to pembrolizumab at the same dose and scheduled for up to 2 years.
As noted, for the primary endpoint of confirmed objective response rates, the rate in the pembrolizumab/chemo group was nearly double that of the chemo-alone group (55% vs. 29%, P = .0016).
Among 33 patients on the pembrolizumab/chemo combination and 18 on chemo alone who had clinical responses according to independent central review, the median time to response was 1.5 months vs. 2.7 months, respectively. The median duration of response had not been reached in either trial arm at the time of data cutoff, and 88% and 78% of patients, respectively, had ongoing treatment responses.
Progression-free survival, a secondary endpoint, was also significantly better with the combo, with a hazard ratio of 0.53 (P = .0102).
There was no difference in overall survival, however: 75% of patients on the combination were alive at 1 year, compared with 72% of the patients on chemo alone.
Grade 3 or greater treatment-related adverse events were seen in 39% of patients on pembrolizumab, compared with 26% of patients on chemotherapy.
The most common grade 3 or greater adverse events in the combination arm were anemia, decreased neutrophil count, acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, sepsis, and thrombocytopenia. In the chemotherapy-alone group, the most common grade 3 or greater events were anemia, decreased neutrophil count, pancytopenia, and thrombocytopenia.
There were three deaths, one from sepsis each in the pembrolizumab-treated group and chemotherapy alone group, and one from pancytopenia in the chemo alone group.
One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis, compared with two (3%) of 62 patients in the chemotherapy group.
Invited discussant Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, said that although the findings of the trial are “intriguing,” there were not enough patients to allow for drawing significant conclusions about the potential use of the combination in clinical practice.
Key clinical point: Adding pembrolizumab to platinum-based chemotherapy for upfront therapy of advanced NSCLC nearly doubled response rates.
Major finding: The overall response rate in the pembrolizumab/chemo group was 55% vs. 29% for chemotherapy alone (P = .0016)
Data source: Phase II randomized, open-label trial in 123 patients with untreated stage IIIB or IV nonsquamous NSCLC.
Disclosures: The study was funded by Merck, Sharp, and Dohme. Dr. Langer disclosed research funding from the company. Dr. Soria disclosed financial relationships (consulting/honoraria, research funding) with several companies, but not Merck.
Patients with stage 1 NSCLC more likely to die of other causes in short term
Patients with stage 1 non–small cell lung cancer who underwent resection with intent to cure were more likely, over the short term, to die of other causes, investigators reported.
“Non–cancer-specific mortality represents a significant competing event for lung cancer–specific mortality, with an increasing impact as age increases,” Takashi Eguchi, MD, and his associates at Memorial Sloan Kettering Cancer Center, New York wrote (J Clin Oncol. 2016 Oct 10. doi: 10.1200/JCO.2016.69.0834).
“These findings can provide patients with more accurate information on survivorship on the basis of their individual preoperative status, and help determine patients’ optimal treatment options.”
The study included 2,186 patients who underwent curative-intent resection of stage 1 non-small cell lung cancer at Memorial Sloan Kettering between 2000 and 2011. The cumulative 5-year lung cancer death rate was 10.4%, but rose with age from 7.5% among patients younger than 65 years to 13.2% among patients who were at least 75 years old. Cumulative 5-year rates of mortality not due to cancer were lower, at 5.3% overall, 1.8% in the youngest cohort, and 9% in the oldest cohort. But a competing risk analysis of the entire cohort showed that non–cancer-specific cumulative mortality was higher than mortality from lung cancer for up to 1.5 years after resection, the investigators found. Furthermore, patients who were at least 75 years old were more likely to die of causes other than cancer for up to 2.5 years after surgery.
In the multivariable analysis, low predicted postoperative diffusing capacity of lung for carbon monoxide (DCLO) independently predicted severe morbidity (P less than .001), 1-year mortality (P less than .001), and non–cancer-specific mortality (P less than .001), the researchers said. These findings reflect prior work linking low DCLO with obstructive, restrictive, and pulmonary vascular disease, chronic heart failure, and poor postoperative outcomes, they noted.
Senior author Prasad S. Adusumilli, MD, provided funding. Dr. Eguchi and Dr. Adusumilli had no relevant financial disclosures.
Patients with stage 1 non–small cell lung cancer who underwent resection with intent to cure were more likely, over the short term, to die of other causes, investigators reported.
“Non–cancer-specific mortality represents a significant competing event for lung cancer–specific mortality, with an increasing impact as age increases,” Takashi Eguchi, MD, and his associates at Memorial Sloan Kettering Cancer Center, New York wrote (J Clin Oncol. 2016 Oct 10. doi: 10.1200/JCO.2016.69.0834).
“These findings can provide patients with more accurate information on survivorship on the basis of their individual preoperative status, and help determine patients’ optimal treatment options.”
The study included 2,186 patients who underwent curative-intent resection of stage 1 non-small cell lung cancer at Memorial Sloan Kettering between 2000 and 2011. The cumulative 5-year lung cancer death rate was 10.4%, but rose with age from 7.5% among patients younger than 65 years to 13.2% among patients who were at least 75 years old. Cumulative 5-year rates of mortality not due to cancer were lower, at 5.3% overall, 1.8% in the youngest cohort, and 9% in the oldest cohort. But a competing risk analysis of the entire cohort showed that non–cancer-specific cumulative mortality was higher than mortality from lung cancer for up to 1.5 years after resection, the investigators found. Furthermore, patients who were at least 75 years old were more likely to die of causes other than cancer for up to 2.5 years after surgery.
In the multivariable analysis, low predicted postoperative diffusing capacity of lung for carbon monoxide (DCLO) independently predicted severe morbidity (P less than .001), 1-year mortality (P less than .001), and non–cancer-specific mortality (P less than .001), the researchers said. These findings reflect prior work linking low DCLO with obstructive, restrictive, and pulmonary vascular disease, chronic heart failure, and poor postoperative outcomes, they noted.
Senior author Prasad S. Adusumilli, MD, provided funding. Dr. Eguchi and Dr. Adusumilli had no relevant financial disclosures.
Patients with stage 1 non–small cell lung cancer who underwent resection with intent to cure were more likely, over the short term, to die of other causes, investigators reported.
“Non–cancer-specific mortality represents a significant competing event for lung cancer–specific mortality, with an increasing impact as age increases,” Takashi Eguchi, MD, and his associates at Memorial Sloan Kettering Cancer Center, New York wrote (J Clin Oncol. 2016 Oct 10. doi: 10.1200/JCO.2016.69.0834).
“These findings can provide patients with more accurate information on survivorship on the basis of their individual preoperative status, and help determine patients’ optimal treatment options.”
The study included 2,186 patients who underwent curative-intent resection of stage 1 non-small cell lung cancer at Memorial Sloan Kettering between 2000 and 2011. The cumulative 5-year lung cancer death rate was 10.4%, but rose with age from 7.5% among patients younger than 65 years to 13.2% among patients who were at least 75 years old. Cumulative 5-year rates of mortality not due to cancer were lower, at 5.3% overall, 1.8% in the youngest cohort, and 9% in the oldest cohort. But a competing risk analysis of the entire cohort showed that non–cancer-specific cumulative mortality was higher than mortality from lung cancer for up to 1.5 years after resection, the investigators found. Furthermore, patients who were at least 75 years old were more likely to die of causes other than cancer for up to 2.5 years after surgery.
In the multivariable analysis, low predicted postoperative diffusing capacity of lung for carbon monoxide (DCLO) independently predicted severe morbidity (P less than .001), 1-year mortality (P less than .001), and non–cancer-specific mortality (P less than .001), the researchers said. These findings reflect prior work linking low DCLO with obstructive, restrictive, and pulmonary vascular disease, chronic heart failure, and poor postoperative outcomes, they noted.
Senior author Prasad S. Adusumilli, MD, provided funding. Dr. Eguchi and Dr. Adusumilli had no relevant financial disclosures.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Patients with resected stage 1 non-small cell lung cancer are more likely to die of other causes in the short term. Major finding: The non–cancer-specific cumulative incidence of death was higher than CID from lung cancer for up to 1.5 years after resection.
Data source: A single-center competing risk analysis of 2,186 patients who underwent curative-intent resection for stage 1 non–small cell lung cancer.
Disclosures: Senior author Prasad Adusumilli, MD, provided funding. Dr. Eguchi and Dr. Adusumilli had no relevant financial disclosures.
Glimmer of promise for nivolumab in neoadjuvant NSCLC therapy
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
COPENHAGEN – Neoadjuvant therapy with the PD-1 checkpoint inhibitor nivolumab is safe, does not delay surgery, and may offer clinical benefit in some patients with early-stage non–small cell lung cancer, preliminary results of a clinical trial show.
Among 17 patients with previously untreated stage I-IIIA non–small cell lung cancer (NSCLC) who had two courses of nivolumab (Opdivo) followed by surgical resection, 12 had pathologic evidence of tumor regression, including 7 who had what investigators termed a “major pathologic response,” defined as less than 10% residual viable tumor, reported Patrick M. Forde, MBBCh, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
To see whether immunotherapy could be safe and practical in the neoadjuvant setting, the investigators enrolled 18 patients with untreated, resectable disease and performed pretreatment tumor biopsies. Patients then received doses of nivolumab 3 mg/kg delivered at 4 weeks and 2 weeks prior to scheduled surgery. Following surgery, patients received adjuvant chemotherapy at the investigator’s discretion.
Treatment related adverse events included one grade 3 to 4 toxicity and one event leading to discontinuation. There were no adverse events requiring delay of surgery.
The investigators also conducted an exploratory analysis of response to treatment among 17 who had sufficient follow-up data for evaluation of the primary endpoints of safety and feasibility.
As noted, 12 patients had a measurable tumor response, and 7 had a major pathologic response. Of this latter group, three had no radiographic evidence of response, but tumor specimens from all 7 showed evidence of “substantial” T-cell infiltration, indicating an enhanced immune response, Dr. Forde said.
In all, 9 of the 17 patients had tumor regression of more than 50%, and 7 patients had pathologic downstaging from their pretreatment clinical stage.
Four of the seven tumors with the major pathologic response were tested with a programmed death–1 ligand immunohistochemical assay, and three were positive for the ligand.
The investigators also isolated both unique and shared T-cell clones from peripheral blood, and detected new infiltration of T-cell clones that were not seen in the tumor specimens taken prior to nivolumab therapy.
Based on these early results, the investigators plan to expand the study, with one cohort planned to receive a third presurgical dose of nivolumab, and a second cohort scheduled to receive both nivolumab and ipilimumab (Yervoy).
It remains to be seen, he said, whether patients should also receive maintenance therapy, and whether combined checkpoint inhibitors might be more effective.
However, Pieter Postmus, chair of thoracic oncology at the University of Liverpool (England), who was not involved in the study, said that he is reserving judgment on efficacy until further data are available.
“There is a potential for bias when comparing a small biopsy, which might not represent the whole tumor, with the resected tumor,” he said in a statement. “This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” he added. “If in this way regression – as defined in the preoperative study – correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.”
AT ESMO 2016
Key clinical point: Checkpoint inhibitors have shown good efficacy for treatment of advanced NSCLC, but use in the neoadjuvant setting is still investigational.
Major finding: Seven of 17 patients had a major pathologic response (less than 10% viable tumor remaining).
Data source: Safety and feasibility study in 18 patients with stage I-IIIA non–small cell lung cancer.
Disclosures: The study was supported by the American Association for Cancer Research, the Cancer Research Institute, LUNGevity, and Stand Up to Cancer. Bristol-Myers Squibb donated nivolumab and provided funding for PD-L1 testing. Dr. Forde disclosed institution research grants from Bristol-Myers Squibb, Kyowa, Novartis, and uncompensated consulting for AstraZeneca and Celgene. Dr. Baas disclosed grants and research support from Bristol-Myers Squibb. Dr. Postmus had no disclosures.
Clinicians call for expanded pulmonary palliative care
Patients with chronic obstructive pulmonary disease or interstitial lung disease have longer stays in the intensive care unit, yet are less likely than patients with metastatic cancer to receive comprehensive palliative care.
This finding, reported in Annals of the American Thoracic Society, underscores the need to expand palliative care programs, incorporate elements of palliative care into routine ICU practices, and identify the most effective components of palliative care, said several experts who were not involved in the study.
“Patients with metastatic cancer are more likely to discuss goals of therapy and code status with their inpatient physician and then receive referrals to palliative care,” said Dr. Michael J. Waxman, medical director of the intensive care unit at Research Medical Center in Kansas City. “I can share many anecdotes over the years where a patient is admitted to my ICU with metastatic cancer, or severe COPD [chronic obstructive pulmonary disease] or IPF [idiopathic pulmonary fibrosis],” he added. “The cognition of these patients in some cases may have been normal, but I learned during my review that they did not receive a good discussion of desires regarding resuscitation or intensity of care. It was regularly assumed that there would be no limits on intensity of care.”
Palliative care historically has focused on patients with cancer, even though mortality rates can be high in noncancer lung disease, Dr. Crystal Brown and her associates at the University of Washington in Seattle wrote in their article (Ann Am Thorac Soc. 2016;13:684-9.). Their secondary analysis of the randomized Integrating Palliative and Critical Care trial examined medical chart data for 592 patients with COPD, 158 patients with metastatic cancer, and 79 patients with interstitial lung disease (ILD) who died in the ICUs of 15 Seattle-area hospitals between 2003 and 2008. The investigators performed regression modeling to test associations between diagnosis and eight elements of palliative care – avoidance of cardiopulmonary resuscitation during the hour before death, pain assessment during the 24 hours before death, the presence of a do-not-resuscitate order at the time of death, discussion of prognosis within 72 hours of ICU admission, withdrawal of life support measures before death, involvement of a spiritual care provider, consultation with a palliative care specialist, and the presence of an advance directive. The statistical models controlled for many potential confounders, including age, sex, race and ethnicity, education level, hospital, and whether patients died before or after hospitals implemented a palliative care quality improvement intervention.
Even though median lengths of ICU stay were significantly longer for ILD patients (4.2 days) and COPD patients (2.9 days) than for metastatic cancer patients (2.3 days), patients with COPD were significantly less likely to avoid CPR in the hour before death (adjusted odds ratio, 0.43; 95% confidence interval, 0.20-0.90), while ILD patients were less likely to have a documented pain assessment in the 24 hours before death (OR, 0.43; 95% CI, 0.19-0.97), compared with metastatic cancer patients. Patients with ILD or COPD also were significantly less likely to have a do-not-resuscitate order in place or documentation of a discussion of their prognosis, Dr. Brown and her associates reported.
The findings raise several concerns. “Clearly, this points to both intensivists and palliative care consultants needing to do more to target patients with nonmalignant end-stage chronic lung diseases, such as some patients with COPD and ILD,” said Dr. Robert Hyzy, director of the critical care medicine unit at the University of Michigan Hospital, Ann Arbor. The difference in length of stay also suggests a need to recognize earlier when critically ill patients have not responded to an appropriate time period of treatment (sometimes called a “time-limited trial”), “which signals the transition from cure to comfort,” he added.
Vera De Palo, MD, MBA, FCCP, who is chief of medicine at Signature Healthcare Brockton (Mass.) Hospital, agreed. “While treatment plans for patients with end-stage ILD and COPD do at times include palliative care, the study points out what is often the experience for most patients,” she said. “Our oncology colleagues have better understood the time line of transition between curative care and palliative care than those of us who also manage noncancer chronic diseases. They are more likely to participate in the development of palliative care programs, ensuring that this avenue of care is also available to their patients.”
This is not the only study to reveal gaps in palliative care for advanced nonmalignant lung disease. In a recent analysis of the Nationwide Inpatient Sample, only 2.6% of COPD patients who were home on oxygen and then were hospitalized with an exacerbation received a palliative care referral (CHEST. 2016 Jul 4. doi:10.1016/j.chest.2016.06.023). Such findings belie the most recent palliative care guidelines from the American Thoracic Society for patients with respiratory diseases and critical illnesses, which not only emphasize most of the same palliative care elements as the study by Dr. Brown and her colleagues, but also recommend “early consultation” with palliative care experts to help manage difficult end-of-life discussions (Am J Respir Crit Care Med. 2008;177:912-27).
Oncology palliative care includes both primary and secondary (specialty-level) services, Dr. Arif Kamal of Duke Cancer Institute at Duke University Medical Center, Durham, N.C., and his associates wrote in a viewpoint published in JAMA. Primary services, such as assessing and managing symptoms, discussing priorities and what to expect, and ensuring continuity of care, are usually left to the oncology team. Secondary services are reserved for more complex or time-consuming cases and are provided by palliative care consultants. “This ‘manage first, refer second’ practice reflects the ethos of the oncology profession – the notion that ‘this is our job’ – while also reflecting a practical humility – ‘It’s hard to be everything to everyone all the time,’ ” Dr. Kamal and his associates wrote.
When it comes to palliative care for advanced nonmalignant lung disease, Dr. De Palo said, patients and families may not feel ready to discuss end-of-life issues, and providers may find it difficult to initiate these conversations. “From the moment of diagnosis, the focus of a patient’s care for providers is curative care.” Including a palliative focus can be difficult.
Nonmalignant pulmonary diseases often carry an “uncertain short-term prognosis,” the ATS guidelines stated, and experts echoed that point. “I believe our confidence in determination of prognosis is a key factor in hesitation or delay in engaging palliative care,” said David Bowton, MD, a professor specializing in critical care at Wake Forest School of Medicine, Winston-Salem, N.C. Oncology patients needing ICU care usually have “considerably higher” mortality than the rates of 20%-45% and 15%-30% that are cited for ILD and COPD patients, respectively, he said. Furthermore, there are seemingly accurate scoring systems for predicting short-term mortality in critically ill cancer patients, which is not the case for ILD or COPD, he added.
Such factors point to differences in disease trajectory. “In this study, it is likely that the patients with cancer diagnoses more often received the elements of palliative care in the ICU because it was clearly communicated to the intensive care providers that the opportunities for curative care were exhausted,” Dr. De Palo said. “With care for end-stage chronic respiratory diseases, ICU care can usually optimize breathing enough to get the patient off the vent and stabilized at their previous functional plateau or, more often, at a lower functional plateau, until the next shortness of breath episode.”
Given these challenges and uncertainties, how can clinicians improve palliative care for patients with advanced nonmalignant lung diseases? “Simple. Have a discussion with everyone about what their expectations are,” said Dr. Waxman. “Find out what is important to them and what their goals of therapy are. Help them understand the reality of what actually will be possible to accomplish in a hospitalization, a surgery, or a therapy.”
Dr. De Palo agreed. “For my patients with end-stage respiratory disease, we often discuss whether a sustaining therapy of mechanical ventilation would offer any benefit, and what role cardiopulmonary resuscitation should play in the context of their wishes for care as their disease progresses,” she said. “I believe that providers and health care organizations should offer patients the spectrum of curative and palliative care, and work together to develop a palliative care program where one does not exist,” she stressed. Access to “the full spectrum of care – from curative to palliative – will provide the compassion and quality of life at each stage of their chronic disease.”
Intensivists should also ensure that all ICU patients receive consultations with providers “who can look more at the big picture of their health care, not just at their admission diagnosis and the specific treatment they are receiving,” Dr. Waxman said. And Dr. Bowton offered a final caveat. “While it appears obvious that providing palliative care consultation or integrating elements of palliative care into our routine ICU care will improve the experience for our patients and their families, this has been difficult to demonstrate in well-designed studies,” he said. “Thus, rather than focusing solely on our apparent shortcomings in providing palliative care to our ICU patients with ILD and COPD, we should vigorously support efforts to ascertain what components of palliative care and what ‘dose’ are most effective in alleviating physical and emotional distress.”
The National Institute of Nursing Research funded the study by Dr. Brown and her associates, who reported no relevant financial conflicts of interest.
Patients with chronic obstructive pulmonary disease or interstitial lung disease have longer stays in the intensive care unit, yet are less likely than patients with metastatic cancer to receive comprehensive palliative care.
This finding, reported in Annals of the American Thoracic Society, underscores the need to expand palliative care programs, incorporate elements of palliative care into routine ICU practices, and identify the most effective components of palliative care, said several experts who were not involved in the study.
“Patients with metastatic cancer are more likely to discuss goals of therapy and code status with their inpatient physician and then receive referrals to palliative care,” said Dr. Michael J. Waxman, medical director of the intensive care unit at Research Medical Center in Kansas City. “I can share many anecdotes over the years where a patient is admitted to my ICU with metastatic cancer, or severe COPD [chronic obstructive pulmonary disease] or IPF [idiopathic pulmonary fibrosis],” he added. “The cognition of these patients in some cases may have been normal, but I learned during my review that they did not receive a good discussion of desires regarding resuscitation or intensity of care. It was regularly assumed that there would be no limits on intensity of care.”
Palliative care historically has focused on patients with cancer, even though mortality rates can be high in noncancer lung disease, Dr. Crystal Brown and her associates at the University of Washington in Seattle wrote in their article (Ann Am Thorac Soc. 2016;13:684-9.). Their secondary analysis of the randomized Integrating Palliative and Critical Care trial examined medical chart data for 592 patients with COPD, 158 patients with metastatic cancer, and 79 patients with interstitial lung disease (ILD) who died in the ICUs of 15 Seattle-area hospitals between 2003 and 2008. The investigators performed regression modeling to test associations between diagnosis and eight elements of palliative care – avoidance of cardiopulmonary resuscitation during the hour before death, pain assessment during the 24 hours before death, the presence of a do-not-resuscitate order at the time of death, discussion of prognosis within 72 hours of ICU admission, withdrawal of life support measures before death, involvement of a spiritual care provider, consultation with a palliative care specialist, and the presence of an advance directive. The statistical models controlled for many potential confounders, including age, sex, race and ethnicity, education level, hospital, and whether patients died before or after hospitals implemented a palliative care quality improvement intervention.
Even though median lengths of ICU stay were significantly longer for ILD patients (4.2 days) and COPD patients (2.9 days) than for metastatic cancer patients (2.3 days), patients with COPD were significantly less likely to avoid CPR in the hour before death (adjusted odds ratio, 0.43; 95% confidence interval, 0.20-0.90), while ILD patients were less likely to have a documented pain assessment in the 24 hours before death (OR, 0.43; 95% CI, 0.19-0.97), compared with metastatic cancer patients. Patients with ILD or COPD also were significantly less likely to have a do-not-resuscitate order in place or documentation of a discussion of their prognosis, Dr. Brown and her associates reported.
The findings raise several concerns. “Clearly, this points to both intensivists and palliative care consultants needing to do more to target patients with nonmalignant end-stage chronic lung diseases, such as some patients with COPD and ILD,” said Dr. Robert Hyzy, director of the critical care medicine unit at the University of Michigan Hospital, Ann Arbor. The difference in length of stay also suggests a need to recognize earlier when critically ill patients have not responded to an appropriate time period of treatment (sometimes called a “time-limited trial”), “which signals the transition from cure to comfort,” he added.
Vera De Palo, MD, MBA, FCCP, who is chief of medicine at Signature Healthcare Brockton (Mass.) Hospital, agreed. “While treatment plans for patients with end-stage ILD and COPD do at times include palliative care, the study points out what is often the experience for most patients,” she said. “Our oncology colleagues have better understood the time line of transition between curative care and palliative care than those of us who also manage noncancer chronic diseases. They are more likely to participate in the development of palliative care programs, ensuring that this avenue of care is also available to their patients.”
This is not the only study to reveal gaps in palliative care for advanced nonmalignant lung disease. In a recent analysis of the Nationwide Inpatient Sample, only 2.6% of COPD patients who were home on oxygen and then were hospitalized with an exacerbation received a palliative care referral (CHEST. 2016 Jul 4. doi:10.1016/j.chest.2016.06.023). Such findings belie the most recent palliative care guidelines from the American Thoracic Society for patients with respiratory diseases and critical illnesses, which not only emphasize most of the same palliative care elements as the study by Dr. Brown and her colleagues, but also recommend “early consultation” with palliative care experts to help manage difficult end-of-life discussions (Am J Respir Crit Care Med. 2008;177:912-27).
Oncology palliative care includes both primary and secondary (specialty-level) services, Dr. Arif Kamal of Duke Cancer Institute at Duke University Medical Center, Durham, N.C., and his associates wrote in a viewpoint published in JAMA. Primary services, such as assessing and managing symptoms, discussing priorities and what to expect, and ensuring continuity of care, are usually left to the oncology team. Secondary services are reserved for more complex or time-consuming cases and are provided by palliative care consultants. “This ‘manage first, refer second’ practice reflects the ethos of the oncology profession – the notion that ‘this is our job’ – while also reflecting a practical humility – ‘It’s hard to be everything to everyone all the time,’ ” Dr. Kamal and his associates wrote.
When it comes to palliative care for advanced nonmalignant lung disease, Dr. De Palo said, patients and families may not feel ready to discuss end-of-life issues, and providers may find it difficult to initiate these conversations. “From the moment of diagnosis, the focus of a patient’s care for providers is curative care.” Including a palliative focus can be difficult.
Nonmalignant pulmonary diseases often carry an “uncertain short-term prognosis,” the ATS guidelines stated, and experts echoed that point. “I believe our confidence in determination of prognosis is a key factor in hesitation or delay in engaging palliative care,” said David Bowton, MD, a professor specializing in critical care at Wake Forest School of Medicine, Winston-Salem, N.C. Oncology patients needing ICU care usually have “considerably higher” mortality than the rates of 20%-45% and 15%-30% that are cited for ILD and COPD patients, respectively, he said. Furthermore, there are seemingly accurate scoring systems for predicting short-term mortality in critically ill cancer patients, which is not the case for ILD or COPD, he added.
Such factors point to differences in disease trajectory. “In this study, it is likely that the patients with cancer diagnoses more often received the elements of palliative care in the ICU because it was clearly communicated to the intensive care providers that the opportunities for curative care were exhausted,” Dr. De Palo said. “With care for end-stage chronic respiratory diseases, ICU care can usually optimize breathing enough to get the patient off the vent and stabilized at their previous functional plateau or, more often, at a lower functional plateau, until the next shortness of breath episode.”
Given these challenges and uncertainties, how can clinicians improve palliative care for patients with advanced nonmalignant lung diseases? “Simple. Have a discussion with everyone about what their expectations are,” said Dr. Waxman. “Find out what is important to them and what their goals of therapy are. Help them understand the reality of what actually will be possible to accomplish in a hospitalization, a surgery, or a therapy.”
Dr. De Palo agreed. “For my patients with end-stage respiratory disease, we often discuss whether a sustaining therapy of mechanical ventilation would offer any benefit, and what role cardiopulmonary resuscitation should play in the context of their wishes for care as their disease progresses,” she said. “I believe that providers and health care organizations should offer patients the spectrum of curative and palliative care, and work together to develop a palliative care program where one does not exist,” she stressed. Access to “the full spectrum of care – from curative to palliative – will provide the compassion and quality of life at each stage of their chronic disease.”
Intensivists should also ensure that all ICU patients receive consultations with providers “who can look more at the big picture of their health care, not just at their admission diagnosis and the specific treatment they are receiving,” Dr. Waxman said. And Dr. Bowton offered a final caveat. “While it appears obvious that providing palliative care consultation or integrating elements of palliative care into our routine ICU care will improve the experience for our patients and their families, this has been difficult to demonstrate in well-designed studies,” he said. “Thus, rather than focusing solely on our apparent shortcomings in providing palliative care to our ICU patients with ILD and COPD, we should vigorously support efforts to ascertain what components of palliative care and what ‘dose’ are most effective in alleviating physical and emotional distress.”
The National Institute of Nursing Research funded the study by Dr. Brown and her associates, who reported no relevant financial conflicts of interest.
Patients with chronic obstructive pulmonary disease or interstitial lung disease have longer stays in the intensive care unit, yet are less likely than patients with metastatic cancer to receive comprehensive palliative care.
This finding, reported in Annals of the American Thoracic Society, underscores the need to expand palliative care programs, incorporate elements of palliative care into routine ICU practices, and identify the most effective components of palliative care, said several experts who were not involved in the study.
“Patients with metastatic cancer are more likely to discuss goals of therapy and code status with their inpatient physician and then receive referrals to palliative care,” said Dr. Michael J. Waxman, medical director of the intensive care unit at Research Medical Center in Kansas City. “I can share many anecdotes over the years where a patient is admitted to my ICU with metastatic cancer, or severe COPD [chronic obstructive pulmonary disease] or IPF [idiopathic pulmonary fibrosis],” he added. “The cognition of these patients in some cases may have been normal, but I learned during my review that they did not receive a good discussion of desires regarding resuscitation or intensity of care. It was regularly assumed that there would be no limits on intensity of care.”
Palliative care historically has focused on patients with cancer, even though mortality rates can be high in noncancer lung disease, Dr. Crystal Brown and her associates at the University of Washington in Seattle wrote in their article (Ann Am Thorac Soc. 2016;13:684-9.). Their secondary analysis of the randomized Integrating Palliative and Critical Care trial examined medical chart data for 592 patients with COPD, 158 patients with metastatic cancer, and 79 patients with interstitial lung disease (ILD) who died in the ICUs of 15 Seattle-area hospitals between 2003 and 2008. The investigators performed regression modeling to test associations between diagnosis and eight elements of palliative care – avoidance of cardiopulmonary resuscitation during the hour before death, pain assessment during the 24 hours before death, the presence of a do-not-resuscitate order at the time of death, discussion of prognosis within 72 hours of ICU admission, withdrawal of life support measures before death, involvement of a spiritual care provider, consultation with a palliative care specialist, and the presence of an advance directive. The statistical models controlled for many potential confounders, including age, sex, race and ethnicity, education level, hospital, and whether patients died before or after hospitals implemented a palliative care quality improvement intervention.
Even though median lengths of ICU stay were significantly longer for ILD patients (4.2 days) and COPD patients (2.9 days) than for metastatic cancer patients (2.3 days), patients with COPD were significantly less likely to avoid CPR in the hour before death (adjusted odds ratio, 0.43; 95% confidence interval, 0.20-0.90), while ILD patients were less likely to have a documented pain assessment in the 24 hours before death (OR, 0.43; 95% CI, 0.19-0.97), compared with metastatic cancer patients. Patients with ILD or COPD also were significantly less likely to have a do-not-resuscitate order in place or documentation of a discussion of their prognosis, Dr. Brown and her associates reported.
The findings raise several concerns. “Clearly, this points to both intensivists and palliative care consultants needing to do more to target patients with nonmalignant end-stage chronic lung diseases, such as some patients with COPD and ILD,” said Dr. Robert Hyzy, director of the critical care medicine unit at the University of Michigan Hospital, Ann Arbor. The difference in length of stay also suggests a need to recognize earlier when critically ill patients have not responded to an appropriate time period of treatment (sometimes called a “time-limited trial”), “which signals the transition from cure to comfort,” he added.
Vera De Palo, MD, MBA, FCCP, who is chief of medicine at Signature Healthcare Brockton (Mass.) Hospital, agreed. “While treatment plans for patients with end-stage ILD and COPD do at times include palliative care, the study points out what is often the experience for most patients,” she said. “Our oncology colleagues have better understood the time line of transition between curative care and palliative care than those of us who also manage noncancer chronic diseases. They are more likely to participate in the development of palliative care programs, ensuring that this avenue of care is also available to their patients.”
This is not the only study to reveal gaps in palliative care for advanced nonmalignant lung disease. In a recent analysis of the Nationwide Inpatient Sample, only 2.6% of COPD patients who were home on oxygen and then were hospitalized with an exacerbation received a palliative care referral (CHEST. 2016 Jul 4. doi:10.1016/j.chest.2016.06.023). Such findings belie the most recent palliative care guidelines from the American Thoracic Society for patients with respiratory diseases and critical illnesses, which not only emphasize most of the same palliative care elements as the study by Dr. Brown and her colleagues, but also recommend “early consultation” with palliative care experts to help manage difficult end-of-life discussions (Am J Respir Crit Care Med. 2008;177:912-27).
Oncology palliative care includes both primary and secondary (specialty-level) services, Dr. Arif Kamal of Duke Cancer Institute at Duke University Medical Center, Durham, N.C., and his associates wrote in a viewpoint published in JAMA. Primary services, such as assessing and managing symptoms, discussing priorities and what to expect, and ensuring continuity of care, are usually left to the oncology team. Secondary services are reserved for more complex or time-consuming cases and are provided by palliative care consultants. “This ‘manage first, refer second’ practice reflects the ethos of the oncology profession – the notion that ‘this is our job’ – while also reflecting a practical humility – ‘It’s hard to be everything to everyone all the time,’ ” Dr. Kamal and his associates wrote.
When it comes to palliative care for advanced nonmalignant lung disease, Dr. De Palo said, patients and families may not feel ready to discuss end-of-life issues, and providers may find it difficult to initiate these conversations. “From the moment of diagnosis, the focus of a patient’s care for providers is curative care.” Including a palliative focus can be difficult.
Nonmalignant pulmonary diseases often carry an “uncertain short-term prognosis,” the ATS guidelines stated, and experts echoed that point. “I believe our confidence in determination of prognosis is a key factor in hesitation or delay in engaging palliative care,” said David Bowton, MD, a professor specializing in critical care at Wake Forest School of Medicine, Winston-Salem, N.C. Oncology patients needing ICU care usually have “considerably higher” mortality than the rates of 20%-45% and 15%-30% that are cited for ILD and COPD patients, respectively, he said. Furthermore, there are seemingly accurate scoring systems for predicting short-term mortality in critically ill cancer patients, which is not the case for ILD or COPD, he added.
Such factors point to differences in disease trajectory. “In this study, it is likely that the patients with cancer diagnoses more often received the elements of palliative care in the ICU because it was clearly communicated to the intensive care providers that the opportunities for curative care were exhausted,” Dr. De Palo said. “With care for end-stage chronic respiratory diseases, ICU care can usually optimize breathing enough to get the patient off the vent and stabilized at their previous functional plateau or, more often, at a lower functional plateau, until the next shortness of breath episode.”
Given these challenges and uncertainties, how can clinicians improve palliative care for patients with advanced nonmalignant lung diseases? “Simple. Have a discussion with everyone about what their expectations are,” said Dr. Waxman. “Find out what is important to them and what their goals of therapy are. Help them understand the reality of what actually will be possible to accomplish in a hospitalization, a surgery, or a therapy.”
Dr. De Palo agreed. “For my patients with end-stage respiratory disease, we often discuss whether a sustaining therapy of mechanical ventilation would offer any benefit, and what role cardiopulmonary resuscitation should play in the context of their wishes for care as their disease progresses,” she said. “I believe that providers and health care organizations should offer patients the spectrum of curative and palliative care, and work together to develop a palliative care program where one does not exist,” she stressed. Access to “the full spectrum of care – from curative to palliative – will provide the compassion and quality of life at each stage of their chronic disease.”
Intensivists should also ensure that all ICU patients receive consultations with providers “who can look more at the big picture of their health care, not just at their admission diagnosis and the specific treatment they are receiving,” Dr. Waxman said. And Dr. Bowton offered a final caveat. “While it appears obvious that providing palliative care consultation or integrating elements of palliative care into our routine ICU care will improve the experience for our patients and their families, this has been difficult to demonstrate in well-designed studies,” he said. “Thus, rather than focusing solely on our apparent shortcomings in providing palliative care to our ICU patients with ILD and COPD, we should vigorously support efforts to ascertain what components of palliative care and what ‘dose’ are most effective in alleviating physical and emotional distress.”
The National Institute of Nursing Research funded the study by Dr. Brown and her associates, who reported no relevant financial conflicts of interest.
FROM ANNALS OF THE AMERICAN THORACIC SOCIETY
NSCLC survival comparable with accelerated and conventional RT
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
BOSTON – Patients with stage II or III non–small-cell lung cancer with comorbidities that make them poor candidates for surgery or chemotherapy may still benefit from accelerated hypofractionated radiation, an interim analysis of a randomized trial suggests.
Among 48 patients followed for a median of 24 months, there were no statistical differences in either overall survival (OS) or progression-free survival between patients with stage II or III NSCLC and poor performance status treated with either conventional radiation delivered over 6 weeks, or image-guided radiation therapy (IGRT) delivered over 3 weeks, reported Puneeth Iyengar, MD, PhD, of the University of Texas Southwestern in Dallas.
“There is limited grade 3-5 toxicity, and as importantly, and more important to patients, is that the treatment time is cut in half and may be acceptable to the patient as well as to the treating physician,” he added.
The investigators are hopeful that the study, when completed, will “change the paradigm of how we treat these patients who can’t receive the standard-of-care treatment.”
The UT Southwestern investigators had previously shown in a phase I dose-escalation study that treating patients with 60 Gy delivered in 15 fractions instead of the conventional 30 fractions did not increase treatment-related toxicity,
In the current study, they explored the question of whether accelerated hypofractionated radiation therapy could improve survival in a difficult-to-treat population.
They have enrolled to date 60 patients with stage II or III NSCLC and Zubrod performance status of 2 or greater.
In arm A, 28 patients were assigned to receive conventional radiation at total doses of 60 to 66 Gy delivered in 30-33 fractions of 2 Gy each, In arm B, 32 patients were assigned to receive a total dose of 60 Gy delivered in 15 fractions of 4 Gy each.
The median age was 68 in both arms. The male-to-female ratio was equal in arm A, but 4:1 in arm B, The distribution of tumor types was equally weighted in each arm, with squamous cell carcinomas accounting for 53% of lesions, and adenocarcinomas accounting for the remainder.
Among all 60 patients, 53 presented with stage III disease, and 7 with stage II.
Of the 60 patients, 48 had follow-up sufficient for interim evaluation, and of this group, 27 (56%) were alive at last follow-up.
Median OS on Kaplan-Meier analysis was 11.5 months, with no statistical differences between the groups (per-group rates were not shown), Median PFS was 14 months, also with no statistical differences.
There were three deaths from hypoxia possibly related to radiation, two in the conventional fractionation arm, and one in the IGRT, accelerated fractionation arm. There were 10 grade 3 radiation-associated toxicities in arm A, and 6 in Arm B. There were no grade 4 toxicities in either group.
George Rodrigues, MD, of London (Ontario) Health Sciences Center, who moderated the briefing, said that in addition to patients with poor performance status, there are some patients who simply do not want to undergo chemotherapy, and for these patients the efficacy, low side effects, and convenience of accelerated fractionation radiation therapy may prove to be a good treatment option.
Key clinical point: Accelerated hypofractionated radiation therapy offers survival and safety comparable to that of conventional radiation in non–small-cell lung cancer in half the time.
Major finding: There were no differences in overall or progression-free survival among patients with NSCLC treated with either accelerated or conventional fractionation radiation.
Data source: Interim analysis of randomized phase III trial in 48 of 60 evaluable patients with stage II or III NSCLC and poor performance status.
Disclosures: UT Southwestern Medical Center, Dallas, sponsored the trial. Dr. Iyengar and Dr. Rodrigues reported having no conflicts of interest.
Racial gaps persist in lung cancer trial enrollment
Elderly women, blacks, Asians, Pacific Islanders, and Hispanics are all still underrepresented in lung cancer clinical trials, while gender- and age-based disparities have improved, according to a report published online in Journal of Clinical Oncology.
Herbert H. Pang, PhD, of the Li Ka Shing Faculty of Medicine, Hong Kong, and his coauthors noted that enrollment disparities in cancer clinical trials have existed for many years, with previous research showing underenrollment of the elderly, women, blacks, and racial and ethnic minorities.
In this study, they analyzed data from 23,006 participants in National Cancer Institute lung cancer trials, and 578,476 patients with lung cancer from the SEER registry (J Clin Oncol. 2016 Sep 19. doi: 10.1200/JCO.2016.67.7088).
When they compared the proportion of each subgroup in the trial population with the proportion in the U.S. lung cancer population over time, they noted consistent underrepresentation of blacks, Asian/Pacific Islander, and Hispanic patients across the entire study period.
The enrollment disparity for patients aged 70 years or older with non–small-cell lung cancer improved significantly from 1990 to 2012, but while there has been an increase in the proportion of elderly patients with small-cell lung cancer in the U.S. population from 1990 to 2012, the proportion of elderly patients in trials for small-cell lung cancer remained static.
The authors suggested that this may have been the result of local enrollment patterns for the mostly smaller, phase II trials in small-cell lung cancer, but also the fact that the therapies investigated for small-cell lung cancer may have posed a greater risk of treatment toxicity, which would limit the enrollment of older patients.
Significant improvements were seen in the proportion of women enrolled in lung cancer trials, with the enrollment gap between the genders closing in 2012, although elderly women were still underrepresented in lung cancer clinical trials.
“These findings suggest a beneficial effect of the NIH Revitalization Act of 1993 that mandated the inclusion of women and minorities in all NIH-funded research,” the authors wrote. “However, other important enrollment disparities, especially for older patients with SCLC, elderly women, and racial/ethnic minorities, continue to persist and require ongoing work to eliminate underrepresentation in lung cancer treatment trials.”
Elderly women, blacks, Asians, Pacific Islanders, and Hispanics are all still underrepresented in lung cancer clinical trials, while gender- and age-based disparities have improved, according to a report published online in Journal of Clinical Oncology.
Herbert H. Pang, PhD, of the Li Ka Shing Faculty of Medicine, Hong Kong, and his coauthors noted that enrollment disparities in cancer clinical trials have existed for many years, with previous research showing underenrollment of the elderly, women, blacks, and racial and ethnic minorities.
In this study, they analyzed data from 23,006 participants in National Cancer Institute lung cancer trials, and 578,476 patients with lung cancer from the SEER registry (J Clin Oncol. 2016 Sep 19. doi: 10.1200/JCO.2016.67.7088).
When they compared the proportion of each subgroup in the trial population with the proportion in the U.S. lung cancer population over time, they noted consistent underrepresentation of blacks, Asian/Pacific Islander, and Hispanic patients across the entire study period.
The enrollment disparity for patients aged 70 years or older with non–small-cell lung cancer improved significantly from 1990 to 2012, but while there has been an increase in the proportion of elderly patients with small-cell lung cancer in the U.S. population from 1990 to 2012, the proportion of elderly patients in trials for small-cell lung cancer remained static.
The authors suggested that this may have been the result of local enrollment patterns for the mostly smaller, phase II trials in small-cell lung cancer, but also the fact that the therapies investigated for small-cell lung cancer may have posed a greater risk of treatment toxicity, which would limit the enrollment of older patients.
Significant improvements were seen in the proportion of women enrolled in lung cancer trials, with the enrollment gap between the genders closing in 2012, although elderly women were still underrepresented in lung cancer clinical trials.
“These findings suggest a beneficial effect of the NIH Revitalization Act of 1993 that mandated the inclusion of women and minorities in all NIH-funded research,” the authors wrote. “However, other important enrollment disparities, especially for older patients with SCLC, elderly women, and racial/ethnic minorities, continue to persist and require ongoing work to eliminate underrepresentation in lung cancer treatment trials.”
Elderly women, blacks, Asians, Pacific Islanders, and Hispanics are all still underrepresented in lung cancer clinical trials, while gender- and age-based disparities have improved, according to a report published online in Journal of Clinical Oncology.
Herbert H. Pang, PhD, of the Li Ka Shing Faculty of Medicine, Hong Kong, and his coauthors noted that enrollment disparities in cancer clinical trials have existed for many years, with previous research showing underenrollment of the elderly, women, blacks, and racial and ethnic minorities.
In this study, they analyzed data from 23,006 participants in National Cancer Institute lung cancer trials, and 578,476 patients with lung cancer from the SEER registry (J Clin Oncol. 2016 Sep 19. doi: 10.1200/JCO.2016.67.7088).
When they compared the proportion of each subgroup in the trial population with the proportion in the U.S. lung cancer population over time, they noted consistent underrepresentation of blacks, Asian/Pacific Islander, and Hispanic patients across the entire study period.
The enrollment disparity for patients aged 70 years or older with non–small-cell lung cancer improved significantly from 1990 to 2012, but while there has been an increase in the proportion of elderly patients with small-cell lung cancer in the U.S. population from 1990 to 2012, the proportion of elderly patients in trials for small-cell lung cancer remained static.
The authors suggested that this may have been the result of local enrollment patterns for the mostly smaller, phase II trials in small-cell lung cancer, but also the fact that the therapies investigated for small-cell lung cancer may have posed a greater risk of treatment toxicity, which would limit the enrollment of older patients.
Significant improvements were seen in the proportion of women enrolled in lung cancer trials, with the enrollment gap between the genders closing in 2012, although elderly women were still underrepresented in lung cancer clinical trials.
“These findings suggest a beneficial effect of the NIH Revitalization Act of 1993 that mandated the inclusion of women and minorities in all NIH-funded research,” the authors wrote. “However, other important enrollment disparities, especially for older patients with SCLC, elderly women, and racial/ethnic minorities, continue to persist and require ongoing work to eliminate underrepresentation in lung cancer treatment trials.”
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Elderly women, blacks, Asians, Pacific Islanders, and Hispanics are all still underrepresented in lung cancer clinical trials, while gender- and age-based disparities have improved.
Major finding: There is consistent underrepresentation of blacks, Asian/Pacific Islander, and Hispanic patients in lung cancer clinical trials, but the enrollment gap between genders has closed.
Data source: Analysis of data from 23,006 participants in National Cancer Institute lung cancer trials, and 578,476 patients with lung cancer from the SEER registry.
Disclosures: The study was supported by the National Institutes of Health, National Institute on Aging, and the Health and Medical Research Fund of Hong Kong, and by the National Institute on Aging. Dr. Wang had no disclosures to report; several coauthors reported relationships with various pharmaceutical companies.
Recommendations for Cancer Moonshot overlook a few issues, YSC says
Overall, the response to Blue Ribbon Panel recommendations for guiding the Cancer Moonshot initiative were well received, though some patient advocates say a few key issues were overlooked.
In early September 2016, the Blue Ribbon Panel, a group of more than 150 scientists, clinicians, patient advocates, and industry representatives convened by the National Cancer Institutes’s National Cancer Advisory Board, published its Top 10 recommendations to guide future endeavors of the Cancer Moonshot Initiative.
The recommendations, which were informed by input from the research community and the public, emphasized “the importance of direct patient engagement in cancer research, a deeper understanding of why some therapies work and others do not, the dynamics of tumor evolution, and the need for mechanisms of data sharing, access, and analysis,” wrote Dinah S. Singer, PhD, and two other cochairs of the Blue Ribbon Panel in an article published in Science (2016 Sep 7. doi: 10.1126/science.aai7862).
“The recommendations that were announced today by the Cancer Moonshot Blue Ribbon Panel are vitally important to accomplishing the goal of the National Cancer Moonshot Initiative, which is to achieve a decade’s worth of advances in five years,” wrote American Association for Cancer Research President Nancy E. Davidson, MD, in a statement.
“The panel’s thoughtful work makes an important contribution to the Cancer Moonshot Initiative,” wrote American Society for Clinical Oncology President Daniel F. Hayes, MD, in a statement. In an interview, Dr. Hayes added that innovations in information technology and the focus on improving interoperability of electronic health records were two important strengths of the recommendations that will be “critically important to deliver high-quality, high-value oncology services to individuals with cancer.”
Michelle Esser, senior program manager at the Young Survival Coalition (YSC), agreed that the recommendations are good initial steps. However, she pointed out two issues that the recommendations overlooked. “First, is the lack of mention or understanding of the adolescent and young adult (AYA) oncology patient population,” Ms. Esser noted during an interview. “The report specifically called out pediatric cancer as an area of needed research, but AYAs, whose survival rates lag behind those of older and younger patients with a similar diagnosis, and for whom cancer is the leading cause of disease-related death, were not mentioned.”
Second, there was little mention of cancer metastasis, she said. “It is not an early-stage cancer diagnosis that kills, it is when cancer metastasizes and spreads that it becomes deadly. Out of the 10 recommendations only 1 mentions metastasis. If we want to make a difference in cancer outcomes, there needs to be focus on understanding why metastasis occurs, how to prevent it, and how to cure it.”
In order for these recommendations to really expedite the nation’s progress against cancer, “It is crucial that Congress provide the necessary funding to support the priority projects identified by the Blue Ribbon Panel and those we will hear about from the Task Force and Vice President’s Executive Reports later this year,” reported Dr. Hayes, a sentiment echoed by Dr. Davidson.
On Twitter @jessnicolecraig
Overall, the response to Blue Ribbon Panel recommendations for guiding the Cancer Moonshot initiative were well received, though some patient advocates say a few key issues were overlooked.
In early September 2016, the Blue Ribbon Panel, a group of more than 150 scientists, clinicians, patient advocates, and industry representatives convened by the National Cancer Institutes’s National Cancer Advisory Board, published its Top 10 recommendations to guide future endeavors of the Cancer Moonshot Initiative.
The recommendations, which were informed by input from the research community and the public, emphasized “the importance of direct patient engagement in cancer research, a deeper understanding of why some therapies work and others do not, the dynamics of tumor evolution, and the need for mechanisms of data sharing, access, and analysis,” wrote Dinah S. Singer, PhD, and two other cochairs of the Blue Ribbon Panel in an article published in Science (2016 Sep 7. doi: 10.1126/science.aai7862).
“The recommendations that were announced today by the Cancer Moonshot Blue Ribbon Panel are vitally important to accomplishing the goal of the National Cancer Moonshot Initiative, which is to achieve a decade’s worth of advances in five years,” wrote American Association for Cancer Research President Nancy E. Davidson, MD, in a statement.
“The panel’s thoughtful work makes an important contribution to the Cancer Moonshot Initiative,” wrote American Society for Clinical Oncology President Daniel F. Hayes, MD, in a statement. In an interview, Dr. Hayes added that innovations in information technology and the focus on improving interoperability of electronic health records were two important strengths of the recommendations that will be “critically important to deliver high-quality, high-value oncology services to individuals with cancer.”
Michelle Esser, senior program manager at the Young Survival Coalition (YSC), agreed that the recommendations are good initial steps. However, she pointed out two issues that the recommendations overlooked. “First, is the lack of mention or understanding of the adolescent and young adult (AYA) oncology patient population,” Ms. Esser noted during an interview. “The report specifically called out pediatric cancer as an area of needed research, but AYAs, whose survival rates lag behind those of older and younger patients with a similar diagnosis, and for whom cancer is the leading cause of disease-related death, were not mentioned.”
Second, there was little mention of cancer metastasis, she said. “It is not an early-stage cancer diagnosis that kills, it is when cancer metastasizes and spreads that it becomes deadly. Out of the 10 recommendations only 1 mentions metastasis. If we want to make a difference in cancer outcomes, there needs to be focus on understanding why metastasis occurs, how to prevent it, and how to cure it.”
In order for these recommendations to really expedite the nation’s progress against cancer, “It is crucial that Congress provide the necessary funding to support the priority projects identified by the Blue Ribbon Panel and those we will hear about from the Task Force and Vice President’s Executive Reports later this year,” reported Dr. Hayes, a sentiment echoed by Dr. Davidson.
On Twitter @jessnicolecraig
Overall, the response to Blue Ribbon Panel recommendations for guiding the Cancer Moonshot initiative were well received, though some patient advocates say a few key issues were overlooked.
In early September 2016, the Blue Ribbon Panel, a group of more than 150 scientists, clinicians, patient advocates, and industry representatives convened by the National Cancer Institutes’s National Cancer Advisory Board, published its Top 10 recommendations to guide future endeavors of the Cancer Moonshot Initiative.
The recommendations, which were informed by input from the research community and the public, emphasized “the importance of direct patient engagement in cancer research, a deeper understanding of why some therapies work and others do not, the dynamics of tumor evolution, and the need for mechanisms of data sharing, access, and analysis,” wrote Dinah S. Singer, PhD, and two other cochairs of the Blue Ribbon Panel in an article published in Science (2016 Sep 7. doi: 10.1126/science.aai7862).
“The recommendations that were announced today by the Cancer Moonshot Blue Ribbon Panel are vitally important to accomplishing the goal of the National Cancer Moonshot Initiative, which is to achieve a decade’s worth of advances in five years,” wrote American Association for Cancer Research President Nancy E. Davidson, MD, in a statement.
“The panel’s thoughtful work makes an important contribution to the Cancer Moonshot Initiative,” wrote American Society for Clinical Oncology President Daniel F. Hayes, MD, in a statement. In an interview, Dr. Hayes added that innovations in information technology and the focus on improving interoperability of electronic health records were two important strengths of the recommendations that will be “critically important to deliver high-quality, high-value oncology services to individuals with cancer.”
Michelle Esser, senior program manager at the Young Survival Coalition (YSC), agreed that the recommendations are good initial steps. However, she pointed out two issues that the recommendations overlooked. “First, is the lack of mention or understanding of the adolescent and young adult (AYA) oncology patient population,” Ms. Esser noted during an interview. “The report specifically called out pediatric cancer as an area of needed research, but AYAs, whose survival rates lag behind those of older and younger patients with a similar diagnosis, and for whom cancer is the leading cause of disease-related death, were not mentioned.”
Second, there was little mention of cancer metastasis, she said. “It is not an early-stage cancer diagnosis that kills, it is when cancer metastasizes and spreads that it becomes deadly. Out of the 10 recommendations only 1 mentions metastasis. If we want to make a difference in cancer outcomes, there needs to be focus on understanding why metastasis occurs, how to prevent it, and how to cure it.”
In order for these recommendations to really expedite the nation’s progress against cancer, “It is crucial that Congress provide the necessary funding to support the priority projects identified by the Blue Ribbon Panel and those we will hear about from the Task Force and Vice President’s Executive Reports later this year,” reported Dr. Hayes, a sentiment echoed by Dr. Davidson.
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FDA modifies dosage regimen for nivolumab
The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.
The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.
The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.
The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.
The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.
The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.
The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.
The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.
The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.
The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.
The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.
The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.
