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Ribociclib/letrozole combo a ‘game changer’ in advanced breast cancer
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
COPENHAGEN – Progression-free survival for postmenopausal women with hormone receptor–positive advanced breast cancer was significantly improved when the cyclin-dependent kinase inhibitor ribociclib was added to standard therapy with the aromatase inhibitor letrozole, interim analysis from a phase III randomized trial shows.
After 18 months of follow-up, the risk of progression-free survival (PFS) among patients assigned to receive letrozole (Femara) and ribociclib was 44% lower than for patients assigned to receive letrozole and placebo, reported Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center, Houston, on behalf of coinvestigators in the MONALEESA-2 trial.
“We concluded that patients who received ribociclib with letrozole had a statistically significant and a clinically meaningful increase in progress-free survival compared to letrozole plus placebo, or letrozole alone,” he said at the European Society for Medical Oncology Congress.
“Is this a game changer? I think it probably is,” said invited discussant Stephen R.D. Johnston, MD, PhD, professor of breast cancer medicine and consultant oncologist at Royal Marsden Hospital in London.
Results of the first interim analysis of MONALEESA-2 (Mammary Oncology Assessment of LEE011’s Efficacy and Safety) were published simultaneously in the New England Journal of Medicine.
CDK 4 and 6 are frequently overexpressed in hormone receptor–positive breast cancer, and are key mediators of endocrine resistance, Dr. Hortobagyi explained.
Ribociclib is an oral small-molecule inhibitor of the pathway that includes CDK4/6 and the retinoblastoma protein, and has been shown to have efficacy in previously untreated HR-positive advanced breast cancer, and in patients with progressive disease on other therapies.
The MONALEESA-2 study is a phase III, double-blind, placebo-controlled trial of 668 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had not received prior therapy for advanced disease. Patients were stratified by the presence or absence of liver and/or lung metastases, and then assigned to receive letrozole 2.5 mg/day plus either ribociclib 600 mg/day for 3 weeks followed by 1 week off, or placebo on the same schedule.
At a preplanned interim analysis, after 243 events (disease progression or death) had occurred, the investigators found that the trial met its primary endpoint of locally assessed PFS, with a hazard ratio for ribociclib of 0.556 (P = .0000329 for superiority).
At the time of the analysis, median PFS had not been reached in the combination arm, compared with 14.7 months for the letrozole/placebo arm.
At 18 months’ follow-up (median 15.3 months), the PFS rate for ribociclib and letrozole was 63%, compared with 42.2% in the placebo group.
Respective response rates for patients with measurable disease at baseline were 52.7% vs. 37.1% (P less than .001).
Grade 3 or 4 adverse events occurring in more than 10% of patients included neutropenia in nearly two-thirds (59.3%) of the women who received ribociclib vs. 0.9% of those who received placebo, and leukopenia in 21% vs. 0.6%, respectively. In all, 7.5% of patients in the ribociclib group discontinued therapy because of adverse events, compared with 2.1% in the placebo group.
The challenge, Dr. Johnston said, will be to figure out how to integrate the findings from this trial and similar results with the CDK4/6 inhibitor palbociclib and letrozole seen in the PALOMA-2 trial into clinical practice.
Clinicians will be faced with deciding how to select various patient groups – endocrine sensitive, endocrine resistant, and treatment-naive – for targeted combinations or perhaps, for some patients, an aromatase inhibitor alone.
It also remains to be seen whether the CDK4/6 inhibitor/AI combination will be cost effective or affordable in many countries, and the pattern of resistance to CDK 4/6 inhibition is sill unknown, Dr. Johnston said.
The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma
Key clinical point: Adding the CDK 4/6 inhibitor ribociclib to an aromatase inhibitor significantly improved PFS in postmenopausal women with HR+/HER2- advanced breast cancer.
Major finding: The hazard ratio for progression with the combination of ribociclib and letrozole was 0.556 compared with letrozole/placebo.
Data source: Randomized phase III, placebo controlled trial in 668 postmenopausal women with untreated HR-positive/HER2- advanced breast cancer.
Disclosures: The study was funded by Novartis. Dr. Hortobagyi disclosed grants and personal fees from the company during the conduct of the study, and personal fees from Eli Lilly and Pfizer outside the submitted work. Dr. Johnston disclosed consulting and/or research funding with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Eli Lilly, Roche/Genentech and Puma.
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.