- Email: [email protected]
III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC
November 2016
Planned enrollment, N Histology Experimental arm Comparator arm
Stratification factors
ClinicalTrials.gov identifier
Abstracts
S305
570 Squamous Atezolizumab (1200 mg q3w) Cisplatin (75 mg/m2 IV q3w) + pemetrexed Cisplatin (75 mg/m2 IV q3w) + gemcitabine 2 (500 mg/m IV q3w) (1200 mg/m2 IV days 1, 8) or or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed Carboplatin (AUC 5 mg/mL/min IV q3w) (500 mg/m2 IV q3w) Maintenance: Pemetrexed + gemcitabine (1000 mg/m2 IV days 1, 8) 2 (500 mg/m IV q3w) Sex ECOG PS Histology (non-squamous vs squamous) PD-L1 expression by IHC NCT02409342 Non-squamous
Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an antiePDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1eselected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively. Methods: Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally assessed PD-L1 expression 1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, z65%). Exclusion criteria include active or untreated CNS metastases, prior immune-checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (nonsquamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRFassessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and
to differentiate non-conventional responses from radiographic progression. Results: Section not applicable. Conclusion: Section not applicable.
PS01.57 IMpower133: a Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with ExtensiveStage SCLC Topic: Medical Oncology Leora Horn,1 Martin Reck,2 Tony Mok,3 Melissa L. Johnson,4 Xiongwen Tang,5 Sivuonthanh Lam,6 Daniel Waterkamp,6 Ariel Lopez-Chavez,6 Alan Sandler,6 Giuseppe Giacconne,7 Stephen V. Liu7 1VanderbiltIngram Cancer Center, Nashville/United States of America, 2 Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf/Germany, 3The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC, 4Sarah Cannon Research Institute, Nashville, TN/United States of America, 5 F. Hoffmann-La Roche Ltd, Basel/Switzerland, 6 Genentech, Inc., South San Francisco, CA/United States of America, 7Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC/United States of America Background: Platinum-based chemotherapy with etoposide is the current first-line (1L) standard of care for the majority of patients with extensive-stage small cell lung cancer (ES-SCLC). Although initial response rates with chemotherapy range from 50% to 70%, survival outcomes remain poor (median overall survival [mOS] < 1 year), and new treatment approaches are needed. Atezolizumab is an antiePDL1 monoclonal antibody that
S306
inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring anti-tumor T-cell activity. In a Phase Ia study, single-agent atezolizumab demonstrated a tolerable safety profile and promising durability of response in patients with ES-SCLC: confirmed ORR was 6% (n ¼ 1/17 [partial response]; DOR of 7 months) by RECIST v1.1 and 24% by immune-related response criteria (irRC) (n ¼ 4/17, with 2 patients on atezolizumab for 12 months). In addition, pre-clinical and Phase I data suggest that atezolizumab plus platinumbased chemotherapy in NSCLC may be synergistic, resulting in durable responses that could potentially translate into improved survival over atezolizumab alone. Taken together, these findings provide a rationale to investigate whether atezolizumab + carboplatin + etoposide can improve survival compared with carboplatin + etoposide in the 1L treatment of ES-SCLC. Methods: IMpower133 (NCT02763579) is a global, Phase I/III, randomized, multicenter, double-blinded, placebocontrolled trial comparing the efficacy and safety of atezolizumab + carboplatin + etoposide with that of placebo + carboplatin + etoposide in treatment-naive patients with ES-SCLC. Patients will be enrolled regardless of PD-L1 expression status. Exclusion criteria include untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC. The study stratification factors include sex, ECOG performance status and presence of brain metastases. Eligible patients will be randomized 1:1 to receive four 21-day cycles of atezolizumab (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min, IV, day 1) and etoposide (100 mg/m2, days 1-3) followed by maintenance with atezolizumab or placebo until PD per RECIST v1.1. Patients can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints of investigator-assessed progression-free survival per RECIST v1.1 and OS will be evaluated. Secondary efficacy endpoints include ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 patients will be enrolled in this trial. Results: Section not applicable. Conclusion: Section not applicable
PS01.58 A Phase 3 Trial of Nivolumab, Nivolumab Plus Ipilimumab, or Placebo Maintenance for Extensive-Stage SCLC After First-Line Chemotherapy Topic: Medical Oncology Taofeek Owonikoko,1 Neal Ready,2 Pieter Postmus,3 Martin Reck,4 Solange Peters,5 Anne Pieters,6
Journal of Thoracic Oncology
Vol. 11 No. 11S
Giovanni Selvaggi,6 Justin Fairchild,6 Ramaswamy Govindan7 1Emory University School of Medicine, Atlanta, GA/United States of America, 2Duke University Medical Center, Durham, NC/United States of America, 3University of Liverpool, Liverpool/United Kingdom, 4LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf/Germany, 5 University of Lausanne, Lausanne/Switzerland, 6BristolMyers Squibb, Princeton, NJ/United States of America, 7 Washington University in St. Louis, St. Louis, MO/United States of America Background: Most patients diagnosed with small cell lung cancer (SCLC) present with extensive-stage disease (ED-SCLC). Although response rates to first-line platinum-based doublet chemotherapy (PT-DC) are high, most patients have rapid disease recurrence, and second-line chemotherapy has low efficacy. There is no approved maintenance therapy for patients who respond to first-line PT-DC. Nivolumab is a programmed death-1 immune checkpoint inhibitor that is approved for patients with previously treated metastatic nonesmall cell lung cancer. A phase 1/2 trial is investigating nivolumab monotherapy as well as the combination of nivolumab with ipilimumab, a cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitor, in patients with previously treated advanced or metastatic SCLC (CheckMate 032, SCLC expansion cohort). Data from the phase 1 part of CheckMate 032 showed that nivolumab alone or in combination with ipilimumab resulted in antitumor activity with durable tumor responses in patients with SCLC whose disease progressed after 1 prior regimens. Safety profiles were consistent with other tumor types. Responses were observed regardless of platinum sensitivity or programmed death-ligand 1 expression. CheckMate 451 (NCT02538666) is a randomized, multicenter, double-blind, phase 3 trial evaluating nivolumab monotherapy or nivolumab plus ipilimumab followed by nivolumab monotherapy versus placebo as consolidation/maintenance treatment after first-line PT-DC for patients with ED-SCLC. Methods: CheckMate 451 will enroll approximately 810 patients aged 18 years or older, with histologically or cytologically confirmed ED-SCLC, ECOG performance status 0e1, and an ongoing response of stable disease or better after a maximum of 4 cycles of first-line PT-DC. Patients with symptomatic central nervous system metastases, autoimmune disease, or who are receiving consolidative chest radiation are not eligible. Patients are randomized in a 1:1:1 ratio to receive nivolumab monotherapy, nivolumab plus ipilimumab followed by nivolumab monotherapy, or placebo. Co-primary endpoints are overall survival and progression-free survival. Secondary endpoints include descriptive analyses to
Planned enrollment, N Histology Experimental arm Comparator arm
Stratification factors
ClinicalTrials.gov identifier
Abstracts
S305
570 Squamous Atezolizumab (1200 mg q3w) Cisplatin (75 mg/m2 IV q3w) + pemetrexed Cisplatin (75 mg/m2 IV q3w) + gemcitabine 2 (500 mg/m IV q3w) (1200 mg/m2 IV days 1, 8) or or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed Carboplatin (AUC 5 mg/mL/min IV q3w) (500 mg/m2 IV q3w) Maintenance: Pemetrexed + gemcitabine (1000 mg/m2 IV days 1, 8) 2 (500 mg/m IV q3w) Sex ECOG PS Histology (non-squamous vs squamous) PD-L1 expression by IHC NCT02409342 Non-squamous
Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an antiePDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1eselected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively. Methods: Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally assessed PD-L1 expression 1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, z65%). Exclusion criteria include active or untreated CNS metastases, prior immune-checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (nonsquamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRFassessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and
to differentiate non-conventional responses from radiographic progression. Results: Section not applicable. Conclusion: Section not applicable.
PS01.57 IMpower133: a Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with ExtensiveStage SCLC Topic: Medical Oncology Leora Horn,1 Martin Reck,2 Tony Mok,3 Melissa L. Johnson,4 Xiongwen Tang,5 Sivuonthanh Lam,6 Daniel Waterkamp,6 Ariel Lopez-Chavez,6 Alan Sandler,6 Giuseppe Giacconne,7 Stephen V. Liu7 1VanderbiltIngram Cancer Center, Nashville/United States of America, 2 Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf/Germany, 3The Chinese University of Hong Kong, Hong Kong/Hong Kong PRC, 4Sarah Cannon Research Institute, Nashville, TN/United States of America, 5 F. Hoffmann-La Roche Ltd, Basel/Switzerland, 6 Genentech, Inc., South San Francisco, CA/United States of America, 7Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC/United States of America Background: Platinum-based chemotherapy with etoposide is the current first-line (1L) standard of care for the majority of patients with extensive-stage small cell lung cancer (ES-SCLC). Although initial response rates with chemotherapy range from 50% to 70%, survival outcomes remain poor (median overall survival [mOS] < 1 year), and new treatment approaches are needed. Atezolizumab is an antiePDL1 monoclonal antibody that
S306
inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring anti-tumor T-cell activity. In a Phase Ia study, single-agent atezolizumab demonstrated a tolerable safety profile and promising durability of response in patients with ES-SCLC: confirmed ORR was 6% (n ¼ 1/17 [partial response]; DOR of 7 months) by RECIST v1.1 and 24% by immune-related response criteria (irRC) (n ¼ 4/17, with 2 patients on atezolizumab for 12 months). In addition, pre-clinical and Phase I data suggest that atezolizumab plus platinumbased chemotherapy in NSCLC may be synergistic, resulting in durable responses that could potentially translate into improved survival over atezolizumab alone. Taken together, these findings provide a rationale to investigate whether atezolizumab + carboplatin + etoposide can improve survival compared with carboplatin + etoposide in the 1L treatment of ES-SCLC. Methods: IMpower133 (NCT02763579) is a global, Phase I/III, randomized, multicenter, double-blinded, placebocontrolled trial comparing the efficacy and safety of atezolizumab + carboplatin + etoposide with that of placebo + carboplatin + etoposide in treatment-naive patients with ES-SCLC. Patients will be enrolled regardless of PD-L1 expression status. Exclusion criteria include untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC. The study stratification factors include sex, ECOG performance status and presence of brain metastases. Eligible patients will be randomized 1:1 to receive four 21-day cycles of atezolizumab (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min, IV, day 1) and etoposide (100 mg/m2, days 1-3) followed by maintenance with atezolizumab or placebo until PD per RECIST v1.1. Patients can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints of investigator-assessed progression-free survival per RECIST v1.1 and OS will be evaluated. Secondary efficacy endpoints include ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 patients will be enrolled in this trial. Results: Section not applicable. Conclusion: Section not applicable
PS01.58 A Phase 3 Trial of Nivolumab, Nivolumab Plus Ipilimumab, or Placebo Maintenance for Extensive-Stage SCLC After First-Line Chemotherapy Topic: Medical Oncology Taofeek Owonikoko,1 Neal Ready,2 Pieter Postmus,3 Martin Reck,4 Solange Peters,5 Anne Pieters,6
Journal of Thoracic Oncology
Vol. 11 No. 11S
Giovanni Selvaggi,6 Justin Fairchild,6 Ramaswamy Govindan7 1Emory University School of Medicine, Atlanta, GA/United States of America, 2Duke University Medical Center, Durham, NC/United States of America, 3University of Liverpool, Liverpool/United Kingdom, 4LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf/Germany, 5 University of Lausanne, Lausanne/Switzerland, 6BristolMyers Squibb, Princeton, NJ/United States of America, 7 Washington University in St. Louis, St. Louis, MO/United States of America Background: Most patients diagnosed with small cell lung cancer (SCLC) present with extensive-stage disease (ED-SCLC). Although response rates to first-line platinum-based doublet chemotherapy (PT-DC) are high, most patients have rapid disease recurrence, and second-line chemotherapy has low efficacy. There is no approved maintenance therapy for patients who respond to first-line PT-DC. Nivolumab is a programmed death-1 immune checkpoint inhibitor that is approved for patients with previously treated metastatic nonesmall cell lung cancer. A phase 1/2 trial is investigating nivolumab monotherapy as well as the combination of nivolumab with ipilimumab, a cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitor, in patients with previously treated advanced or metastatic SCLC (CheckMate 032, SCLC expansion cohort). Data from the phase 1 part of CheckMate 032 showed that nivolumab alone or in combination with ipilimumab resulted in antitumor activity with durable tumor responses in patients with SCLC whose disease progressed after 1 prior regimens. Safety profiles were consistent with other tumor types. Responses were observed regardless of platinum sensitivity or programmed death-ligand 1 expression. CheckMate 451 (NCT02538666) is a randomized, multicenter, double-blind, phase 3 trial evaluating nivolumab monotherapy or nivolumab plus ipilimumab followed by nivolumab monotherapy versus placebo as consolidation/maintenance treatment after first-line PT-DC for patients with ED-SCLC. Methods: CheckMate 451 will enroll approximately 810 patients aged 18 years or older, with histologically or cytologically confirmed ED-SCLC, ECOG performance status 0e1, and an ongoing response of stable disease or better after a maximum of 4 cycles of first-line PT-DC. Patients with symptomatic central nervous system metastases, autoimmune disease, or who are receiving consolidative chest radiation are not eligible. Patients are randomized in a 1:1:1 ratio to receive nivolumab monotherapy, nivolumab plus ipilimumab followed by nivolumab monotherapy, or placebo. Co-primary endpoints are overall survival and progression-free survival. Secondary endpoints include descriptive analyses to