AN UPDATE OF A PHASE II STUDY OF NIVOLUMAB (NIVO) OR IPILIMUMAB (IPI) WITH AZACITIDINE IN PTS WITH PREVIOUSLY TREATED OR UNTREATED MYELODYSPLASTIC SYNDROMES (MDS)
(Abstract release date: 05/18/17)
EHA Library. Montalban-Bravo G. 06/24/17; 181774; S487
Guillermo Montalban-Bravo
Contributions
Contributions
Abstract
Abstract: S487
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30
Location: Room N105
Background
Outcomes of pts with MDS after hypomethylating agent (HMA) failure remain poor. Upregulation of PD-1, PD-L1 and CTLA-4 in MDS CD34+ cells after exposure and loss of response to HMA have been reported. Nivo and Ipi are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors.
Aims
To evaluate the potential activity of immune checkpoint antibodies in patients with previously treated or untreated MDS
Methods
We designed a phase II study of Nivo or Ipi in monotherapy or combination for pts with MDS. Pts with prior therapy with HMA were to be treated in one of 3 consecutive cohorts: cohort #1: Nivo 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipi 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. Pts with previously untreated MDS were to be treated in one of 3 consecutive cohorts combining AZA 75mg/m2 iv daily days 1-5 of a 28 day cycle with: cohort #4: Nivo 3mg/kg iv Days 6 and 20; cohort #5: Ipi 3mg/kg iv on day 6; and cohort #6: Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. The maximum size per cohort is 20 pts. The primary endpoint is to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 IWG criteria. The study included stopping rules for response and toxicity.
Results
A total of 63 pts have been enrolled, 54 (86%) are evaluable for response and toxicity including 21 treated with frontline AZA+Nivo, and 15 and 18 with Nivo or Ipi after HMA failure, respectively Median age is 69 years (range 39-85). The median number of treatment cycles was 3 (range 1-11). A total of 3 (27%) pts in the AZA+Nivo cohort, 6 (40%) in the Nivo cohort, and 3 (33%) in the Ipi cohort having related grade ≥3 non-hematologic AEs. Therefore, the stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to AEs were required in 9 pts due to: rash (N=1), adrenal insufficiency (N=1), colitis (N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage. The ORR was 80% (13/21) in the AZA+Nivo cohort including 6 CR. The ORR was 0% and 30% (5/18) in the Nivo and Ipi arms, respectively. Therefore, the stopping rule for response was met on the Nivo arm, and enrollment after patient 15 was stopped. Immunophenotypic analysis of stem cell and progenitor compartments was performed in 27 pts, including PD-1 and PD-L1 expression analysis in 16 pts. Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 pts, respectively. Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression.
Conclusion
Preliminary results indicate that PD-1 blockade with Nivo in combination with AZA in untreated higher-risk MDS pts is associated with a tolerable safety profile and clinical activity. Single-agent Ipi is capable of inducing responses in previously treated MDS pts. Single-agent Nivo did not show clinical activity.
Session topic: 10. Myelodysplastic syndromes - Clinical
Keyword(s): Immune therapy, Therapy, MDS
Abstract: S487
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30
Location: Room N105
Background
Outcomes of pts with MDS after hypomethylating agent (HMA) failure remain poor. Upregulation of PD-1, PD-L1 and CTLA-4 in MDS CD34+ cells after exposure and loss of response to HMA have been reported. Nivo and Ipi are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors.
Aims
To evaluate the potential activity of immune checkpoint antibodies in patients with previously treated or untreated MDS
Methods
We designed a phase II study of Nivo or Ipi in monotherapy or combination for pts with MDS. Pts with prior therapy with HMA were to be treated in one of 3 consecutive cohorts: cohort #1: Nivo 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipi 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. Pts with previously untreated MDS were to be treated in one of 3 consecutive cohorts combining AZA 75mg/m2 iv daily days 1-5 of a 28 day cycle with: cohort #4: Nivo 3mg/kg iv Days 6 and 20; cohort #5: Ipi 3mg/kg iv on day 6; and cohort #6: Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. The maximum size per cohort is 20 pts. The primary endpoint is to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 IWG criteria. The study included stopping rules for response and toxicity.
Results
A total of 63 pts have been enrolled, 54 (86%) are evaluable for response and toxicity including 21 treated with frontline AZA+Nivo, and 15 and 18 with Nivo or Ipi after HMA failure, respectively Median age is 69 years (range 39-85). The median number of treatment cycles was 3 (range 1-11). A total of 3 (27%) pts in the AZA+Nivo cohort, 6 (40%) in the Nivo cohort, and 3 (33%) in the Ipi cohort having related grade ≥3 non-hematologic AEs. Therefore, the stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to AEs were required in 9 pts due to: rash (N=1), adrenal insufficiency (N=1), colitis (N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage. The ORR was 80% (13/21) in the AZA+Nivo cohort including 6 CR. The ORR was 0% and 30% (5/18) in the Nivo and Ipi arms, respectively. Therefore, the stopping rule for response was met on the Nivo arm, and enrollment after patient 15 was stopped. Immunophenotypic analysis of stem cell and progenitor compartments was performed in 27 pts, including PD-1 and PD-L1 expression analysis in 16 pts. Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 pts, respectively. Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression.
Conclusion
Preliminary results indicate that PD-1 blockade with Nivo in combination with AZA in untreated higher-risk MDS pts is associated with a tolerable safety profile and clinical activity. Single-agent Ipi is capable of inducing responses in previously treated MDS pts. Single-agent Nivo did not show clinical activity.
Session topic: 10. Myelodysplastic syndromes - Clinical
Keyword(s): Immune therapy, Therapy, MDS
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