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906 Safety, Efficacy, and Biomarkers of Response to Azacitidine (AZA) with Nivolumab (Nivo) and AZA with Nivo and Ipilimumab (Ipi) in Relapsed/Refractory Acute Myeloid Leukemia: A Non-Randomized, Phase 2 StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Immunotherapy
Hematology Disease Topics & Pathways:
Biological, AML, Diseases, Therapies, checkpoint inhibitors, Biological Processes, epigenetics, Clinically relevant, Myeloid Malignancies, immune mechanism
Monday, December 3, 2018: 5:45 PM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Naval G. Daver, MD1, Guillermo Garcia-Manero, MD2, Sreyashi Basu, PhD3*, Jorge E. Cortes, MD4*, Farhad Ravandi, MBBS5, Tapan M. Kadia, MD6, Marina Y. Konopleva, MD, PhD1, Elias J. Jabbour, MD 7, Courtney D. DiNardo, MD, MSc8, Rita Assi, MD4*, Sherry A. Pierce, BSN, BA4*, Yesid Alvarado, MD2, Zeev E. Estrov, MD2, Naveen Pemmaraju, MD9, Koichi Takahashi, MD10, Jing Ning, PhD11*, Graciela M. Nogueras González, MPH12*, Steven M. Kornblau, MD1, Mansour Alfayez, MD4, Jairo Matthews, BA1*, Wilmer Flores13*, Jorge Blando, DVM3*, James P Allison, PhD3*, Padmanee Sharma, MD, PhD3* and Hagop M. Kantarjian, MD14

1Department of Leukemia, MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
7Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
8Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
9Department of Leukemia, The University of Texas MD Anderson Cancer Center, Bellaire, TX
10Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
11Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston
12University of Texas MD Anderson Cancer Center, Houston
13Leukemia, University of Texas - MD Anderson Cancer Center, Houston, TX
14Department of Leukemia, The University of Texas, Houston

Background: Preclinically blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. PD-1 positive CD8 T-cells were increased in the bone marrow (BM) of pts with AML (Daver et al, ASH 2016). Azacitidine up-regulates PD-1 and interferon-gamma signaling (Yang et al., Leukemia 2013).

Methods: Pts were eligible for the AZA+Nivo (cohort 1) if they had relapsed/refractory AML (R/R AML), ECOG ≤ 2, and adequate organ function. The recommended phase 2 dose was established as AZA 75mg/m2 Days 1-7 with Nivo 3mg/kg Day 1 and 14. Courses were repeated approximately every 4-5 weeks indefinitely. 70 R/R AML pts have been treated; cohort 1 is closed.

A subsequent cohort of AZA+Nivo+Ipi in R/R AML was opened (cohort 2), with the same eligibility criteria as cohort 1 except that enrollment was restricted to pts with salvage 1 and 2 AML. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule. This dosing was based on lung and melanoma dosing for Ipi + Nivo.

Responses in both cohorts included best response within 3 months of therapy initiation.

Results:

Cohort 1: 70 R/R AML pts with median (med) age 70 years (range, 22-90), secondary AML (44%), poor risk cytogenetics (34%), med salvage 2 (range, 1-7) were enrolled. The ORR was 33% including 15 CR/CRi (22%) (4 CR, 11 CRi), 1 PR, and 7 HI maintained on study >6 months (10%) without allogeneic stem cell transplant. Additionally, 6 pts (9%) remained on study with stable disease (SD) >6 months. The remaining 41 pts (58%) had no response. 8-week (wk) mortality was 10%. Patients who achieved a CR/CRi/PR/HI/SD (n=29; 42%) had significantly improved overall survival (OS) compared with NRs (n=41; 58%) (16.1 versus 4.1 months; p<0·001). By univariate analysis (UVA) improved ORR was seen in pts with pretherapy BM blast <20%, circulating WBC </=10,000/mL, ASXL1 mutation, and no prior HMA-based therapy (Table 1). By UVA improved OS was seen in pts who achieved any response or SD (CR/CRi/PR/HI/SD), were salvage 1 status, and had ASXL1 mutation. The med OS with Aza+Nivo compared favorably to historical med OS with AZA-based protocols in salvage 1 or 2 pts at MDACC (6.0 versus 4.7 months; p=0.03)(Fig 1), with the most prominent improvement seen in salvage 1 pts (11.1 versus 4.1 months; P<0.001). Grade 3/4 immune related adverse events (irAEs) were observed in 8 (11%) pts, including pneumonitis (n=3), colitis (n=2), and nephritis, skin rash, and hypophysitis (1 each). The majority (12 of 16; 75%) of these occurred in the first 8 wks after nivo initiation. These responded rapidly to steroids when initiated early.

Flow-cytometry (MFC) was performed on pre- and post-therapy BMAs, after 2 doses (end of cycle 1 or EOC1) and 4 doses (EOC2) of nivol in 19 of 23 responders (R) (CR/CRi/PR/HI) (83%) and 28 of 41 NRs (68%). 36 parameter CyTOF was performed at same time-points in 5R and 5NRs. On pretherapy BMAs, R had a higher frequency of CD3+ (p=0.04) and CD8+ cells (p=0.09) on MFC (Fig 2A). CD3+ in the pretherapy BMA with a cut-off of 13.2%, had a sensitivity of 74% and a specificity of 65% for predicting response. The CD3+ was >13.2% in 26 of 47 pts (55%) who had an evaluable pretherapy BMA. Immunohistochemistry confirmed that CD3+ cells were increased in pretherapy BMs in R. PhenoGraph clustering of all CD3-gated cells revealed 24 meta-clusters (Fig 2B). The frequency of an effector CD8+ T cell cluster (C2) expressing CD45RA+PD1loTbethiEomeslo was significantly higher in the pretherapy BMAs of R versus NRs (11.2% versus 2.5%; p=0.002), and was further expanded in R not in NRs in the EOC1, EOC2, and EOC4 BMAs (Fig 2C).

Cohort 2: 20 pts with R/R AML, med salvage 2 (range 1-2), med age 68 (range, 25-83), secondary AML (36%), adverse cytogenetics (25%), and common molecular mutations TP53 in 5, RAS in 4, DNMT3A/ASXL1 in 2 pts each, were enrolled. 14 pts enrolled before May 1, 2018 were evaluable for response: 6 CR/CRp/CRi (43%) (including 2 CR, 2CRp, 2CRi), 2 stable disease > 6 mths, and 6 no response. The 8-wk mortality was 0. Grade 3/4 irAEs noted in 26% of the pts, most common pneumonitis. Med cycles to response of 2 (1-3). The med OS for all pts was not reached and the projected 1-yr OS in R/R AML was encouraging at 58% (Fig 1).

Conclusion: AZA+Nivo was effective in pts with AML in Salvage 1 or those with increased pretherapy CD3+ BM infiltrate by MFC or IHC. BM CD3 and CD8 are simple assays to select pts for future trials of AZA+PD1 inhibitors in AML. AZA+Nivo+Ipi had a encouraging CR/CRp/CRi rate (43%) and med OS (NR) in pts with salvage 1/2 AML and is enrolling.

Disclosures: Daver: Karyopharm: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Research Funding; Otsuka: Consultancy; Pfizer: Research Funding; Sunesis: Consultancy; Novartis: Consultancy, Research Funding; Alexion: Consultancy; Kiromic: Research Funding. Cortes: Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; AROG: Research Funding. Ravandi: Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia: Takeda: Consultancy; Abbvie: Consultancy; BMS: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Konopleva: Stemline Therapeutics: Research Funding. Jabbour: Spectrum: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy. DiNardo: Abbvie: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Celgene: Consultancy; Agios: Consultancy; Karyopharm: Honoraria; Jazz: Honoraria; Syros: Honoraria. Pemmaraju: daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; novartis: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding. Takahashi: Symbio Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Agios: Consultancy. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria.

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