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619 The Combination of Duvelisib and Romidepsin (DR) Is Highly Active Against Relapsed/Refractory Peripheral T-Cell Lymphoma with Low Rates of Transaminitis: Final Results and Biomarker Analysis

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: T/NK Cell Lymphoma Relapsed Therapy
Hematology Disease Topics & Pathways:
Clinical Trials, Non-Biological, Translational Research, Clinical Research, Chemotherapy, Therapies, Pharmacology
Monday, December 13, 2021: 10:30 AM

Steven M. Horwitz, MD1, Anastasia Nikitina, PhD2*, Nikita Kotlov, MS3*, Ajit J. Nirmal, PhD4,5*, Ran Xu, PhD4,5, Alexander Bagaev, PhD6*, Maria Sorokina, MD2*, Sandrine Degryse2*, Alison J. Moskowitz, MD1, Neha Mehta-Shah, MD7, Eric D Jacobsen, MD4,5, Michael S. Khodadoust, MD, PhD8, Nivetha Ganesan, MPH9*, Esther Drill, DrPH1*, Helen Hancock, ANP1*, Theresa Davey, MMSc, PA-C1*, Patricia Myskowski, MD1*, Catherine Maccaro1*, William Blouin, MBA1*, Leslie Perez, RN1*, Sunyoung Ryu, RN1*, Natasha Galasso, MSW9*, Ahmet Dogan, MD, PhD1, Nathan H. Fowler, MD3, Youn H. Kim, MD8 and David M. Weinstock, MD5,10

1Memorial Sloan Kettering Cancer Center, New York, NY
2BostonGene Inc., Waltham, MA
3BostonGene, Corp, Waltham, MA
4Dana Farber Cancer Institute, Boston, MA
5Harvard Medical School, Boston, MA
6BostonGene Corp., Waltham, MA
7Washington University in St. Louis, Department of Medicine, Division of Hematology/Oncology, St. Louis, MO
8Stanford University Medical Center, Stanford, CA
9Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
10Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA

Standard therapies for relapsed/refractory (R/R) T-cell lymphomas (TCL) have overall response rates (ORR) of 25%-35%. Phosphoinositide-3-kinase (PI3K) δ and γ isoforms can promote tumor cell autonomous and non-autonomous effects in TCL. Initial studies of the PI3K-δ/γ inhibitor duvelisib (D) in R/R TCL showed an ORR of 50% and CR of 19%, but also a 40% rate of grade (Gr) 3/4 ALT elevation at the MTD of 75 mg BID (Horwitz et al Blood 2018). Based on preclinical data, we initiated a phase I study of D with either romidepsin (R) or bortezomib (NCT02783625). Based on efficacy and safety, Arm A (DR) was expanded to further describe safety and subtype-specific efficacy. To identify mechanisms for differential response, we performed integrated genomic and transcriptomic analyses and longitudinal assessments of tumor evolution on therapy and at relapse.

In Arm A, 59/66 patients were treated at the MTD of D (75 mg BID + R 10 mg/m2) on days 1, 8, and 15 of a 28-day cycle with prophylaxis against VZV and PJP. Response was assessed q2 cycles x 3 then q3 cycles. 10 patients received 1 cycle (Lead In) of D (75 mg BID) prior to combination DR. We performed whole exome sequencing (WES) on 43 (25 PTCL, 18 CTCL) baseline samples and RNA sequencing on 58 (38 PTCL, 20 CTCL) samples, of which 25 (18 PTCL, 7 CTCL) were baseline, 14 were on D lead-In, 8 were on DR, and 11 were end of treatment (EOT).

55 PTCL and 11 CTCL patients were treated (Table 1). At the MTD, 50/59 (85%) had AEs Gr 3-4 (no Gr 5), possibly related to study drug. AEs ≥Gr 3 in ≥10% of patients were: neutropenia (36%), diarrhea (15%), increased ALT/AST (14%), thrombocytopenia (10%), and infection (10%). Five patients (9%) had ≥Gr 3 rash. 10 had Gr 1/2 oropharyngeal/esophageal candidiasis and 2 had Gr 3. No unexpected toxicities were seen. In 10 patients who began on D-only Lead In, 4 (40%) had ≥Gr 3 ALT/AST and 3/10 had ≥Gr 3 diarrhea. Conversely, only 4/49 (8%) who got DR in cycle 1 had Gr 3-4 ALT/AST (p=.022) and 6/49 had ≥Gr 3 diarrhea (p=.170).

64/66 patients were evaluable for response. ORR was 55% (35/64) and CR was 34% (22/64). In PTCL, ORR was 58% (31/53) and CR was 42% (22/53). In CTCL, ORR was 36% (4/11), all PR. Of responders, 15/35 (43%) proceeded to allogenic stem cell transplantation (ASCT). Patients were censored at change of treatment (including ASCT) and withdrawal of consent to further survival follow up. Median PFS was 6.9 m for PTCL and 5.5 m for CTCL. Median DOR was 8.1 m. 4 subjects had CR on D Lead-in and did not proceed to DR; 2/4 went to SCT and 1 remained on D at 42m.

Among 43 baseline samples (21 (13 PTCL, 8 CTCL) responders, 22 (12 PTCL, 10 CTCL) non-responders), exome sequencing identified high rates of mutations in known TCL-associated genes: TET2 (CTCL: 6%, PTCL: 40%), DNMT3A, (CTCL: 17%, PTCL: 8%), RHOA (CTCL: 6%, PTCL: 12%), VAV1 (CTCL: 11%, PTCL: 8%) and TP53 (CTCL: 11%, PTCL: 12%). Using a RNAseq-based fusion detection algorithm, we discovered previously uncharacterized fusions and known recurrent gene translocations. WES analysis revealed that TET2 mutations were significantly associated with response in PTCL (9/13 R vs 1/12 NR, p<0.0036). Mutations in RHOA or VAV1, members of the same pathway, were exclusively identified in responders (7/21 R vs 0/22 NR p=0.002). In contrast, mutations in TP53 (0/13 R vs. 3/12 NR, p=0.2) in PTCL cases were associated with non-response.

Cell deconvolution analysis based on RNAseq detected higher involvement of B cells in baseline samples from R vs. NR (p<0.05). Through gene signature dynamics analysis, we observed a significant decrease in Tfh cells (c=-1.67, p<0.004 in R; c=0.1, p=ns in NR) and proliferation rate (c=-1.5, p<0.002 in R; c=-0.48, p=ns in NR), and an increase in lymphatic endothelium (c=1.77, p<0.05 in R, p=ns in NR). Transcriptional signatures for PI3K signaling decreased from baseline to EOT in R (coefficient (c)=-1.24, p<0.009) but not NR (c=-0.38, p=ns).

In conclusion, DR is highly active and tolerable, especially in R/R PTCL (58% ORR, 42% CR). Moreover, DR provided adequate response to allow frequent bridging to ASCT. Compared to a previous study of D alone, DR was associated with lower rates of transaminitis and a higher CR rate. TET2 mutations and greater involvement by B cells predicted response while TP53 mutations were exclusively seen in NR. These findings suggest that biomarker-driven patient selection can further improve ORR to DR.

Disclosures: Horwitz: Millennium /Takeda: Consultancy, Research Funding; Celgene: Research Funding; Forty Seven, Inc.: Research Funding; ONO Pharmaceuticals: Consultancy; Affimed: Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Acrotech Biopharma: Consultancy; Myeloid Therapeutics: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Aileron: Research Funding; Daiichi Sankyo: Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Tubulis: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Research Funding. Nikitina: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Sorokina: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company. Degryse: BostonGene Inc.: Current Employment, Current holder of stock options in a privately-held company. Moskowitz: Merck: Consultancy, Research Funding; Miragen: Research Funding; Takeda: Consultancy; Beigene: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Incyte: Research Funding; Janpix Ltd.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Research Funding. Mehta-Shah: Corvus Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Innate Pharmaceuticals: Research Funding; Verastem: Research Funding; Secura Bio: Consultancy, Research Funding; Ono Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Kiowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding. Dogan: EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Physicians’ Education Resource: Honoraria; Roche: Consultancy, Research Funding. Fowler: BostonGene: Current Employment, Current holder of stock options in a privately-held company. Kim: Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Eisai: Research Funding; Soligenix: Research Funding; Elorac: Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weinstock: SecuraBio: Consultancy; ASELL: Consultancy; Bantam: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Ajax: Other: Founder/Equity; AstraZeneca: Consultancy; Travera: Other: Founder/Equity.

OffLabel Disclosure: Duvelisib is off-label for PTCL

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