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1697 The Combination of Nivolumab and CC-486 Is Active in Hodgkin Lymphoma Refractory to PD-1 Blockade

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas and T/NK Cell Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Hodgkin lymphoma, Biological therapies, Lymphomas, Clinical Research, Combination therapy, Checkpoint Inhibitor, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Matthew G. Mei, MD1, Lu Chen, PhD2*, Sandrine Puverel, PhD3*, Elizabeth Lihua Elizabeth Budde, MD, PhD4, Swetha Kambhampati, MD3, Shari Daniels1*, Bev Dunning1*, Melissa Banez, CCR5*, Larry W. Kwak3 and Alex F. Herrera, MD6

1City of Hope National Medical Center, Duarte, CA
2Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA
3Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA
4Department of Hematology and HCT, City of Hope, Duarte, CA
5Clinical Trials Office, City of Hope National Medical Center, Duarte, CA
6City of Hope, Duarte, CA

Introduction: PD1 blockade is highly active in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL); however, most patients ultimately progress on therapy, and HL that is refractory to PD1 blockade remains an unmet need. Furthermore, as PD-1 directed therapies are being administered in earlier lines, it is anticipated that pts with RR HL will be increasingly refractory to PD-1 directed therapies. Hypomethylating agents (HMA) have been shown to increase T-cell infiltration and upregulate PD-1 and CTLA-4 expression in tumors, as well as suppress myeloid-derived suppressor cells. We hypothesized that HMA might restore the sentivity of HL to PD-1 directed therapies. Therefore, we conducted a phase I study evaluating the safety and efficacy of nivolumab and CC-486, an oral HMA, in pts with RR HL refractory to PD-1 blockade.

Methods: Adult pts with RR HL who had progressed after at least 1 prior line of therapy and were refractory to PD-1 therapy were enrolled to receive oral CC-486 and nivolumab IV in 28-day cycles. PD-1 refractoriness was defined as progressive disease (PD) as best response, or PD while receiving or within 12 weeks of the last anti-PD-1 directed therapy. Pts were treated in a dose-finding cohort at 2 dose levels (DL) using a Rolling 6 design and then in a dose expansion cohort at the recommended phase 2 dose (RP2D). In DL1, CC-486 was administered at 200 mg PO daily on days 1-7, and in DL2 CC-486 was dosed at 300 mg PO daily on days 1-7; nivolumab 480 mg IV was given on day 8 in both DLs. Treatment could be continued for up to 2 years. Primary endpoints were determination of the RP2D and overall response rate (ORR) defined as the proportion of patients with a complete response (CR) or partial response (PR). Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification.

Results: As of July 7, 2023, 21 pts have been enrolled including 3 at DL1 and 18 at DL2 (RP2D). At baseline, 57% were male with a median age of 40 years (range 25-71), 95% had stage III-IV disease, and 71% had primary refractory disease, defined as lack of a complete remission (CR) or relapse within 3 months of frontline treatment. The median number of prior therapies was 6 (range 2-14), and 90% had prior brentuximab vedotin (BV). 76% of pts had received pembrolizumab, 67% had received nivolumab, and 43% had received both agents previously. 52% had undergone autologous stem cell transplant and 5% had had prior allogeneic stem cell transplant. Baseline characteristics are shown in Table 1.

The median number of cycles was 7 (range: 3-17). Among 19 pts evaluable for response (2 pending), ORR was 63% and CR rate was 10%. An additional 32% had SD as their best response; only one pt had PD as the best response. The median follow-up time was 9 months (range 2.8-16.3), and 71% of pts remain on treatment with an estimated median PFS of 11.3 months (95% CI: 7.1-N/A). 6 pts stopped therapy, including 4 for disease progression, 1 at treating physician’s discretion and 1 due to patient preference.

The most common adverse events (AEs), any grade (Gr), were nausea (86%), diarrhea (71%), vomiting (48%), headache (33%), fatigue (29%), neutropenia (19%), and anemia (19%). Only two Gr 3+ AEs were recorded: one patient experienced Gr 3 anemia and another Gr 4 hypercalcemia. Notably, the hypercalcemia fully resolved with supportive care and did not recur with subsequent cycles. The only immune-related AE was grade 1 hypophysitis in a single pt.

Conclusions: Nivolumab combined with CC-486 is tolerable and elicits a high response rate in a PD-1 refractory cohort. At this time, the study has been amended to enroll 10 more patients at DL2 to provide a better estimation of the efficacy.

Disclosures: Mei: CTI: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Seagen: Honoraria, Speakers Bureau; BMS: Research Funding; Incyte: Research Funding, Speakers Bureau; Beigene: Research Funding; Incyte: Research Funding. Budde: Amgen: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Novartis, Gilead, F. Hoffmann-La Roche Ltd, BeiGene, Genentech, Inc.: Consultancy; Roche: Consultancy; AstraZeneca: Consultancy, Research Funding; MustangBio: Research Funding. Kambhampati: ADC Therapeutics: Research Funding; Genentech: Research Funding; Genmab: Research Funding. Kwak: PeproMene Bio. Inc: Consultancy, Current equity holder in private company. Herrera: Caribou Biosciences: Consultancy; Adicet Bio: Consultancy; Genmab: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Regeneron: Consultancy; Tubulis GmbH: Consultancy; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy; AstraZeneca/MedImmune: Consultancy; Kite, a Gilead Company: Research Funding; Merck: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; BMS: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding; Allogene Therapeutics: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding.

OffLabel Disclosure: CC-486 (oral azacitidine) for use in relapsed/refractory Hodgkin lymphoma

*signifies non-member of ASH