A Phase I California Cancer Consortium Study of Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin Lymphoma: Updated Results and Immune Correlative Analyses

Background: We previously reported preliminary results of a phase I trial with blinatumomab/lenalidomide (blina/len) in relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) (Poh, Blood, 2019). We provide an updated analysis of outcomes and immune correlative analyses not previously presented.

Methods: This was a phase I trial of patients ≥18 years with R/R CD19+ B-NHL who received ≥2 prior treatments as previously described. Patients were treated at 2 dose levels and 2 schedules, which define cohorts 1,2, and 3 (C1, C2, and C3). All cohorts received induction with blina at 9 mcg/d CIV on days 1-7, 28 mcg/day CIV on days 8-14, and 112 mcg/day CIV on days 15-56. C1 received len 10 mg PO on days 29-49, C2 received len 20 mg PO days 29-49, and C3 received len 20 mg PO days 1-21 and days 29-49. Induction cycles were 56 days followed by a 28-day rest period. In responding patients induction was followed by 6 cycles of consolidation with blina 112 mcg/d CIV days 1-7 and len 20 mg PO days 1-21, and a max of 26 cycles of maintenance with len 20 mg PO days 1-21, or until disease progression or unacceptable toxicity. Peripheral blood samples were drawn at days 0, 15, 29, and 57 of treatment and assessed by cytokine and immunophenotypic profiling that were correlated with response. Primary endpoints were adverse events (AEs) and determining the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) during induction. Secondary endpoints were overall and complete response rate (ORR and CRR), progression free and overall survival (PFS and OS).

Results: 34 patients were enrolled as of July 25, 2022. 7 patients were treated in C1, 11 in C2, and 16 in C3. The median age (range) was 60.5 years (22-84). Males consisted of 68%, and 88% of patients had an ECOG ≤1. There were 15 with DLBCL, 6 with mantle cell lymphoma, 5 with unspecified B-NHL, 4 with follicular lymphoma, and 1 each with Burkitt lymphoma, marginal zone lymphoma, primary mediastinal B-cell lymphoma, and small lymphocytic lymphoma. The median number of prior therapies was 3 (range, 1-9). Seven (21%) and 9 (26%) patients previously received chimeric antigen receptor (CAR) T-cells and autologous stem cell transplant, respectively.

The MTD/RP2D was the C3 dose and schedule. In C3 (n=16), one patient had treatment-related grade 4 sepsis (6%) and 5 patients (31%) had grade 4 neutropenia. Four had grade 4 lymphopenia (25%). The most common grade 3 AEs at the RP2D included neurotoxicity (n=4, 25%) and neutropenia (n=2, 13%). There were no grade ≥3 cytokine release syndrome events or treatment-related deaths on any dose level.

At the RP2D, there were 7 CRs (7/16, 44%), and no PRs. 5 patients remain alive and in CR at last contact. Of the 14 evaluable at the RP2D, the CR rate was 50%. In all patients treated, best response of CR was obtained in 13/34 (38%) patients. In patients who were evaluated for a response, the CR rate was 13/29 (45%). OS and PFS for all patients are shown in Figure 1.

We examined 209 different immunophenotypic subsets via flow cytometry as a screening evaluation, and found 18 (9%) that were predictive biomarkers of response at baseline (Table 1) when unadjusted for multiple comparisons. On this initial screening assessment, lower pretreatment levels of NK and iNKT cell subsets, and higher levels of regulatory T cell subsets predicted response.

Conclusion: The combination of blinatumomab and lenalidomide, given at the RP2D dose of 112 mcg and 20 mg daily respectively, is safe with mostly manageable toxicity, but moderately limited by neurotoxicity. This regimen demonstrates encouraging efficacy with the C3 dose and schedule, producing the highest CR rates in this heavily pretreated patient population and is a promising alternative treatment option for R/R NHL. No treatment-related deaths were seen. Pretreatment correlative analysis identified T and NK cell subsets that may predict response. Additional correlatives analyses including serum cytokines and on-treatment immunophenotypic subset characterization are ongoing.

Abedi:Orca Bio: Research Funding; Kite, a Gilead Company: Speakers Bureau; AbbVie: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; CytoDyn: Current equity holder in publicly-traded company. Zain:Secura Bio: Consultancy, Research Funding; Daichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Myeloid: Consultancy, Research Funding; CRSPR: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; 3M: Current holder of stock options in a privately-held company; Affirmed: Research Funding; Kiyowa Kirin: Speakers Bureau. Budde:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Mustang Therapeutics: Research Funding; Merck: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding. Mei:CTI: Honoraria; Morphosys: Research Funding, Speakers Bureau; Novartis: Consultancy; Incyte: Research Funding; Beigene: Research Funding; Celgene: Research Funding; EUSA: Honoraria. Rosenberg:Bristol Myers Squib: Research Funding; Takeda: Other: Institutional Research; Kangpu: Other: Institutional Research; Adaptive: Consultancy; Janssen, Takeda: Speakers Bureau. Hoeg:Orca Bio: Research Funding. Costello:BMS, Takeda, Janssen, Pfizer: Honoraria, Research Funding. Foss:Astex: Consultancy; Seagen: Consultancy, Speakers Bureau; Daiichi: Consultancy; Conjupro: Consultancy; Kyowa: Consultancy. William:Guidepoint global: Consultancy. Villalona-Calero:Amgen: Speakers Bureau; Moderna: Current equity holder in private company; Eli Lily: Membership on an entity's Board of Directors or advisory committees. Tuscano:Takeda: Research Funding; Achrotech: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene: Research Funding; ADC therapeutics: Research Funding; BMS: Research Funding.

Blinatumomab is an off-label use in NHL. Lenalidomide is an off-label use in some NHL histologies, like DLBCL.