Phase 1 trial of durvalumab (anti-PD-L1) combined with lenalidomide in relapsed/refractory cutaneous T-cell lymphoma

Abstract

Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via programmed cell death 1/programmed cell death ligand 1 blockade (durvalumab) may restore an antitumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL sought to assess the safety and tolerability and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate the efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1 to 3 (DLT evaluation period), and dose level 3 was identified as the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1 or 2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% confidence interval (95% CI), 27.7-84.8%) and 75% (95% CI: 42.8-94.5%), respectively. The median cycles of treatment were 11, and the median duration of response was 25.5 months. The combination showed clinical activity with 7 partial responses and 4 stable disease. Potentially predictive immune signatures were downregulation of -α signaling via NF-κB, interferon gamma, and phosphoinositide 3 kinase-AKT-mammalian target of rapamycin signaling pathways in responders and upregulation of MYC targets and proinflammatory pathways in nonresponders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response. This trial was registered at www.ClinicalTrials.gov as #NCT03011814.

T cell exhaustion and an immunosuppressive microenvironment is a hallmark of CTCL. Durvalumab combined with lenalidomide has the potential to enhance anti-tumor immunity in CTCL.

Figure 1.

Response to durvalumab plus lenalidomide treatment. (A) Waterfall plot of best response in skin from baseline by modified Severity Weighted Assessment Tool (mSWAT) scoring. (B) Representative images of responding patients (Pts) with tumors (top) and plaques (bottom). (C) Swimmer plot denoting time to response and response duration. (D) Spider plot of longitudinal response trajectory from baseline mSWAT. E, erythrodermic; FMF, folliculotropic MF; N/A, not applicable.

Figure 2.

Gene expression and pathway analysis reveal distinct expression profiles associated with combined immunotherapy. (A) Hierarchical clustering heat map of genome-wide mRNA expression profiles using pre- and on-treatment skin samples from Pts as indicated. (B) The top enriched Hallmark pathway terms of DEGs that correlated with treatment involved immune response pathways, such as IFN response and inflammatory response. The minimally enriched and negatively enriched Hallmark pathway terms among DEGs are also shown. (C) Hierarchical clustering heat map between the responders (blue) and nonresponders (red). (D) Upregulated genes with disease-associated pathway terms in nonresponders in comparison with responders shown in −log10(FDR) values. abs(NES), absolute value of the normalized enrichment score; C1D1, cycle 1 day 1; FDR, false discovery rate.

Figure 3.

Durvalumab and lenalidomide treatment enhances tumor-infiltrating CD8⁺ T-cell subsets. (A) CIBERSORTx analysis of bulk RNA revealed T-cell subset gene clusters in pre- and on-treatment samples (n = 12). The CD8⁺ cell subset was increased in on-treatment samples. Significant differences were identified using 1-way analysis of variance (ANOVA), followed by Tukey post hoc test, and a P value ≤.05 was considered significant. ∗∗∗∗P < .0001. (B) Heat map of immune checkpoint (IC) molecules in pre- and on-treatment samples in responders (PR) vs nonresponders (SD/PD) revealed a mild decrease in IC expression in those with PR, but the differences were not significant. (C) Heat map stratified by response demonstrates increased expression of Trm transcripts in responders when compared with nonresponders. FPKM, fragments per kilobase of transcript per million mapped reads.

Figure 4.

Combining durvalumab with lenalidomide is effective in targeting the CTCL TME and reveals dynamic changes in immune cell subsets and signaling pathways over time. (A) CIBERSORTx analysis of bulk RNA shows proportions of immune cell subsets in on-treatment samples and reveals a significant increase in activated NK cells and decreased Treg gene clusters in on-treatment samples of responders (PR) when compared with nonresponders (SD/PD). Significant differences were identified using 1-way ANOVA, followed by Tukey post hoc test, and P ≤ .05 was considered significant. ∗∗P < .01. (B) DEGs over time identified using RNA sequencing data of pre- and posttreatment skin biopsies reveal dynamic changes during treatment. (C) Activated pathways after treatment in responders (PR) when compared with nonresponders (SD/PD). (D) The IL-12, IFN-γ, IL-2R, and IL-17 levels in plasma samples were assessed using a multiplex cytokine assay at baseline and during treatment. The data are presented as mean ± standard deviation of 3 biological replicates. A 2-tailed Student t test was used, and P ≤ .05 was considered significant. ∗P < .05. IL-2R, interleukin-2 receptor.