Therapies that demonstrate durable, long-term responses with manageable safety and tolerability are needed for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer, demonstrated single-agent antitumor activity in the pivotal phase II LOTIS-2 study in heavily pretreated patients with R/R DLBCL. Here we present updated efficacy and safety analyses from LOTIS-2, performed for all patients and in subsets of patients with a complete response (CR), including patients with CR who were event-free (no progressive disease or death) for ≥1 year and ≥2 years from cycle 1, day 1 of treatment. Lonca was administered every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles). As of the final data cutoff (September 15, 2022; median follow-up: 7.8 months [range, 0.3-42.6]), 70 of 145 (48.3%) patients achieved an overall response. Thirty-six (24.8%) patients achieved CR, of which 16 (44%) and 11 (31%) were event-free for ≥1 year and ≥2 years, respectively. In the all-treated population, the median overall survival was 9.5 months; the median progression-free survival was 4.9 months. Among patients with CR, median overall survival and progression-free survival were not reached, with 24-month overall and progression-free survival rates of 68.2% (95% CI: 50.0-81.0) and 72.5% (95% CI: 48.2-86.8), respectively. No new safety concerns were detected. With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR (clinicaltrials gov. Identifier: NCT03589469).

Diffuse large B-cell lymphoma (DLBCL) is

Introduction: Circulating tumor DNA (ctDNA) has emerged as a tool to characterize tumors and track minimal residual disease (MRD) in many malignancies, including diffuse large B-cell lymphoma (DLBCL). ctDNA levels have been shown as prognostic after first-line treatment and CD19-targeted chimeric antigen receptor (CAR19) T cell therapy in DLBCL. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an antibody-drug conjugate comprising an antibody targeting CD19 and a pyrrolobenzodiazepine dimer cytotoxin, is approved for relapsed/refractory (R/R) DLBCL. The ultrasensitive ctDNA-MRD detection method, phased variant enrichment and detection sequencing (PhasED-Seq) was applied to evaluate molecular response and mutational genotypes in patients (pts) undergoing Lonca treatment. Methods: LOTIS-2 study (NCT03589469) evaluated the efficacy of Lonca in R/R DLBCL after ≥ 2 lines of prior systemic therapy. Samples from 33 LOTIS-2 pts were profiled by PhasED-Seq (Foresight Diagnostics), representing a range of best responses to therapy, including 8 complete response (CR), 14 partial response (PR), and 11 progressive disease (PD). Pts received a median of 4 treatment cycles with Lonca (range 2-22). Baseline plasma and peripheral blood mononuclear cells were used to identify tumor-specific phased variants (PVs), which were used to monitor ctDNA-MRD after 1 cycle of treatment (cycle 2, day 1 [C2D1]) and at the end of treatment (EOT). Samples were reported quantitatively with levels of ctDNA-MRD and qualitatively as ctDNA-MRD positive or negative. Absolute ctDNA levels and log-fold change (LFC) in ctDNA were compared with outcomes including best overall response, progression-free survival (PFS), and overall survival (OS), as determined by the independent review committee. The ctDNA mutational profile of each pt was evaluated at baseline and EOT to assess emerging clonal alterations with emphasis on CD19. Results: PVs were successfully genotyped from pretreatment plasma in 31/33 pts (94%) with sufficient material for analysis. The median pretreatment ctDNA level was 141 haploid genome equivalents /mL (hGE/mL) (range 0.4-3608), similar to previous DLBCL studies in first-line and relapsed settings. Interestingly, pretreatment ctDNA levels were not predictive of outcomes to treatment (hazard ratio [HR] 0.99, P=0.96). The prognostic value of ctDNA levels was assessed at C2D1. Absolute ctDNA levels and the change from baseline levels were significantly prognostic for the response to treatment. Pts achieving either a CR or a PR had significantly greater reduction in their ctDNA levels than those failing to respond (CR vs PD, median LFC -1.5 vs 0.1, P=0.001; PR vs PD, median LFC -1.1 vs 0.1, P=0.006) (Fig 1A). Interestingly, pts achieving a CR or a PR did not have significantly different changes in ctDNA at C2D1 ( P=0.15). When dividing pts at the median into those with high vs low ctDNA levels at C2D1, lower levels of ctDNA were significantly associated with superior PFS and OS (PFS: HR 4.4, P=0.009; OS: HR 3.2, P=0.01) (Fig 1B). At the EOT, 5 of 6 CR pts had cleared their ctDNA-MRD to undetectable levels vs 1 of 6 at C2D1. The CR pt who did not show deepening of molecular response was the only CR pt who ended Lonca treatment for radiographic disease progression; all other CR pts ended treatment for other reasons (e.g., toxicity, transplant, or persistent complete remission). To assess for emergent clonal mutations, the mutational profiles of pts were evaluated before Lonca treatment and at EOT. Prior studies in DLBCL after CAR19 T-cell therapy have revealed recurrent, although infrequent, mutations in CD19 as a mechanism of resistance. In this cohort, no emergent alterations in CD19 at the EOT (0/31 pts) were observed. One pt was identified with a baseline mutation in CD19 (R363C); this pt achieved a PR followed by PD after 3 cycles of treatment with persistence of the mutation in CD19. Conclusions: ctDNA molecular response assessment using PhasED-Seq is prognostic for outcomes in pts receiving Lonca monotherapy. ctDNA levels as early as C2D1 can predict outcomes and are indicative of a fast response to Lonca. Furthermore, molecular responses can deepen with additional cycles. CD19 alterations do not appear to be a common emergent mechanism of resistance to Lonca. In this exploratory study, ctDNA-MRD predicts Lonca efficacy and outcomes and should be further considered as a universal biomarker in DLBCL.

CD19-targeting treatments have shown promise in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is a CD19-targeting antibody-drug conjugate indicated for R/R DLBCL after at least two systemic treatments. CD19 expression was evaluated in patients receiving Lonca in the LOTIS-2 clinical trial with available tissue samples obtained after last systemic therapy/before Lonca treatment. Lonca cytotoxicity was evaluated in a panel of six lymphoma cell lines with various CD19 expression levels. Quantitative systems pharmacology (QSP) modelling was used to predict Lonca responses. Lonca responses were seen in patients across all CD19 expression levels, including patients with low/no detectable CD19 expression and H-scores at baseline. Similarly, Lonca induced cytotoxicity in cell lines with different levels of CD19 expression, including one with very low expression. QSP modelling predicted that CD19 expression by immunohistochemistry alone does not predict Lonca response, whereas inclusion of CD19 surface density improved response prediction. Virtual patients responded to Lonca with estimated CD19 as low as 1000 molecules/cell of CD19, normally below the immunohistochemistry detection level. We found Lonca is an effective treatment for R/R DLBCL regardless of CD19 expression by immunohistochemistry. These results provide the basis for future studies addressing CD19-targeted agent sequencing.

ADC Therapeutics SA; medical writing: CiTRUS Health Group.

Introduction: CD19 is a clinically-validated target for the treatment of B-cell malignancies, and several CD19-targeted therapies have received approval, including chimeric antigen receptor T-cell (CAR-T) therapy, antibody-drug conjugates (ADCs), monoclonal antibodies, and bispecific agents. However, the optimal sequencing of these treatments has not yet been clarified. Loncastuximab tesirine (loncastuximab tesirine-lypl; Lonca) is an ADC comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin, indicated for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 systemic treatments. Prior CAR-T therapy does not preclude a response to Lonca, and responses were also observed in patients who received CAR-T therapy post-Lonca. The present analysis was performed to determine the contribution of CD19 expression to responses in patients treated with Lonca. Methods: CD19 expression determined by immunohistochemistry (IHC) was evaluated in a cohort of patients enrolled in the LOTIS-2 clinical trial (NCT03589469) with available tissue samples obtained after their last anti-cancer systemic therapy and prior to Lonca. IHC was performed using the LE-CD19 antibody (DAKO), and expression was analyzed using the BenchMark ULTRA platform (Ventana). CD19 expression was assessed by semiquantitative scoring of both the percentage of positive tumor cells and the H-Score (semiquantitative assessment of the percentage of CD19 positive cells and staining intensity). Quantitative Systems Pharmacology (QSP) modeling was used to predict response to Lonca and to test hypotheses regarding patient-specific covariates. Results: The cohort included patients with any prior systemic therapies (n = 59), including patients who received CAR-T as the last therapy prior to biopsy (n = 9). Responses to Lonca were seen in patients across all levels of CD19 expression, including patients with extremely low or no detectable CD19 expression at baseline and extremely low H-Scores. On the basis of the QSP modeling, patients are anticipated to achieve disease response to Lonca with CD19 tumor cell-surface densities as low as 1,000 molecules/cell (Figure 2). Conclusions: Response to Lonca was observed in R/R DLBCL patients with very low CD19 tumor expression as measured by IHC. QSP modeling predicts that CD19 expression level by IHC is not predictive of response to Lonca, whereas the addition of CD19 surface density improves the response prediction. Patients responded to Lonca with estimated tumor cell surface densities as low as 1,000 molecules/cell, normally below the level of IHC detection. Our findings indicate that Lonca is an effective treatment option for patients with R/R DLBCL following ≥ 2 lines of treatment, even in patients expected to have a low level of CD19 expression. These results serve as a basis for future studies addressing sequencing of CD19-targeted agents. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction: Green tea is related to the reduction of liver enzymes, lipoprotein, and body mass index. However, some reports related green tea to the risk of developing liver cancer, but their outcomes were conflicting. Hence, the present study aimed to determine the relationship between green tea intake and lipoprotein, liver enzymes, body mass index, and liver cancer. Methods: A systematic literature search up to January 2020 was performed and 22 studies included 169599 subjects with 97316 of them use green tea intake. Odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CIs) was calculated to evaluate the relationship between green tea intake and lipoprotein, liver enzymes, body mass index, and liver cancer using the dichotomous or the contentious method with a fixed effect or a random effect models. Results: Green tea intake significantly lowered the risk of developing liver cancer, and body mass index compared to no green tea intake. Also, there was a significant lowering effect of green tea intake on liver enzymes, lipoprotein compared to no green tea intake. However, no significant different was found between green tea intake and no green tea intake on high-density lipoprotein. Conclusions: Based on this meta-analysis, green tea intake had a significant lowering effect on the risk of developing liver cancer and had a significantly improving effect on body mass index, liver enzymes, and lipoprotein compared to no green tea intake. These results suggest that green tea may be added to the daily dietary program to improve cardiovascular status with no possible risk of liver cancer. It even may have a protecting effect against liver cancer in the usual daily number of cups.

9064 Background: To better understand genetic determinants of response to ceritinib, tumor biopsies from NSCLC pts treated with ceritinib in ASCEND-1 (NCT01283516) were analyzed by next-generation sequencing (NGS). Methods: Biopsies were assayed by NGS using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14 Apr 2014). Results: NGS data were generated for 85 pts (ALK inhibitor [ALKi]-pretreated [n=54]; ALKi-naïve [n=31]). Baseline (BL) biopsy collection times differed among pts. The most frequent ALK rearrangements detected were EML4-ALK variant 1 (26/85) and variant 3 (23/85); 6 pts did not carry an EML4-ALK fusion but had an ALK rearrangement with another gene (HIP1 [n=2]; CLTC, CRIM1, STRN and TFG [n=1 each]). Comprehensive analysis correlating genetic landscape with ceritinib efficacy will be presented, including for 2 pts with ceritinib BL and post-progression biopsies. Of 28 pts with biopsies collected during or after prior ALKi treatment (Tx), 10 harbored an ALK tyrosine kinase domain mutation. Among these 10 pts, 8 had BL biopsies collected after (or less than 7 days before) the last day of prior ALKi Tx. All but one of these 8 pts benefited from ceritinib Tx (Table 1). One pt ALKi-naïve had a MET amplification in a ceritinib post-progression biopsy (among other somatic mutations) but not in BL biopsy. Conclusions: This analysis increases our knowledge of the mechanisms of resistance to ALK inhibition and their impact on ceritinib Tx, including the potential role of MET amplification. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated pts. Ceritinib efficacy in pts with ALK mutations in biopsies collected after (or close to) last day of prior ALKi Tx. Pt ALK mutation(s) BOR PFS, days 1 E1129V PR 337 2 L1196M PR 267 3 I1171T, F1174V PR 250 4b C1156Y SD 246+ 5 L1196M PR 213 6c C1156Y PR 174 7 L1196M PR 163 8 G1202R Unknown 26 aEfficacy per blinded independent review committee. bBiopsy 5 days before end of crizotinib Tx; + pt ongoing without event cBiopsy on last day of crizotinib Tx. BOR, best overall response; PFS, progression-free survival; PR, partial response; SD, stable disease.