Higher Complete Response Research Articles

High complete response rate with TNB-486 in relapsed/refractory follicular lymphoma: Interim results from an ongoing phase 1 study.

7524 Background: Follicular lymphoma (FL) is incurable with a relapsing/remitting pattern and decreasing progression-free survival (PFS) interval per recurrence. In the relapsed/refractory (R/R) setting, patients (pts) failing CAR T or CD20 bispecific T-cell engagers (TCE) have few options. TNB-486 is a novel bispecific CD19xCD3 TCE that induces T-cell–mediated cytotoxicity with reduced cytokine release via a low-affinity αCD3 moiety. We present interim data from a phase 1 dose-escalation study of TNB-486 (NCT04594642). Methods: Third-line+ R/R FL pts (grade [G] 1–3a) were enrolled (prior CD19 therapy allowed). Escalating fixed TNB-486 doses (0.03–2.4 mg) without priming were evaluated prior to implementing single (day [D] 1) and double priming doses (D1 & 8) prior to target dose (D15). TNB-486 was given IV every 2 weeks in 28-d cycles (C) for up to 2 y. Response was assessed with RECIL 2017 by central image review. Adverse events (AEs) and CRS/ICANS were graded by CTCAE v5.0 and 2019 ASTCT criteria. Results: As of Dec 31, 2022, 17 pts received TNB-486 at target doses 0.03–10 mg (median age 68 y [range 33–86]; 53% male; 65% stage III/IV; 25% CD20− disease; median prior lines of therapy [LOT] 3 [range 2–9]). Prior therapies included αCD20 Ab (100%), alkylator (76%), IMiD (47%), CD20 TCE (12%), CD19 CAR T (12%), and ASCT (6%); 53% progressed or started 2nd LOT within 24 mo of initiating 1st LOT (POD24). Median time on study was 7 mo (range 1–22). Eleven pts were response evaluable for efficacy at target doses ≥2.4 mg. Objective response rate (ORR) and complete response (CR) rate were 91% (Table). ORR/CR for pts with CD20− disease, prior CD20 TCE, and POD24 was 100%. One pt progressed at C6 with preserved CD19 expression; all others remain in remission to date. The 6-mo PFS rate was 91%. No G3+ CRS occurred (59% G1, 12% G2). Neurologic events consistent with ICANS were reported in 24%, all G1–2 except 1 with a G3 event (confusion). All CRS/NT were transient, resolving in a median of 1.5 d (range 1–5). G3+ treatment-related AEs in >10% of pts included decreased lymphocytes (35%) and neutropenia (12%). No treatment-related deaths or AEs leading to discontinuation occurred (1 pt died and 1 discontinued due to COVID-19). One pt received double step-up priming dosing to date with no CRS/NT. Conclusions: TNB-486 induces high complete remission rates during early phase dose escalation. With limited follow-up, responses appear durable in heavily pretreated FL pts, with a manageable safety profile. Dose escalation is ongoing to identify the RP2D. Clinical trial information: NCT04594642 . [Table: see text]

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events

BackgroundManagement of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the...

Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: Results from the observational study GEM1801.

9547 Background: Most patients with BRAF-mutant melanoma eventually develop resistance to therapy with BRAF/MEK inhibitors and immune-checkpoint blockade. Alternative treatment strategies are required in these patients since further therapy options lack survival benefit. Small series have shown promising activity from re-exposure to BRAF/MEK inhibitors after a treatment free interval of targeted therapy (TT), probably due to regression of resistant tumors and proliferation of clones that maintain sensitivity to BRAF/MEKi. However, prospective evidence for this approach is limited. Here we report the results of 30 patients who received a second course of TT at relapse after adjuvant therapy (retreatment) or after first progression on TT in the advanced setting (rechallenge). Methods: GEM1801 is a prospective observational study from the Spanish Melanoma Group (GEM) including 893 patients with melanoma treated in 37 centers. This is a descriptive analysis of basal characteristics, response rates (RR), progression free survival (PFS) and overall survival (OS) from 30 patients that received retreatment or rechallenge with BRAF/MEKi in GEM1801 study. Results: 4 patients received retreatment and 26 rechallenge. For retreatment, BRAF/MEKi median free interval from end of adjuvant TT to subsequent retreatment was 17.8 months (range: 12.4 - 57.7). RR with retreatment were 25%, with a median PFS and OS of 5.7 and 8.5 months. For rechallenge, RR was 38.5% and median PFS and OS 11.1 and 22.2 months respectively. Patients who were selected for rechallenge had higher complete response (CR) rates to first TT (26.9% vs 20.3%; p= 0.026). Patients who experimented deeper responses with 1st TT in the metastatic setting showed a correlation to longer PFS to 2nd TT with 12-m PFS rates of 66.7% versus 35.7% (HR 9.09 [95%CI: 1.42-58]; p= 0.02). OS showed a not statistically significant improvement in patients who reported CR to first TD (24-m OS rate of 75% versus 40.7% respectively). BRAF/MEKi free interval since first progression and retreatment or rechallenge was not associated with prognosis. Prognostic factors as LDH and number of metastatic sites did not correlate with the efficacy of retreatment. Conclusions: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting achieved encouraging efficacy and may be a valid therapeutic strategy in a selected group of patients. Response to first treatment, retreatment and rechallenge with BRAF/MEKi. Clinical trial information: NCT03605771 . [Table: see text]

Baseline and early post-infusion biomarkers associated with optimal response to idecabtagene vicleucel (ide-cel) in the KarMMa-3 study of triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM).

8031 Background: Ide-cel, a B-cell maturation antigen (BCMA) chimeric antigen receptor T cell therapy, significantly improved median progression-free survival (mPFS) and overall response rate (ORR) vs standard regimens (SRs) in patients (pts) with TCE RRMM in the KarMMa-3 study (NCT03651128; Rodríguez-Otero et al. NEJM 2023). Previous analyses in KarMMa (Munshi et al. NEJM 2021) of pts with later-line (4L+) TCE RRMM identified low baseline (BL) levels and complete clearance of soluble BCMA (sBCMA, a measure of tumor burden) and early minimal residual disease (MRD) negativity as correlates of durable response to ide-cel. The current analysis explored the association between biomarkers and efficacy or severity of inflammatory adverse events of ide-cel in KarMMa-3. Methods: sBCMA levels were measured in blood samples collected from pts in KarMMa-3 at BL and regular intervals from treatment (tx) initiation until confirmed progression. MRD status was assessed in bone marrow aspirate (clonoSeq; 10-5 sensitivity) at 6 and 12 mo post infusion and reported in all pts, regardless of response. Biomarker analyses were based on pts who received ide-cel or ≥1 dose of SR. Post hoc analyses assessed correlations between biomarkers and efficacy endpoints or cytokine release syndrome (CRS) and investigator-identified neurotoxicity (iiNT); associations of interest were identified using a ranked sum test and nominal P value < 0.05. Results: Lower BL sBCMA levels were associated with higher ORR ( < partial response [PR] vs ≥PR) in both tx arms (ide-cel, P= 0.0223; SR, P= 0.0395), indicating this may be agnostic of the BCMA-directed modality. Lower BL sBCMA was also associated with higher complete response (CR) rate ( < CR vs ≥CR) in the ide-cel arm ( P= 0.0038). Additionally, lower BL sBCMA levels in the ide-cel arm were associated with lower grade (gr) of CRS (gr 0–1 vs 2 vs ≥3; P= 0.0022) and iiNT (gr 0–1 vs ≥2; P= 0.0113); however, overlapping ranges may limit predictive utility. Further analyses will be presented. In the ide-cel arm, landmark mPFS was longer in pts with undetectable versus detectable sBCMA at 2 mo post infusion (16.3 vs 5.2 mo; HR, 0.26) or at 6 mo (16.8 vs 9.6 mo; HR, 0.62). Furthermore, landmark mPFS was also longer in pts with MRD negativity versus pts with positive/indeterminate MRD status at 6 mo (17.2 vs 5.8 mo; HR, 0.288) or at 12 mo (13.8 vs 4.6 mo; HR, 0.121). Conclusions: BL sBCMA levels correlated with response and CRS and iiNT grade in the ide-cel arm of KarMMa-3, potentially reinforcing the importance of management of BL tumor burden for optimal response to ide-cel. Early clearance of sBCMA at 2 mo, sustained clearance of sBCMA at 6 mo, and MRD negativity at 6 or 12 mo, regardless of clinical response, may be useful biomarkers for identifying pts likely to achieve a complete and durable response to ide-cel. Clinical trial information: NCT03651128 .

Immunotherapy for localized MSI-H colorectal cancer: Characterizing endoscopic and imaging response.

3610 Background: Early data suggests that immunotherapy (IO) for localized colorectal cancer (CRC) is associated with high rates of pathologic complete response (pCR) and durable remission. This study aims to characterize endoscopic, imaging, and pathological outcomes among patients who received IO for localized CRC. Methods: This was a single-institution retrospective analysis of patients with MSI-H CRC who received at least one cycle of anti-PD-1 therapy for localized (stage I-III) MSI-H CRC. Patient and tumor characteristics were obtained from the clinical record. Endoscopy reports were assessed using standardized criteria to determine response and imaging was assessed using RECIST v1.1 where applicable. Endoscopic complete response (endoCR) was characterized by flat, white scar and/or telangiectasia without residual ulcer or nodularity. Categorical variables were compared using Fisher’s exact test. Results: 37 patients who received a median of 8 cycles of pembrolizumab (n = 36) or nivolumab (n = 1) for localized CRC were identified, of which 16 (43%) had a rectal primary. 10 patients (27%) had mucinous features on pathology. The best endoscopic response was complete response (CR) in 13 of 30 (43%) patients, which was achieved after a median of 6 cycles. The rate of endoCR after ≤ 4 cycles of IO was similar to the rate of endoCR after > 4 cycles (29% vs 50%, p = 0.284). The best imaging response was CR in 6 of 32 (19%) of patients. The rate of CR on imaging after ≤ 4 cycles and > 4 cycles of IO was 6% and 36% respectively (p = 0.064). In cases where imaging and endoscopy were available (n = 24), discrepancy in best response was noted in 14 (58%) cases. The most common discrepancy was partial response on imaging when endoCR was noted (n = 6 cases). 16 patients proceeded to surgical resection (after a median of 8 cycles) of which 11 (69%) had pCR despite non-CR on either endoscopy (n = 7) or imaging (n = 9). The endoscopic reports indicating residual disease prior to surgery included findings such as ulceration, scarring, strictures, and an obstructing mass. Of 15 patients who did not proceed to surgery and had follow-up more than 6 months after completion of IO, 13 (87%) had no evidence of progression at a median follow-up of 19.3 months from IO start. Conclusions: Discrepancies between endoscopic, imaging, and pathological outcomes were frequent, indicating a need for improved clinical response criteria. Nevertheless, immunotherapy was associated with deep and durable responses in most patients with localized MSI-H CRC.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Epcoritamab, an off-the-shelf, subcutaneous CD3xCD20 T-cell–engaging bispecific antibody that redirects T cells to eliminate malignant CD20+ B cells, showed single-agent efficacy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) with a manageable safety profile. The phase 1/2 EPCORE NHL-1 trial (NCT03625037) of epcoritamab in patients with R/R DLBCL who received ≥2 prior lines of systemic therapy showed high complete response (CR) and minimal residual disease rates. Methods: This matching-adjusted indirect comparison included published data on overall response rate (ORR), CR rate, and overall survival (OS) for axi-cel (ZUMA-1 trial, N = 101) and individual patient-level data (IPD) for epcoritamab (EPCORE NHL-1 trial). Patients in EPCORE NHL-1 with prior CAR T therapy were excluded as ZUMA-1 included only patients without prior CAR T therapy. Analyses were adjusted for imbalances in baseline characteristics between IPD from EPCORE NHL-1 and aggregate data from ZUMA-1. Propensity score weights were applied to estimate risk differences for ORR and CR rate; weighted Cox proportional-hazards models were used to estimate OS hazard ratio (HR). Subgroup analyses of CAR T-eligible patients assessed patients with more similar clinical characteristics. Results: Compared with the ZUMA-1 population, the majority of patients enrolled in EPCORE NHL-1 (N = 86) were men (61.6% vs. 23.8%) with a median age of 69.5 y (vs. 58.0 y), and were refractory to ≥2 consecutive lines of therapy (62.8% vs. 53.5%). Among the CAR T-adjusted matched population, response rates were not statistically different in those treated with epcoritamab versus axi-cel (ORR: 73.4% vs. 74.3%, respectively; difference in ORR: −0.8%; P = 0.927; CR rate: 48.5% vs. 54.5%; difference in CR rate, −6.0%; P = 0.583). In a subgroup of CAR T-naive patients that were CAR T eligible and treated with epcoritamab (n = 50), response rates also did not significantly differ from those in patients treated with axi-cel (ORR 72.7% vs. 74.3%, respectively; difference in ORR: −1.6%; P = 0.873; CR rate: 47.7% vs. 54.5%; difference in CR rate, −6.8%; P = 0.576). In all CAR T-naive patients, OS was not statistically different between those treated with epcoritamab versus axi-cel (HR: 0.695; 95% CI: 0.351, 1.376; P = 0.297). Likewise, the CAR T-eligible subpopulation treated with epcoritamab did not have statistically different OS versus axi-cel (HR: 0.708; 95% CI: 0.309, 1.626; P = 0.416). Conclusions: Findings from this cross-study comparison suggest that epcoritamab is a promising, emerging, novel therapy with no statistically significant difference in efficacy versus axi-cel in patients with highly refractory, hard-to-treat DLBCL. Additional analyses are needed to better understand the therapeutic potential of epcoritamab as an off-the shelf, subcutaneously delivered core therapy for these patients. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Epcoritamab is jointly developed by Genmab A/S and AbbVie Inc.; AbbVie and Genmab are sponsoring this study. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. C. Thieblemont Consultant or advisory role: AbbVie, BeiGene, BMS/Celgene, Roche, Janssen, Kite/Gilead, Novartis, Regeneron, and Takeda C. P. Fox Consultant or advisory role: GenMab and AbbVie Other remuneration: Steering Committee: GenMab A. Wang Consultant or advisory role: AbbVie, BeiGene, BMS/Celgene, Roche, Janssen, Kite/Gilead, Novartis, Regeneron, and Takeda K. Sail Employment or leadership position: AbbVie Stock ownership: AbbVie A. Alshreef Employment or leadership position: AbbVie Stock ownership: AbbVie M. Moran Employment or leadership position: AbbVie Stock ownership: AbbVie A. Mutebi Employment or leadership position: Genmab Stock ownership: Genmab J. Blaedel Employment or leadership position: Genmab Stock ownership: Genmab V. Chirikov Employment or leadership position: OPEN Health, which received funding support from AbbVie to conduct the research G. Salles Consultant or advisory role: AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, and Takeda

Glofitamab monotherapy in pts with relapsed/refractory (R/R) large B-cell lymphoma (LBCL): Extended follow-up and landmark analyses from a pivotal phase II study.

7550 Background: Glofitamab is a CD3xCD20 bispecific antibody delivered in a fixed course of 12 three-weekly cycles. In a Phase II study (NCT03075696), glofitamab induced high complete response (CR) rates and had manageable toxicity in pts with R/R LBCL (Dickinson et al. 2022). We present an extended follow-up and a landmark analysis to assess the outcomes of pts in CR. Methods: Pts with LBCL and ≥2 prior therapies received 1000mg obinutuzumab pretreatment 7 days prior to the first glofitamab dose. IV glofitamab was given as step-up doses: 2.5mg on Day (D) 1 of Cycle (C) 1, 10mg on C1D8 and 30mg (target dose) on D1 of C2–12 (21-day cycles). The primary endpoint was independent review committee (IRC)-assessed CR rate. PFS and OS post-hoc analyses were performed in responders (landmark for CR at C3 or end of treatment [EOT]). Results: As of Oct 10, 2022, 154 pts had received ≥1 dose of study treatment; baseline characteristics were as previously presented. Median number of prior therapies was 3 (range: 2–7); 33% had received prior CAR T-cells and 85% were refractory to their most recent regimen. Median time on study was 20.1 months (range: 0–32). The investigator (INV)-assessed CR rate (BOR) was 38% (40% by IRC) and overall response rate was 59% (52% by IRC). CR rates were consistent in pts with and without prior CAR-Ts (37% vs 39%). After a median follow-up of 18.3 months (range: 0–30) in pts with a CR (BOR), most CRs (39/59; 66%) were ongoing. Median duration of CR (DoCR) was 24.1 months (95% CI: 19.8–NE); an estimated 70% of pts with a CR at any time remained in remission at 18 months. The 18-month OS rate was 41% (95% CI: 32.1–49.3). Landmark analyses at 1 year in pts with a CR pre-C3 (PFS rate: 71%, OS rate: 92%) and in pts with a CR at EOT (PFS rate: 80%, OS rate: 94%) showed that most pts were progression free and alive. In a cohort of 101 pts treated with glofitamab doses below the recommended Phase II dose but ≥10mg with longer median CR follow-up (31 months, range: 1–49), the median DoCR was 30.1 months (95% CI: 5.5–NE) and 55% of pts were still in remission at data cut-off. This further confirms the highly durable responses achieved with glofitamab. CRS (by ASTCT) remained the most common adverse event (AE), occurring in 64% of pts, and was mostly Grade (Gr) 1 (48%) or Gr 2 (12%); Gr 3 (3%) and Gr 4 (1%) events were uncommon. The incidence of AEs and serious AEs was stable compared with earlier analyses, with one new Gr 3 AE (acute kidney injury), one new Gr 2 neurologic AE (agitation) and no new glofitamab-related Gr 5 AEs reported. Conclusions: Glofitamab continued to demonstrate durable responses, with most pts in CR at EOT still in remission without new AEs. These data support the potential for favorable long-term outcomes with fixed-duration glofitamab for R/R LBCL. Updated analyses, including a larger population with a median CR follow up of approximately 20 months post-EOT, will be presented. Clinical trial information: NCT03075696 .

SUBCUTANEOUS EPCORITAMAB INDUCES DEEP, DURABLE COMPLETE REMISSIONS IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA: LONGER FOLLOW‐UP FROM THE PIVOTAL EPCORE NHL‐1 TRIAL

SUBCUTANEOUS EPCORITAMAB INDUCES DEEP, DURABLE COMPLETE REMISSIONS IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA: LONGER FOLLOW‐UP FROM THE PIVOTAL EPCORE NHL‐1 TRIAL

Effect of follow-up time on the ability of subcutaneous epcoritamab to induce deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: Updated results from the pivotal EPCORE NHL-1 trial.

7525 Background: Outcomes are poor for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Effective treatments (tx) that drive deep, durable responses and long-term benefit are needed. In the pivotal EPCORE NHL-1 trial (NCT03625037), single-agent epcoritamab (epcor) showed high complete response (CR) and MRD-negativity rates, a median duration of response (mDoR) not reached (NR) in pts who achieved CR, and a manageable safety profile as an off-the-shelf, subcutaneous (SC), CD3xCD20 T-cell–engaging bispecific antibody (Thieblemont et al, JCO 2022). We present updated results with longer follow-up in a challenging-to-treat population. Methods: Pts with R/R CD20+ LBCL received SC epcor (step-up priming and intermediate doses followed by 48-mg full doses) in 28-d cycles (Cs): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until PD or unacceptable toxicity. Results: As of Nov 18, 2022, of 157 pts (median age, 64 y) with LBCL (including DLBCL [n=139], HGBCL [n=9], PMBCL [n=4], and FL grade 3B [n=5]; 13/99 double/triple-hit by FISH), 36 remain on tx. Pts had a median of 1.6 y from initial diagnosis to first dose and a median of 3 (range, 2–11) prior tx lines; 61% of pts had primary refractory disease, and 39% had prior CAR T, of whom 75% progressed ≤6 mo of tx. Median follow-up was 20 mo (range, 0.3+ to 28.2). Pts received a mean of 9.1 cycles. LBCL overall response and CR rates were 63.1% and 39.5%, respectively, and were consistent for DLBCL (61.9% and 39.6%). The mDoCR was 20.8 mo. Median time to CR was 2.7 mo; 8 pts converted from partial response to CR at ≥36 wk. Median overall survival (mOS) was 18.5 mo (95% CI, 11.7–NR), with an estimated 58% of pts alive at 12 mo. mOS was NR in pts who achieved CR. Additional outcomes for pts with CR are shown in Table. The most common TEAEs of any grade (G) were: CRS 51%, neutropenia 24%, pyrexia 24%, fatigue 23%, nausea 22%, and diarrhea 21%. Nine pts (6%) had G1–2 ICANS, and 1 pt had a G5 event with confounding factors. Fatal TEAEs occurred in 15 pts; 2 were considered related (COVID-19, ICANS). CRS was predominantly low grade (48% G1–2; 3% G3) and occurred following the first full dose (C1D15). One pt discontinued tx due to G1 CRS. Total metabolic tumor volume (TMTV) data will be presented. Conclusions: These data with longer follow-up reaffirm single-agent SC epcor induces durable CRs with improved outcomes and a manageable safety profile. No new safety signals were observed in these hard-to-treat pts. These impressive data support the ongoing phase 3 studies evaluating epcor across different lines of tx and in various combinations. Clinical trial information: NCT03625037 . [Table: see text]

Personalized circulating tumor DNA (ctDNA) analysis in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC).

e16062 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. A “Watch and Wait” strategy has been proposed for patients with clinical complete response (cCR) after nCRT. However, clinical assessments would inevitably misclassify non-pCR as cCR. We previously showed that ctDNA analysis with tumor-naïve fixed panel could improve the prediction of cCR. This study further investigates the value of personalized ctDNA analysis in predicting tumor response and residual disease after nCRT in ESCC. Methods: This is a side study of the prospective, diagnostic preSINO trial (NCT03937362). After completion of nCRT, patients underwent one or two clinical response evaluations (CREs) before planned surgery. CRE‐1 was 4–6 weeks after nCRT. CRE‐2 was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE-1. Individual tumors and matched white blood cells at baseline (B0) were whole-exome sequenced and somatic mutations were identified. Serial plasma samples were analyzed by brPROPHET tracking up to 50 somatic mutations at three timepoints: B0, CRE-1, CRE-2. This assay was developed to detect residual disease with a limit of detection of 0.004% and sample-level specificity of greater than 99% in the analytical validation. Residual disease was also detected and quantified through TNFP in the same samples for a head-to-head comparison. We correlated post-nCRT ctDNA status with pCR and major locoregional residual disease (MLRD) (>10% residual cancer or any residual nodal disease). Results: At this interim analysis, 55 ESCC patients (stage III, 87%) who received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 27 % (15/55). 98% (2918/2966) of variants selected for patient-specific panel design were private to a specific patient, only 3% (92/2966) of variants were included in the fixed panel. After nCRT, ctDNA was detected by brPROPHET prior to nCRT in 100% of samples (n=55), significantly higher than that by TNFP assay (73%, 40/55). ctDNA was detected in 55% (30/55) of patients at CRE-1, 43% (10/23) at CRE-2. Importantly, the brPROPHET achieved higher sensitivity than TNFP in predicting non-pCR and MLRD owing to its ability to detect extremely low ctDNA fractions (to 1.14 x 10-5). Moreover, combining brPROPHET with CREs could further improve the sensitivity. Conclusions: Personalized ctDNA analysis can supplement the clinical assessment to decrease the false negative rate in identifying patients with residual disease after nCRT, and might become useful in the “Watch and Wait” strategy for the management of ESCC. Clinical trial information: NCT03937362 . [Table: see text]

A phase 2 trial of mosunetuzumab with lenalidomide augmentation as first-line therapy for follicular (FL) and marginal zone lymphoma (MZL).

TPS7588 Background: First-line therapy for high-burden FL and MZL includes immunochemotherapy (most commonly rituximab with bendamustine), which is associated with toxicities, is not curative, and leads to a prolonged T-cell depletion. The alternative of rituximab with full-dose lenalidomide did not improve efficacy or toxicity [Morschhauser et al., NEJM 2018]. However, lower-dose, short-course lenalidomide (15mg) may enhance cytotoxic T-cell immunity and efficacy of rituximab [Zucca et al, Blood 2019]. Mosunetuzumab is a CD20xCD3-binding, T-cell-engaging bispecific antibody approved for relapsed/refractory FL after 2 lines of therapy. It results in a complete response (CR) rate of 60% in that setting [Budde et al., Lancet Oncol, 2022], despite prior exposure to immunosuppressive therapies. This trial proposes a novel therapeutic approach to first-line treatment of FL/MZL, exploring 3 hypotheses: 1) that mosunetuzumab will lead to a high rate of CR, and possibly eradication, of FL/MZL when applied before exposure to immunosuppressive modalities; 2) that low-dose lenalidomide can augment the cytotoxic T-cell response when CR is not achieved with mosunetuzumab alone, and 3) that baseline host immune environment measured in treatment-naïve state can predict CR to bispecific antibody therapy. Methods: The Brown University Oncology Research Group BrUOG-401/ML43251 ( NCT04792502 ) is an investigator-initiated, multi-center, single-arm, phase 2 clinical trial for patients (pts) with FL and MZL in need of first-line systemic therapy. Pts with FL must meet the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria of high-burden disease, whereas pts with MZL must require therapy in the investigators’ opinion. As of January 2023, 7 of the planned 52 pts have been enrolled. The trial uses a response-adapted design: pts start with 4 courses of subcutaneous mosunetuzumab monotherapy, using step-up dosing during Cycle 1 (5mg → 45mg → 45mg) to mitigate the risk of cytokine release syndrome (CRS). Pts attaining CR (by Lugano criteria) after Cycle 4 continue for a total of 8 cycles of mosunetuzumab monotherapy. Pts attaining partial response or stable disease receive 4 additional cycles of mosunetuzumab with low-dose lenalidomide augmentation (10mg daily), with further 4 cycles of mosunetuzumab/lenalidomide if CR after C8 is still not attained. The primary endpoints include the ORR and CR rate at final assessment, and rates of toxicities, particularly CRS, tumor flare, and immune-mediated events. PFS and rate of progression of disease at 24 months (POD24) are among secondary endpoints. The study uses Simon’s two-stage design, with the null hypothesis that the CR rate is 53% (based on prior RELEVANCE trial). Correlative studies aim at determining predictive biomarkers of response, including immune signatures and dynamics of circulating tumor DNA during study therapy. Clinical trial information: NCT04792502 .

Durvalumab + tremelimumab in biologically selected advanced/metastatic solid tumors.

2604 Background: Tremelimumab (T) in combination with Durvalumab (D) is approved by the FDA for the treatment of unresectable hepatocellular carcinoma and metastatic non–small cell lung cancer. We prospectively examined its clinical activity in a cohort of biologically-selected advanced/metastatic solid tumors from the MOST Plus clinical trial (NCT NCT02029001). Methods: Adult patients (pts) previously treated by at least one prior line but immunotherapy-naive were eligible if their tumor harbored TMB-H (>10mut/Mb) and/or MSI/dMMR (by PCR and IHC tests), and/or PD1/PD-L1/CTLA4 amplification and/or POLD1 or POLE mutation. T was administered for up to 4 cycles (75mg, IV, Q4W) and D (1500mg, IV, Q4W) until disease progression, unacceptable toxicity or patient/investigator decision. Tumor response was assessed as per RECIST 1.1 and adverse events reported according to NCI-CTCAE v4.03. Results: 70 patients were enrolled (24 male, median age: 65 years [33-88], MSI n=56, TMB-H n=10, PDL1 and PDL2 ampl. n=1, POLE mut. n=1, MSH6 mut. n=1, MSH2 mut. n=1). The median number of prior lines of systemic therapy was 1 (range: 0-4). Main tumor types were colorectal (44%), endometrial (19%), and stomach (7%) carcinomas. As of October 2022, overall response (ORR) rate was 52.8% (21.4% CR, 31.4% PR). With a median follow-up of 37 months, median PFS and OS were 8.4 months [95% CI: 4.4- 22.1] and 37.2 months [95% CI: 10.4-NE], respectively. Median duration response of response was not reached. Overall, 24.3% of patients experienced at least one serious treatment-related (TR) adverse event. Two TR-deaths were reported (haemophagocytic lymphohistiocytosis and nephritis). ORR, median PFS and OS are reported. Conclusions: T+D is a highly efficient combination in biologically selected tumors leading to a high complete response rate. Enrolment is still ongoing, to further evaluate the utility of a maintenance treatment, i.e the optimal treatment duration. Clinical trial information: NCT02029001 . [Table: see text]

Comparison the acute toxicity of two different induction chemotherapy schedules with cisplatin and fluorouracil in nasopharyngeal carcinoma patients

PurposeTo compare the acute toxicity of two different induction chemotherapy (IndCT) regimen followed by the same IMRT in patients with advanced nasopharyngeal carcinoma (NPC). Materials and methodsFrom July 2015 to December 2016, 110 NPC patients with stage III-IV diseases were prospectively randomized to receive either a conventional triweekly cisplatin + 5-fluorouracil (PF) for 3 cycles or weekly P-F for 10 doses, followed by the same IMRT to both arms. The primary endpoints of this study were grade 3/4 and any grade acute toxicities during IndCT period. The secondary endpoints included tumor response and various survivals. ResultsBaseline patient characteristics were comparable in both groups. Patients who received weekly P-F experienced significant reduction of grade 3/4 acute toxicities, including neutropenia (12.7% vs. 40.0%, P = 0.0012), anorexia (0% vs. 14.6%, P = 0.0059), mucositis (0% vs. 14.6%, P = 0.0059), and hyponatremia (0% vs. 16.4%, P = 0.0027), compared with the triweekly PF group, resulting in fewer IndCT interruptions (1.8% vs. 16.4%, P = 0.0203), emergency room visits (0% vs. 12.7%, P = 0.0128), and additional hospitalizations (0% vs. 9.1%, P = 0.0568). The acute toxicities during IMRT period were similar. Weekly P-F arm had higher complete response rates (83.6% vs. 61.8%, P = 0.0152) and lower relapse rates (16.4% vs. 33.3%, P = 0.0402) after a median follow-up of 67 months. Kaplan-Meier survival analyses revealed a better trend of locoregional failure-free (P = 0.0892), distant metastasis failure-free (P = 0.0775), and progression-free (P = 0.0709) survivals, favoring the weekly P-F arm. ConclusionIndCT of weekly schedule does reduce acute toxicities without compromised tumor response and survivals.

Predictive Factors of Complete Response to Transarterial Chemoembolization in Intermediate Stage Hepatocellular Carcinoma beyond Up-To-7 Criteria.

To clarify the prognosis and identify predictors for obtaining a complete response (CR) by transarterial chemoembolization (TACE) in intermediate stage HCC beyond up-to-7 criteria. Of the 120 patients with intermediate stage HCC who were treated by TACE as the initial treatment from February 2007 to January 2016, 72 finally matched the following inclusion criteria: beyond up-to-7 criteria; Child-Pugh score under 7; and no combined therapy within 4 weeks after the initial TACE. The CR rate and overall survival (OS) were evaluated. Logistic regression analysis was performed to identify predictors of CR. The deterioration of liver function after TACE was also evaluated. The CR rate was 56.9%, and the overall median survival time (MST) was 37.7 months. The MST was 38.7 months in the CR group and 28.0 months in the non-CR group (p = 0.018). HCC within up-to-11 criteria was the only predictor of CR. The CR rate and MST were 70.7% and 37.7 months, respectively, in patients with HCC within up-to-11 criteria and 38.7% and 32.7 months, respectively, in the patients beyond up-to-11 criteria. Deterioration of the Child-Pugh score after the initial TACE and the 2nd TACE occurred in 24.2% and 12.0%, respectively, and deterioration of the modified albumin-bilirubin (mALBI) grade occurred in 17.6% and 7.4%, respectively. TACE can achieve high CR rates with prolonged overall survival for intermediate stage HCC beyond up-to-7 criteria. The predictor of CR was within up-to-11 criteria. Deterioration of liver function was not severe, but requires caution. Multidisciplinary approach as additional treatment after TACE is important.

Outcome and patterns of relapse in primary gastric diffuse large B cell lymphoma treated with RCHOP

ABSTRACTObjectivesPatterns and predictors of relapse in primary gastric diffuse large B cell lymphoma (DLBCL) were variably reported. Our study aims to evaluate the patterns and predictors of relapse in early-stage gastric DLBCL treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone (RCHOP).MethodsFrom 2005 to 2019, the medical records of 72 patients with stage I or stage II gastric DLBCL treated with six cycles of RCHOP without radiotherapy were reviewed. Different variables were correlated with progression free survival (PFS), overall survival (OS), and local relapse free survival (LRFS).Results64 (88.1%) patients achieved a complete response (CR), while 8 (11.9%) had refractory disease. After CR, 9 (14%) patients relapsed; 7 (78%) relapses were loco-regional. Abnormal LDH (p = 0.028), H. pylori negative (p = 0.032) and, stage adjusted international prognostic index (sa-IPI) > 1 (p = 0.013) correlated with loco-regional failure. The 5-year PFS, OS, and LRFS were 74.8%, 75.3%, and 87.5%, respectively, after a median follow-up of 58 (range: 6–185) months. The median time to progression or relapse was 9 months (range: 5–54 months). In multivariate analysis, a sa-IPI >1 (HR: 3.56, CI: 1.35–8.8, p = 0.01) was associated with PFS while low albumin (HR: 8.85, CI: 1.09–71.4, p = 0.041) was associated with worse OS. None of the variables were associated with LRFS.ConclusionTreatment of primary gastric DLBCL with RCHOP results in a high CR rate. The majority of treatment failures were loco-regional. Sa-IPI and H. pylori status may be used to identify patients who may benefit from combined modality treatment.

Single-Fraction Radiation Therapy for Localized Cutaneous T-Cell Lymphoma

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL). Single-fraction radiation therapy has been used as a skin-targeted therapy to treat localized CTCL lesions. The objective of this study was to investigate the treatment outcomes associated with single-fraction radiation therapy for CTCL. We retrospectively studied the outcomes among patients with CTCL treated with single-fraction radiation therapy at our institution between October 2013 and August 2022. Clinical response (complete response [CR], partial response [PR], or no response [NR]) and retreatment response were evaluated. A total of 242 lesions from 46 patients were analyzed, for an average of 5.3 lesions treated per patient. The majority of lesions presented with a plaque morphology (n=145, 60.0%). All lesions were treated to a dose of 8 Gy in 1 fraction. Median follow-up was 24.6 months (range, 1-88 months). Of the 242 lesions, 36 (14.8%) had an initial PR or NR; all were retreated with the same regimen to the same site at a median interval of 8 weeks. Eighteen of the retreated lesions (50.0%) went on to have a CR. Thus, the overall CR rate for CTCL lesions was 92.6%. No recurrences were noted in the treated areas after achieving CR. Single-fraction radiation therapy to a dose of 8 Gy in 1 fraction to localized areas provided a high rate of complete and durable responses in the affected sites.

Nonoperative Management of dMMR/MSI-H Colorectal Cancer following Neoadjuvant Immunotherapy: A Narrative Review.

Immunotherapy with PD-1 blockade has achieved a great success in colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR), and has become the first-line therapy in metastatic setting. Studies of neoadjuvant immunotherapy also report exciting results, showing high rates of clinical complete response (cCR) and pathological complete response. The high efficacy and long duration of response of immunotherapy has prompt attempts to adopt watch-and-wait strategy for patients achieving cCR following the treatment. Thankfully, the watch-and-wait approach has been proposed for nearly 20 years for patients undergoing chemoradiotherapy and has gained ground among patients as well as clinicians. In this narrative review, we combed through the available information on immunotherapy for CRC and on the watch-and-wait strategy in chemoradiotherapy, and looked forward to a future where neoadjuvant immunotherapy as a curative therapy would play a big part in the treatment of MSI-H/dMMR CRC.

Abstract 4536: Investigating the correlation between molecular diagnostics, targeted therapies and treatment outcomes in Rosai Dorfman disease: a single-institution experience

Abstract Introduction: Rosai Dorfman Disease (RDD) is a non-Langerhans cell histiocytic disease whose pathologic features include sinus histiocytosis with variable emperipolesis. Traditional management consists of local therapies (resection, radiation) for limited lesions and myelosuppressive therapies for systemic disease. Recent studies, however, have identified MAP Kinase pathway mutations in RDD, prompting further research into the utility of targeted agents. Methods: A retrospective analysis was conducted at a single institution over a 20-year period (2002-2022) of 40 patients with RDD. Inclusion criteria included age ≥18 and histopathologic evidence of RDD without obscuring secondary malignancies. Clinical data points included biological gender, age at diagnosis, molecular diagnostics, imaging and therapies administered. Binary data was utilized for statistical analysis and comparison of outcomes by treatment type, time to diagnosis and use of targeted agents. Results: In this analysis, 72% of patients were female and 28% male with an average age at diagnosis of 45.8 years, over 50% of whom were diagnosed between 1 and 12 months of presentation. Primary disease was most commonly extranodal (>90%), found in cutaneous, osseous and CNS structures (50%, 36% and 16.6%, respectively). Regarding management, surgery was most common in >36% of patients, followed by steroid and myelosuppressive therapies (25% each), immunotherapy (13.88%) and targeted molecular therapies (11.1%). Disease responses were considered stable if grossly unchanged during serial exam or imaging surveillance, partial if diminished but still present and complete if disease was grossly and radiographically resolved; a partial response or better was observed in >75% of patients. With respect to treatment rendered, stable disease was equally likely between recipients of molecular and conventional (non-molecular) therapy at 25%. Partial responses were higher in molecular therapy recipients (75% as compared to 42%), although complete responses have not yet been observed in this cohort. Patients diagnosed at <1 month from symptom onset had higher rates of disease stability and complete responses compared to those diagnosed at >24 months. Conclusions: To our knowledge, this study is the largest of its kind in adult Rosai Dorfman Disease. Early recognition and utilization of targeted molecular therapies, based on our preliminary data, are associated with higher rates of achieving disease stability and at least a partial response. The current absence of complete responses in patients receiving targeted molecular therapy is likely attributable to the still-emerging use of these agents and interim response assessments not yet being completed. Higher complete response rates in targeted agents relative to conventional therapies are anticipated in ongoing analyses. Citation Format: Samuel B. Reynolds, Sabrina R. Wilcox, Moshe Talpaz, Asra Z. Ahmed. Investigating the correlation between molecular diagnostics, targeted therapies and treatment outcomes in Rosai Dorfman disease: a single-institution experience. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4536.

Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement

ABSTRACT Introduction Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangements (MLNFGFR1) are rare entities with aggressive features and poor prognosis. Presentation is heterogeneous, ranging from myeloproliferative neoplasms (with or without eosinophilia) to T-cell lymphoma and acute leukemia. Historical treatments have been guided by the presenting phenotype with induction chemotherapy frequently used. Pemigatinib is a FGFR1–3 tyrosine kinase inhibitor that has demonstrated high complete hematologic and cytogenetic response rates in MLNFGFR1. Areas covered We discuss the pathogenesis, presentation, and historical treatments for MLNFGFR1, in addition to clinical data using pemigatinib and other targeted therapies. Discussion of the mechanism of action and adverse events is also included. Expert opinion Pemigatinib represents a significant advance in the management of MLNFGFR1. High rates of complete hematologic and cytogenetic response have been observed. While direct comparative data are unavailable, outcomes appear favorable compared to conventional approaches. Long-term efficacy and tolerability are not yet known, and allogeneic hematopoietic stem cell transplant (alloHSCT) continues to be the treatment with the highest chance of long-term disease free survival in responding patients. Combinations of pemigatinib and chemotherapy, particularly for more aggressive phenotypes, warrant future investigation as does the use of pemigatinib maintenance following alloHSCT.

Brentuximab vedotin plus doxorubicin and dacarbazine innonbulky limited-stage classical Hodgkin lymphoma.

ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).