Longer Duration Of Response Research Articles

Phase I/II trial of plinabulin in combination with nivolumab and ipilimumab in patients with recurrent small cell lung cancer (SCLC): Big ten cancer research consortium (BTCRC-LUN17-127) study

BackgroundPlinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC. MethodsIn Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS). ResultsBetween 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively. ConclusionsPlinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.

Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. InventisBio.

A Review of Current Data on Duration of Effect in Glabellar Lines After Treatment With AbobotulinumtoxinA 50 U.

AbobotulinumtoxinA has become well established as a treatment option for moderate to severe glabellar lines since its first aesthetic approval in 2009. Pivotal trials leading to regulatory approval showed that abobotulinumtoxinA treatment was associated with high responder rates when defined as achievement of none or mild glabellar lines (0 or 1 on the glabellar line severity scale) and a duration of action of up to 5 months. More recently, the goals for treatment of glabellar lines have shifted toward not only achieving a decrease in glabellar line severity but also ensuring that patients are satisfied with their experience. Patients seek an improvement in the appearance of their glabellar lines while maintaining a "natural look," fast onset of effect, and long duration of response. Trial designs have evolved to meet these new targets, including expanding the definition of responders to those having at least 1-grade improvement in the glabellar line severity scale score from baseline coupled with the use of subject satisfaction and psychological well-being questionnaires. The findings demonstrate that abobotulinumtoxinA remains a well-tolerated and consistently effective treatment option associated with a rapid onset of effect, duration of efficacy lasting up to 6 months, and high, long-lasting levels of patient satisfaction.

A randomized, multi-center, phase 2 study of ivaltinostat (Ival) plus capecitabine (Cape) versus capecitabine alone in the maintenance setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

TPS4206 Background: Front-line chemotherapy for patients (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/cape in mouse models. RP2D of the Phase 1b combination study of ival and cape in advanced pancreatic cancer was ival 250mg/m2 IV on days 1 and 8 with cape 1000mg/m2 po days 1-14 of a 21-day cycle. Both ival and cape treatment-related AEs &gt;15% were fatigue, nausea, diarrhea, and decreased appetite. Palmar-plantar erythrodysaesthesia syndrome was also commonly observed; all events were attributed to cape. PK and PD demonstrated dose proportionality. Overall and progression-free survival (PFS) were immature, but 70% of pts who enrolled with measurable disease had stable disease as best response. Several pts remained on study with the longest duration of response about 10 months, as of the data cut off for ASCO GI 2024. Based on this data, a randomized phase 2 study is being conducted comparing the combination of ival and cape versus cape alone in the maintenance setting for pts with mPDAC after first line FOLFIRINOX, mFOLFIRINOX or NALFIRINOX therapy. Methods: Key eligibility criteria for the randomized Phase 2 study include: mPDAC; no evidence of disease progression following at least 16 weeks of front-line FOLFIRINOX or NALIRIFOX at full or modified doses; ECOG PS 0-1; and no known germline BRCA1/2 mutation. A total of 52 pts will be randomized 1:1 to receive cape with or without ival until disease progression, with tumor assessments occurring at 6-week intervals. The primary endpoint is investigator-adjudicated PFS, and the primary analysis will compare PFS distributions in the ival/cape and cape alone arms using a one-sided log rank test with an alpha=0.10. The assumed 6-mo PFS rates are 35% (cape), based on historic data, and 60% (ival/cape), corresponding to an HR of 0.487. Enrollment in the phase 2 study began in January 2024 across multiple sites in the US. Accrual is anticipated to complete 4Q2024. Clinical trial information: NCT05249101 .

A phase 1 single-arm, open-label study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in patients (pts) with acute myeloid leukemia (AML) in complete response (CR) with measurable residual disease (MRD).

TPS6587 Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these 3 onco-proteins by emavusertib may address the unmet need for novel therapies in AML. Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses in pts with relapsed or refractory AML (Metzeler 2022). Azacitidine + venetoclax (aza+ven) is an approved therapy for newly diagnosed pts with AML, unfit for intensive chemotherapy. Pre-clinical studies have demonstrated that emavusertib in combination with aza+ven has synergistic and antileukemic effects. In the VIALE-A study, composite CR (CRc) (CR, CRh, or CRi) in the absence of MRD of &lt;1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS) compared with AML pts who achieved CRc but were MRD+ (Pratz, 2022). Therefore, adding emavusertib to aza+ven in CR or CRh, MRD+ pts may convert MRD status without significant toxicity and become a potential new regimen in front-line therapy. Methods: This is a single-arm, open-label Phase 1 study of emavusertib in combination with first line aza+ven in AML pts ≥60 years of age who achieved CR or CRh with MRD+ status based on local testing. The primary objective is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include determining the MRD conversion rate, pharmacokinetics, DOR, and OS. The study will enroll approximately 24 pts at 5 to 10 sites globally. Pts will have received aza+ven as first line therapy and achieved CR or CRh after 1-6 cycles of aza+ven. If MRD status remains positive, emavusertib will be added to the existing aza+ven regimen. Key exclusion criteria include residual toxicities and significant comorbidities. In the first cohort, the starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. The duration of emavusertib treatment will extend to 14 and 21 days, in subsequent cohorts. The pts will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- after 6 cycles of treatment. Enrollment to cohort 1 began in December 2023. (EU CT Number 2023-505828-58). Clinical trial information: 2023-505828-58.

ARTEMIS-002: Phase 2 study of HS-20093 in patients with relapsed or refractory osteosarcoma.

11507 Background: Patients (pts) with relapsed and refractory (R/R) osteosarcoma have a poor prognosis with limited therapeutic options. HS-20093 is a novel antibody-drug conjugate (ADC) targeting B7-H3, which showed preliminary anti-tumor activity in phase 1 ARTEMIS-001 study (NCT05276609). Here we report results in R/R osteosarcoma pts treated with HS-20093 from ARTEMIS-002 study (NCT05830123). Methods: ARTEMIS-002 trial is an open label, two-arm phase 2 trial in pts with R/R osteosarcoma or other sarcomas progressed upon standard systemic treatment. Based on the results of the phase 1 trial that the maximum tolerated dose was 12 mg/kg once every 3 weeks (Q3W) intravenous infusion, the osteosarcoma pts in the phase 2 trial were randomized to receiving HS-20093 either at 8 mg/kg or 12 mg/kg Q3W at a ratio of 1:1. The primary endpoint was objective response rate (ORR) according to RECIST1.1. B7-H3 expression was retrospectively evaluated by IHC in osteosarcoma FFPE tissue. Results: A total of 34 pts with R/R osteosarcoma were enrolled from June to December in 2023, receiving HS-20093 at the dose of either 8.0 mg/kg (N = 15) or 12.0 mg/kg (N = 19). Median age was 21.5 years (range: 18~65). At baseline, most pts were evaluated with clinical stage IV disease (32/34, 94.1%) and pulmonary metastasis (28/34, 82.4%). Twenty-two pts (64.7%) had received ≥3 prior lines therapy. Twenty-six pts (76.5%) had received 4 types of standard chemotherapies consisting of platinum, anthracyclines, ifosfamide and methotrexate. Treatment emergent adverse event (TEAEs) occurred in 33 pts (97.1%). The common grade 3/4 TEAEs (≥5%) were: neutropenia, leukopenia, thrombocytopenia, lymphopenia and anemia. The incidences of discontinuations, dose withhold and dose reductions were 2.9%, 11.8% and 23.5%, respectively. There was no TEAE leading to death. As of cut-off date (25 December, 2023), the median follow-up time was 4.1 months (95% CI: 1.4~5.5) among 21 response-evaluable pts (11 treated with 8 mg/kg and 10 with 12.0 mg/kg). The ORR of 12.0 mg/kg HS-20093 was 20.0%. Two confirmed partial responses were observed in pts with 12.0 mg/kg and remained on response until last follow-up, of which the longest duration of response was 4.0 months. The disease control rate was 81.8% (9/11) and 100% (10/10) in pts with 8 mg/kg and 12.0 mg/kg. The median progression-free survival of all 21 pts was not mature. B7-H3 is highly expressed in osteosarcoma with median H-score 185 (0~260). No correlation was observed between tumor response and B7-H3 expression level. The PK exposure of HS-20093 ADC, total Ab and payload increased with dose, approximately proportional to dose, with a half-life of 4 to 6 days, and no or minor accumulation after multiple doses of Q3W. Conclusions: The data has demonstrated that HS-20093 exhibited promising antitumor activity with acceptable toxicity in pts of heavily-pretreated R/R osteosarcoma. The enrollment of ARTEMIS-002 is continuing. Clinical trial information: NCT05830123 .

A single-arm, multicenter, phase II study of utidelone in advanced solid tumors: Efficacy data from screening and the expansion cohort assessing utidelone plus sintilimab and oxaliplatin for advanced gastric cancer.

e16055 Background: Treatment regimens for many advanced solid tumors are limited and alternative options are needed.Utidelone is approved for the treatment of advanced breast cancer in China. NCT04911907 is a single-arm, multicenter, phase II study to assess the efficacy and safety of utidelone in advanced cancer. Stage I of the trial, completed in October 2023, included patients (pts) with pretreated advanced solid tumors. Based on the stage I data, a stage II expansion cohort (USO-G) investigated utidelone plus sintilimab and oxaliplatin as first-line therapy for advanced gastric cancer (GC). Here, we report efficacy and safety data from stage I and stage II for interim analysis. Methods: Eligible pts aged 18–70 years with pretreated advanced solid tumors were enrolled in stage I and received utidelone monotherapy (35 mg/m2/day iv on days 1–5 every 21 days). In stage II, eligible pts with metastatic and/or unresectable HER2 negative GC received utidelone (30mg/m2/day iv on days 1–5 every 21 days) plus sintilimab (200 mg iv Q3W) and oxaliplatin (130 mg/m2/day Q3W for up to 6 cycles), until disease progression or unacceptable toxicity. Results: From March 18th 2021 to October 13th 2022, 79 pts were enrolled into 7 tumor cohorts and 54 pts were evaluable for efficacy. The best overall responses were 1 CR, 3 PRs and 3 SDs in 10 esophageal cancer pts, 3 PRs and 5 SDs in 15 GC pts, 1 PR and 3 SDs in 10 ovarian cancer pts, SD for all 4 cholangiocarcinoma pts, 3 SDs in 4 cervical cancer pts, 2 SDs in 3 pancreatic cancer pts and a PR in 1 neuroectodermal tumor patient. Grade 3/4 TRAEs occurred in 27.8% of pts in stage I, and included anemia (13.9%), peripheral neuropathy (11.4%) and neutropenia (7.6%). No treatment-related deaths occurred. Gastric cancer was chosen as the expansion cohort indication. As of February 1st 2024, 14 eligible pts with GC with a median age of 57 years (range, 41–69) were enrolled. The median follow-up was 5.5 months (range, 1.0–9.7) and the longest duration of response was 8.0 months. A total of 8 PRs and 3 SDs were achieved in the 11 pts evaluable for efficacy, and 6 pts including the 3 with SD were still receiving treatment. Grade 3/4 TRAEs occurred in 28.6% of pts including diarrhea (14.3%), fatigue (14.3%), neutropenia (14.3%), and vomiting (7.1%). Other AEs were all Grade 1 or 2, with no treatment-related deaths. Conclusions: Utidelone monotherapy showed antitumor activity and manageable toxicity in pts with advanced solid tumors. Utidelone plus sintilimab and oxaliplatin demonstrated promising efficacy and an acceptable safety profile as first-line treatment for pts with GC. Stage II of the USO-G study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT04911907 .

Abstract CT150: Trial in progress: A phase 1b single-arm, open-label, study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in acute myeloid leukemia patients in complete response with measurable residual disease

Abstract Background: Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022). Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of &amp;lt;1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy. Study Design: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities. Citation Format: Reinhard von Roemeling, Adolfo De La Fuente, Claudio Cerchione, Sebastian Scholl, Jan Moritz Middeke, Gaurav S. Choudhary, Maria Lamar, Steven Angelides, Uwe Platzbecker. Trial in progress: A phase 1b single-arm, open-label, study of emavusertib (CA-4948) in combination with azacitidine and venetoclax in acute myeloid leukemia patients in complete response with measurable residual disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT150.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson’s disease

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson’s disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting “on demand” therapy for patients with Parkinson’s disease experiencing motor fluctuations.

Learning to Have a Long-Duration Response.

Learning to Have a Long-Duration Response.

Tislelizumab plus chemotherapy (chemo) versus placebo plus chemo as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 European/North American patient subgroup.

330 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, demonstrated significant overall survival (OS) benefit vs placebo (PBO) plus chemo (15.0 vs 12.9 months [mo], hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.70, 0.92, P=0.0011) as first-line therapy in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) in the randomized, double-blind, global, phase 3 RATIONALE-305 study (NCT03777657). Here we present results from the European/North American (Eu/NA) pts subgroup analysis. Methods: This double-blind, global, phase 3 study evaluated adult pts with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable, or metastatic GC/GEJC, regardless of programmed death-ligand 1 (PD-L1) expression status. Eligible pts were randomized (1:1) to receive TIS 200 mg or PBO intravenously once every 3 weeks plus investigator chosen chemo (5-fluorouracil + cisplatin or capecitabine + oxaliplatin). The primary endpoint was OS in the PD-L1+ (patients with tumor area positivity score ≥5%) and intent-to-treat (ITT) analysis sets. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Of 997 pts enrolled, 249 (25.0%) were from Eu/NA (TIS plus chemo arm, n=125; PBO plus chemo arm, n=124). In the Eu/NA pts subgroup, after a minimum follow-up of 26.6 mo at final analysis, TIS plus chemo resulted in OS improvements vs PBO plus chemo in the PD-L1+ (HR=0.75, [95% CI: 0.52, 1.07]; 24 mo rate 27.6% vs 12.5%) and ITT analysis sets (HR=0.71, [95% CI: 0.54, 0.94]; 24 mo rate 27.6% vs 13.6%). TIS plus chemo resulted in favorable PFS vs PBO plus chemo (HR=0.84, 95% CI: 0.63, 1.11), numerically higher ORR (36.0% vs 31.5%), and longer DoR (median 7.5 mo [95% CI: 4.4, 12.0] vs 5.0 mo [95% CI: 3.9, 6.7]). Sixty (48.8%) pts in the TIS plus chemo arm and 61 (49.2%) pts in the PBO plus chemo arm experienced grade ≥3 treatment-related treatment-emergent adverse events (TRAEs). Sixteen (13.0%) and seven (5.6%) pts discontinued treatment due to TRAEs in the TIS plus chemo and PBO plus chemo arms, respectively. Deaths due to TRAEs occurred in two (1.6%) pts in the TIS plus chemo arm and one (0.8%) pt in the PBO plus chemo arm. Conclusions: TIS plus chemo showed OS benefit compared with PBO plus chemo and a manageable safety profile in pts in the Eu/NA subgroup with previously untreated, HER2-negative, locally advanced unresectable, or metastatic GC/GEJC. These findings are consistent with the published results in the overall study population. Clinical trial information: NCT03777657 .

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

Motivational Vigor in Parkinson's Disease Requires the Short and Long Duration Response to Levodopa.

Impaired movement vigor (bradykinesia) is a cardinal feature of Parkinson's disease (PD) and hypothesized to result from abnormal motivational processes-impaired motivation-vigor coupling. Dopamine replacement therapy (DRT) improves bradykinesia, but the response to DRT is multifaceted, comprising a short-duration response (SDR) and a long-duration response (LDR) only manifesting with chronic treatment. Prior experiments assessing motivation-vigor coupling in PD used chronically treated subjects, obscuring the roles of the SDR and LDR. To disambiguate the SDR and LDR, 11 de novo PD subjects (6 male [M]:5 female [F]; mean age, 67) were studied before treatment, after an acute levodopa (l-dopa) dose, and in both the practical "off" (LDR) and "on" (LDR + SDR) states after chronic stable treatment. At each visit, subjects were characterized with a standard battery including the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and an incentivized joystick task to assess motor performance in response to varying rewards. l-Dopa induced a robust SDR and LDR, with further improvement in the combined SDR + LDR state. At baseline, after acute treatment (SDR), and after LDR induction, subjects did not exhibit the normal increase in movement speed with increasing reward. Only in the combined SDR + LDR state was there restoration of motivation-vigor coupling. Although consistent with prior results in chronically treated PD subjects, the significant improvement in motor performance observed with the SDR and LDR suggests that bradykinesia is not solely secondary to deficient modulation of motivational processes. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Molecular Monitoring with Tumor DNA and Nivolumab Maintenance: A Pilot Study in Diffuse Large B-Cell Lymphoma

Introduction Molecular minimal residual disease (MRD) has been shown to correlate with disease relapse in patients (pts) with Diffuse Large B cell Lymphoma (DLBCL)[1-4]. However, the clinical impact of detectable MRD (dMRD) prior to clinical relapse is unknown. Checkpoint inhibitor (CPI) therapy has some activity in certain pts with DLBCL, particularly after CAR-T therapy attributed to effects on T cell activity [5-8]. We hypothesized that early intervention with CPI may lower relapse rate in pts with molecular recurrence only. Patients were monitored for detectable MRD (dMRD) by circulating tumor DNA (ctDNA) using the clonoSEQ assay monthly. We conducted a pilot study in high risk pts in remission after most recent line of therapy (LOT) in which maintenance nivolumab (MN) was offered at time of dMRD to assess effect on MRD clearance and relapse rate. Methods Pts &amp;gt;18 years with high-risk DLBCL (ABC-subtype, high grade B cell lymphoma (HGBCL), MYC translocation, relapsed/refractory disease, or Ki67 &amp;gt;90%) who had achieved CR on most recent LOT. Pts had monthly MRD and every 4 month CT or PET/CT and exam for 2 years. If conversion to dMRD without clinical relapse, pts received MN (240 mg IV q2 weeks) until clinical relapse or toxicity for up to 2 years (26 cycles). Pts with overt relapse at time of dMRD were ineligible for MN and taken off trial. The primary endpoint was rate of conversion from +MRD to undetectable MRD (uMRD) in pts receiving . Results 20 pts were screened and 15 pts were enrolled between June 2018 and March 2022. 5 pts had non-GCB subtype, 2 had GCB subtype, and two had unknown cell of origin. 4 had transformed DLBCL (2 from FL, 1 from MZL, and 1 Richter's), 2 pts had HGBCL (one of which was also transformed). Of the 8 pts who enrolled after 1 prior LOT, none had molecular or clinical relapse (Figure). In 7 pts who enrolled after 2+ prior LOT, 3 had dMRD. 2/3 had clinical relapse at same time as dMRD and were taken off study– one at initial enrollment with dMRD at first ctDNA screening and one converting from uMRD to dMRD after 135 days post enrollment. In the single patient who was eligible for MN, dMRD preceded radiographic relapse by 105 days, 410 days after enrollment. The pt went on to receive 2 cycles of MN before clinical progression and was taken off study. This pt failed to achieve conversion of dMRD to uMRD. Conclusions Due to small sample size and lower than expected relapse rates, we were unable to demonstrate conversion of dMRD to uMRD using MN. Of the 3 pts with dMRD, 2 were not eligible for MN due to clinical relapse at same time as dMRD and both died due to lymphoma progression. In the single pt who received MN, this intervention did not achieve uMRD or prevent relapse. However, this pt went on to achieve CR to subsequent CAR-T and remains in prolonged remission despite multiple relapsed/refractory disease. It is unknown if this patient's positive outcome was impacted by the effect of nivolumab on T cells and/or related to slower disease kinetics as this pt had a 3 month period between dMRD and radiographic detection and long duration of response to prior lines. A larger study is needed to adequately assess impact of early intervention MN using MRD kinetics, particularly in patients receiving CAR-T. All pts with dMRD had radiographic relapse within 4 months of molecular relapse. No pts with uMRD by ctDNA had clinical relapse on study during 2 year follow up, confirming uMRD correlates with disease free survival. If a strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans.

Molecular Measurable Residual Disease (MRD) Clearance (≤1%) Is Associated with Improved Clinical Outcomes in Patients with Higher-Risk Myelodysplastic Neoplasms (HR-MDS): An Exploratory Analysis of Stimulus-MDS1 in Patients Receiving Sabatolimab or Placebo + Hypomethylating Agent (HMA)

Background: Sabatolimab (MBG453) is a novel immunotherapy targeting TIM-3, an immuno-myeloid regulator expressed on both immune and leukemic stem cells. In the randomized, double-blind, placebo-controlled, Phase (Ph) II STIMULUS-MDS1 study (NCT03946670) in patients (pts) with HR-MDS, although improvements in complete remission (CR) and progression-free survival (PFS) were not statistically significant, sabatolimab + HMA was associated with longer duration of response (DoR), and the data suggest a delayed-onset benefit in the sabatolimab arm, as well as a potential treatment effect in pts with lower disease burden (Zeidan AM, et al. ASH 2022). The clinical significance of MRD in HR-MDS is not well established. We report an exploratory analysis of mutational clearance and MRD by next-generation sequencing (NGS) to evaluate the association with clinical outcomes. Methods: Treatment-naive pts aged ≥18 years with intermediate (+ ≥5% bone marrow [BM] blasts), high or very high risk MDS by Revised International Prognostic Scoring System were randomized to sabatolimab or placebo added to azacitidine/decitabine (Zeidan AM, et al. ASH 2022). Peripheral blood (PBMC) and/or BM mononuclear cell (BMMC) samples were collected and NGS performed on genomic DNA extracted from baseline (BL) and on-treatment samples using a 38-gene NGS-error-corrected panel with sensitivity of 2% and 0.2% variant allelic frequency (VAF), respectively. Concordance and correlation between PBMC and BMMC were assessed. The prognostic value of clonal clearance at different VAF cut-offs (0.2%, 0.5% or 1%) was assessed. MRD-x status was defined as any mutation call above VAF cut-off x, excluding mutations in DNMT3A, TET2 and ASXL1 ( DTA). Association between MRD status and clinical outcomes was analyzed regardless of treatment to increase sample and used best overall response, 6-month landmark analysis, and a time-dependent Cox model to rule out immortal bias. Results: NGS was run on 332 BMMC samples from 112 pts and 439 PBMC samples from 123 pts (127 pts randomized). 112 pts had ≥1 qualifying BL mutation (NGS cohort) and 106 pts (sabatolimab + HMA, N=56; placebo + HMA, N=50) had ≥1 at follow-up (MRD cohort). BL characteristics were balanced between NGS/MRD cohorts and between treatments in the MRD cohort. Overall agreement in mutation calling at variant level between BMMC and PBMC was &amp;gt;97% (8312/8566 total mutation calls), with &amp;gt;88% positive (817/926) and &amp;gt;98% negative agreement (7495/7640). Across reported mutated variants (N=817), there was good correlation (pearson cor=0.88) in VAF between BMMC and PBMC. When considering all paired samples, concordance of best MRD status using PBMC or BMMC results at the pt level (N=95) was: MRD-0.2, 97%; MRD-0.5, 89%; MRD-1, 90%. Given good PBMC and BMMC agreement, results were combined (higher VAF used if both) for outcomes analysis. In the MRD cohort, 11% (N=12), 18% (N=19) and 27% (N=29) of pts achieved MRD-0.2, MRD-0.5 and MRD-1 negativity, respectively. Most pts with MRD-0.2, -0.5 and -1 clearance had documented response of CR/marrow CR [mCR] (&amp;gt;80%) or CR/partial remission [PR]/hematologic improvement [HI] (&amp;gt;75%). Best overall response of MRD-1 negativity achieved anytime on treatment was associated with improved PFS and overall survival (OS) in the overall population and for responding pts (CR/mCR or CR/PR/HI). Similar results were obtained in a landmark analysis at 6 months ( Fig 1). This was supported by a time-dependent Cox-model indicating that MRD-x negativity was associated with a lower hazard ratio for PFS and OS vs MRD-x positivity ( Fig 2). A consistently higher proportion of pts in the sabatolimab (N=56) vs placebo (N=50) arms had on-treatment mutation clearance at different cut-offs: MRD-0.2, 16.1% vs 6.0%; MRD-0.5, 25.0% vs 10.0%; MRD-1, 35.7% vs 18.0%, respectively. Conclusions: We present the first results from a prospective, controlled, randomized study demonstrating the potential prognostic value of MRD for PFS and OS in HR-MDS. Our results demonstrate high NGS concordance between PBMC and BMMC on-treatment samples, indicating that PBMC could represent an alternative for clonal monitoring. Interestingly, more pts treated with sabatolimab + HMA reached MRD negativity while in remission, potentially explaining the longer DoR in pts receiving sabatolimab + HMA vs placebo + HMA. These findings will be further explored in the ongoing Ph III STIMULUS-MDS2 study (NCT04266301).

First Report of Phase 1 Studies of DZD8586, a BBB Penetrant LYN/BTK Dual Inhibitor, in Patients with B-Cell Non-Hodgkin Lymphoma (B-NHL)

Introduction Resistance to covalent (ibrutinib, acalabrutinib and zanubrutinib) and non-covalent BTK inhibitors (pirtobrutinib) is an emerging clinical challenge. DZD8586 was designed as a full blood-brain barrier (BBB) penetrable LYN/BTK dual inhibitor. Preclinical study suggested DZD8586 has a good selectivity against other TEC family kinases (TEC, ITK, TXK, BMX). DZD8586 inhibits BTK-dependent and BTK-independent BCR signaling pathways by targeting LYN and BTK, which could potentially overcome resistance to both covalent and non-covalent BTK inhibitors for the treatment of CLL and MCL, as well as DLBCL. Two phase 1 clinical studies are ongoing in patients with relapsed or refractory (r/r) B-NHL to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor efficacy of DZD8586. Methods TAI-SHAN1 (NCT05844956; CTR20220558) and TAI-SHAN5 (NCT05824585) are phase 1 dose escalation and expansion studies in patients with r/r B-NHL. Both studies have similar dose escalation strategies. Patients who progressed following or intolerant of prior systemic therapy were enrolled. Pooled safety and efficacy analysis was performed. In addition, modulation of PD biomarkers was also evaluated. Tumor responses were investigator assessed according to Lugano 2014, IPCG 2005, or iwCLL 2018, as appropriate. Results As of June 15, 2023, 17 patients with r/r B-NHL have been enrolled and received DZD8586 at doses ranging from 10 to 100 mg once daily (QD) (10 mg， n=1；25 mg， n=4；50 mg， n=7；100 mg， n=5). The median age was 61 years, 71% were male, and 53% had an ECOG PS of 1. Histological subtypes included CLL, SCNSL, DLBCL, MCL, FL and MZL. The median number of prior therapies was 3 (range 2 - 8). All patients received prior chemotherapy and anti-CD20 therapy. Six patients, including 1 CLL, 2 MCL, 1 MZL, 1 SCNSL and 1 DLBCL had received prior treatment with covalent BTK inhibitors. DZD8586 was well tolerated across the doses investigated. Drug-related treatment emergent adverse events (TEAEs) reported in &amp;gt; 2 patients included thrombocytopenia (10/17), neutropenia (5/17), and upper respiratory tract infection (3/17). The most common ≥ grade 3 TEAE was thrombocytopenia (3/17, all at 100 mg). Other ≥ grade 3 TEAEs, including neutropenia, drug eruption and upper respiratory tract infection, were each reported by one patient. Bleeding, atrial fibrillation, and arthralgia were not reported. Grade 1 diarrhoea was reported in one patient. The maximum tolerated dose was defined as 100 mg QD. All these TEAEs were reversible after dose interruption and/or with supportive care. The longest duration on treatment was 10+ months. Among 13 patients treated at doses ≥ 25 mg QD with at least one tumor assessment, the objective response rate (ORR) was 9/13 (69.2%). Responses were observed across different histological subtypes (1/2 in SCNSL; 4/5 in DLBCL; 1/2 in FL; 1/1 in MCL, 1/2 in MZL and 1/1 CLL carrying C481S mutation). Among the 5 evaluable BTKi treated patients, tumor responses were observed in 3 patients. The longest duration of response (DoR) was 6.4+ months, and the patient was still ongoing with DZD8586 treatment and responding. PK was generally dose-proportional across the dose ranges of 10 to 100 mg. DZD8586 was absorbed with median t max 1.5 hours, and eliminated with mean terminal half-life of ~18 hours. Accumulation of about two folds in AUC was noted at steady state following once daily dosing. Dose dependent pBTK modulation in whole blood cells was detected, and at the doses ≥ 25 mg, sustained pBTK inhibition was observed. The unbound CSF-to-plasma concentration ratio (K puu,CSF) was 1.2 from one CNSL patient with available CSF samples, suggesting excellent CNS penetration of DZD8586 in humans. Conclusion In the preliminary pooled analysis of two ongoing phase 1 trials, DZD8586 has encouraging anti-tumor activity and safety in heavily pre-treated B-NHL patients. The combination of BBB penetration, dual inhibition of LYN/BTK and potential to overcome C481S mutant CLL and other covalent BTKi resistant lymphomas suggest this may be a useful agent. Updated data will be presented at the meeting.

Biomarker Correlates of Response to Ciltacabtagene Autoleucel in Patients with Relapsed or Refractory Multiple Myeloma from CARTITUDE-1, a Phase 1b/2 Open-Label Study, at the ~3 Year Follow-up

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA. Despite cilta-cel's outstanding overall response rate (97.9%) and duration of response (DOR) in RRMM patients, relapse still occurs. Biomarkers associated with this durable response and acquired resistance remain to be elucidated. We present updated correlative data from the CARTITUDE-1 study. At the ~3 year follow-up (October 2022 data cutoff), 97 patients had received a single infusion of cilta-cel (median 0.71 x10 6 cells/kg [range 0.52 x10 6-0.94 x10 6]); the median follow up was 33.4 months (range 1.5-45.2), median DOR was 33.9 months (95% CI, 25.5-not estimable [NE]) and median PFS was 34.9 months (95% CI, 25.2-NE) (Lin Y et al, ASCO 2023). Drug product (DP), baseline and on-treatment whole blood and bone marrow samples from enrolled patients were analyzed by methods including flow cytometry, MSD immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and TCR sequencing. In CARTITUDE-1, the DP contained a mixture of transduced and non-transduced T cells; the median transduction efficiency was 16% (range 5-32%), with a balanced distribution of CAR+CD4+ and CAR+CD8+ cells, median frequency 12% (range 2-28%) and 6% (range 2-20%), respectively. Further, the DP T cell subset composition was variable but balanced between central (Tcm) and effector memory (Tem) phenotypes. CAR+ T cells expanded reaching a median peak concentration (C max of 730 cells/µL; range 3-13805 cells/µL) in blood between days 12-14 post-infusion and persisted in circulation for a median of 100 days (range 20-912 days). High efficacy (best response) and DOR were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. At C max, the CD4:CD8 ratio (based on % of CAR+ cells) was 0.29, demonstrating a CAR+CD8+ T cell preferential expansion, and both CAR+CD4+ and CAR+CD8+ T cells were predominantly of a Tcm phenotype, median 95% (range 62-99.5%) and 96% (range 33-99.7%), respectively. Higher frequency of early-memory T cell phenotypes has been associated with clinical responses to CAR-T therapies in MM (Dancy et al., Blood 2018). CITE-seq analyses showed that DP characteristics such as a high CD8+ stem-like phenotype and a low CD4+ Treg-like phenotype in the CAR+ T cell compartment associated with longer DOR. Some of the most abundant clones in the DP single cell TCR data were CAR+CD8+ T cells expressing granzyme B, suggesting high cytotoxic potential. Additional bulk TCR sequencing data suggest both diversity and individual clonal expansion longitudinally after cilta-cel infusion. We also evaluated tumor and patient intrinsic characteristics at baseline. BCMA expression on bone marrow PC was prevalent and highly variable among RRMM patients; however, expression did not associate with best response or DOR. Further, high ORR was observed in patients with high-risk cytogenetics, high tumor burden (&amp;gt;= 60% bone marrow PC), or baseline plasmacytomas, although with a non-statistically significant shorter PFS. Sustained MRD negativity strongly associated with longer DOR. Conversely, patient-intrinsic characteristics associated with inflammation (CRP, ferritin, neutrophils, pro-inflammatory cytokines) correlated with shorter DOR. Treatment benefit of the magnitude seen with cilta-cel had not been reported with any other approved therapy in this setting. Correlative analyses suggest an emerging profile to help understand such outstanding clinical activity: a balanced CD4/CD8 ratio and Tcm/Tem phenotype of the manufactured DP and preferential expansion of CAR+CD8+ Tcm cells. Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose

Background: B-cell lymphoma-2 (BCL2) family proteins represent attractive therapeutic targets as they play an important role in MM cell survival. In patients with relapsed/refractory (R/R) MM harboring t(11;14) for whom multiple prior lines of therapy failed, single-agent venetoclax, a first generation BCL2 inhibitor, demonstrated antimyeloma activity (Kumar S, et al. Blood. 2017). Dexamethasone, a long-standing mainstay of treatment for MM, increases the expression of both BCL2 and Bim. This results in a greater dependency on BCL2 for tumor survival, ultimately increasing the sensitivity to a BCL2 inhibitor. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency &amp;gt;10x that of venetoclax in biochemical assays. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 trial designed to evaluate safety and efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, or in combination with dexamethasone plus carfilzomib in patients with R/R MM harboring the t(11;14). Here, we report preliminary data from the sonrotoclax plus dexamethasone dose-escalation (DE) cohorts. Methods: Eligible patients have R/R MM that is t(11;14) positive by fluorescence in situ hybridization (per central assessment) who have received 1-7 prior lines of therapy for MM with previous exposure to a proteasome inhibitor and an IMiD agent. In dose escalation, patients received 80, 160, 320, or 640 mg of sonrotoclax daily with 40 mg of dexamethasone weekly until intolerability, disease progression, or death. The primary objectives in the DE cohorts were to assess the overall safety/tolerability profile as well as determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD) and establish the recommended phase 2 dose (RP2D). AEs were reported per CTCAEs v5.0; safety was assessed by a safety monitoring committee (SMC) after a 21-day dose-limiting toxicity (DLT) window for each cohort and was guided by a modified toxicity probability interval method (mTPI-2). Disease responses were assessed per International Myeloma Working Group 2016 criteria. Results: As of May 26, 2023, 19 patients have been enrolled in the 80-, 160-, and 320-mg (n=3 each) and 640-mg (n=10 patients) dose-escalation cohorts. The median age was 68 years (range, 52-81 years). The median prior lines of therapy was 4 (range, 1-12) and 11 patients (58%) failed on a prior anti-CD38 antibody. The most common AEs (&amp;gt;20% of all patients) were insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%); none of which were severity grade ≥3. Three patients (16%) experienced grade ≥3 treatment-emergent AEs (TEAEs). One patient (33%) in the 160-mg cohort had grade 3 increases in liver enzymes and diarrhea; one patient (10%) in the 640-mg cohort had a grade 3 decrease lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment. Three patients experienced COVID-19 (grade 1-2, n=2; grade ≥3, n=1). Three patients experienced TEAEs that led to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No patient, across all dose levels tested, experienced a DLTs; thus, sonrotoclax 640 mg daily was the determined to be the MAD and the RP2D in combination with dexamethasone. Four patients (21%) died while on study; however, no deaths were determined by the investigators to be associated with study treatment. One patient died from COVID-19 while receiving study therapy; three additional patients died ≥50 days after treatment discontinuation (COVID, progressive disease, and unknown causes, n=1 each). With a median treatment duration of 120 days (range, 30-526), ORR was 58%; 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]; Figure). The ORR for the 640-mg cohort was 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). Nine patients remained on treatment; the longest duration of response was 483 days (20 cycles) which, at data cutoff, was still ongoing. Conclusion: Sonrotoclax plus dexamethasone was generally well tolerated in patients with R/R MM harboring t(11;14) at doses up to 640 mg, and initial safety and efficacy results are promising. The SMC has recommended 640 mg in combination with dexamethasone as the RP2D. Recruitment is ongoing for the sonrotoclax in combination with dexamethasone and carfilzomib dose-finding arms and the sonrotoclax plus dexamethasone indication expansion cohort.

Trial in Progress: A Phase 1b Single-Arm, Open-Label Study of Emavusertib (CA-4948) in Combination with Azacitidine and Venetoclax in Acute Myeloid Leukemia Patients in Complete Response with Measurable Residual Disease

Background Emavusertib is a novel potent oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Inhibition of these onco-proteins may induce remission thereby addressing a critical unmet need for novel therapies in acute myeloid leukemia (AML). Clinical studies with emavusertib monotherapy have demonstrated a significant reduction in AML blasts with clinical and molecular responses, including patients with relapsed or refractory AML, previously treated with an HMA and/or FLT3 inhibitors (Metzeler 2022). Azacitidine + venetoclax (aza+ven) has been approved in newly diagnosed, unfit patients with AML. In the VIALE-A study, composite complete response (CRc) (CR, CRh, or CRi) in the absence of measurable residual disease (MRD) of &amp;lt;1 residual blast/1000 leukocytes (MRD negative [MRD−]) resulted in longer duration of response (DOR), event-free survival, and overall survival (OS), and better HSCT outcome compared with patients who achieved CRc but were MRD+ (Pratz, 2022). In pre-clinical studies, emavusertib in combination with aza+ven demonstrated synergistic antileukemic effects in AML cell lines, including azacitidine- or venetoclax-resistant cell lines. Adding emavusertib to aza+ven in MRD+ patients at the time of CR may convert MRD status without adding significant toxicity and confirm that emavusertib can be safely added to aza+ven as a potential new regimen in front-line therapy. Study Design: This is a single-arm, open-label Phase 1b trial evaluating safety and tolerability, PK, and conversion of MRD status with emavusertib as an add-on agent to aza+ven in AML patients who achieved CR or CRh with MRD+ based on local testing (EU CT Number 2023-505828-58-00). The primary objective of the study is to determine a safe and tolerable dosing schedule for the triple combination. Secondary objectives include MRD conversion rate, DOR, OS, and pharmacokinetics. The study will enroll approximately 24 patients at 5 to 10 sites globally. Patients will have received azacitidine and venetoclax as first line therapy and achieved CR or CRh after 1-6 cycles of aza/ven. If MRD status remains positive, emavusertib will be added to the existing well tolerated aza+ven regimen. The starting emavusertib dose is 200 mg BID for 7 days per cycle of 28 days. If well tolerated, duration of emavusertib treatment will be extended to 14 and 21, respectively; no intra-patient change of emavusertib dosing duration is planned. The patients will continue triple treatment (emavusertib+aza+ven) until consent withdrawal, disease progression, intolerable toxicity, or not achieving MRD- within 6 cycles of triple treatment. In this Phase 1b trial, MRD can be evaluated by local testing of bone marrow. Key exclusion criteria include residual toxicities and significant comorbidities.

Modern diagnostics and treatment of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with epithelial and neuroendocrine differentiation, the incidence of which has increased substantially during the last decades. Risk factors include advanced age, fair skin type, UV exposure, and immunosuppression. Pathogenetically, a type caused by the Merkel cell polyomavirus is distinguished from a UV-induced type with a high tumor mutational burden. Clinically, MCC presents as a mostly painless, rapidly growing, reddish-violet tumor with a shiny surface, which is preferentially localized in the head-neck region and at the distal extremities. A reliable diagnosis can only be made based on histological and immunohistochemical features. At initial diagnosis, 20-26% of patients show locoregional metastases and 8-14% distant metastases, making staging examinations indispensable. If there is no clinical evidence of metastases, a sentinel lymph node biopsy is recommended. Essential columns of therapy are surgery, adjuvant or palliative radiotherapy and, in advanced inoperable stages, medicamentous tumor therapy. The introduction of immune checkpoint inhibitors has led to a paradigm shift, as they provide a considerably longer duration of response and better survival rates than chemotherapy. The PD-L1 inhibitor avelumab is approved for treatment of metastatic MCC in Germany, but the PD-1 antibodies pembrolizumab and nivolumab are also used with success. Adjuvant and neoadjuvant treatment concepts, immune combination therapies and targeted therapies as monotherapy or in combination with immune checkpoint inhibitors are in the clinical trial phase.