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T-cell engager; Eeuroendocrine carcinoma; Small-cell lung cancer Acoplador de cèl·lula T; Carcinoma neuroendocrí; Càncer de pulmó de cèl·lules petites Acoplador de célula T; Carcinoma neuroendocrino; Cáncer de pulmón de células pequeñas Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy. This study was funded by Boehringer Ingelheim. M Wermke received honoraria from Novartis, Pfizer, Roche, Lilly; reports consulting or advisory role for Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, Immatics; received research funding from Roche; travel, accommodations, expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche Amgen, GEMoaB. E Felip received personal fees for advisory boards from AbbVie, Guardant Health, Janssen, Medscape, Merck KGaA, GlaxoSmithKline, Bayer; advisory board and speakers' bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; speakers' bureau fees from Prime Oncology, Touchime; research funding from Grant for Oncology Innovation (GOI), Fundacion Merck Salud; Grífols: independent member of the board. Y Kuboki received honoraria from Taiho, ONO, Bayer, Sanofi; consulting fees from Takeda, Boehringer Ingelheim, Taiho; grants or funds from Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas, Daiichi-Sankyo. D Morgensztern received consulting fees from AbbVie, Gilead, PharmaMar, Lilly, Bristol-Myers Squibb, G1 Therapeutics, Mirati, Boehringer Ingelheim. ZO' Hamed, M Liu and M Studeny report employment with Boehringer Ingelheim. TK Owonikoko received consulting fees from Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, XCovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, Merck, Bayer, Jazz Pharmaceuticals; and research funding from Novartis, Astellas Pharma, Bayer, StemCentRx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol-Myers, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Mersana, Turning Point, and Oncorus. V Gambardella reports no conflicts of interest. All authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Purpose: Retrospective, surrogate marker–based studies have found inconsistent associations between systemic iron overload (SIO) and adverse outcome in patients undergoing allogeneic stem cell transplantation (allo-SCT). As a consequence, the impact of SIO in this context remains under debate. The aim of this study was to test whether the objective pretransplant quantification of liver-iron content (LIC) by magnetic resonance imaging (MRI) could circumvent these limitations and conclusively define the prognostic relevance of SIO.Experimental Design: The correlation between pretransplant LIC and surrogate parameters as well as the impact of SIO on posttransplant outcome was assessed within an observational study of patients (n = 88) with either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allo-SCT.Results: Ferritin levels of 1,000 ng/mL or more provided only poor specificity (31.8%) for predicting elevated LIC (≥125 μmol/g) and even higher thresholds (≥2,500 ng/mL) lacked an association with nonrelapse mortality (NRM). In contrast, LIC 125 μmol/g or more was a significant risk factor for NRM in uni- and multivariate analysis (HR = 2.98; P = 0.016). Multivariate Cox-regression further showed that LIC 125 μmol/g or more was associated with a decreased overall survival (HR = 2.24, P = 0.038), whereas ferritin or transfusion burden were not.Conclusions: SIO reflected by LIC is an independent negative prognostic factor for posttransplant outcome in patients with AML and MDS undergoing allo-SCT. Therefore, MRI-based LIC, and not interference-prone serum markers such as ferritin, should be preferred for pretransplant risk stratification and patient selection in future clinical trials. Clin Cancer Res; 18(23); 6460–8. ©2012 AACR.

PDF file - 170K, Cumulative incidence curves of acute GvHD grade 2 to 4 with respect to LIC, transfusion burden and ferritin

PDF file - 103K, Contains supplementary tables S1 - S6 and legends for supplementary figures Supplementary table S1. Impact of pre-transplant variables on the cumulative incidence of relapse one year after transplantation. The cumulative incidences are given with 95% confidence intervals. Supplementary table S2. Causes of Non-replapse mortality. Absolute numbers and percentages in the respective LIC group are given. GvHD - Graft-versus-Host-Disease. Supplementary table S3. Multivariate competing risk regression analysis assessing serum ferritin in the context of other risk factors for NRM. Supplementary table S4. Multivariate competing risk regression analysis assessing transfusion burden in the context of other risk factors for NRM. Supplementary table S5. Multivariate Cox-regression analysis of overall survival including serum ferritin instead of LIC. Supplementary table S6. Multivariate Cox-regression analysis of overall survival including transfusion burden instead of LIC.

PDF file - 137K, Receiver-Operator-Characteristics of Transfusion Burden and Ferritin for the prediction of an LIC ≥ 125 �mol/g

PDF file - 98K, Graph depicting sensitivity, specificity and accuracy of different LIC thresholds for the prediction of Overall Survival

PURPOSE No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS)–mutant melanoma is currently available. PATIENTS AND METHODS In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725 ), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non–small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel–related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Introduction The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood. Methods We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors. Conclusion Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.

Although the treatment and prognosis of many solid tumor types in the metastatic situation could be considerably improved during the last decade, for a long time no significant progress in the treatment of small cell lung cancer (SCLC) could be achieved.The aim of this article is to describe the current treatment standard for SCLC and to discuss potential approaches for further improvement.A selective literature search was carried out in PubMed and abstract lists of relevant conferences.Given the recent approval of two immunochemotherapy regimens based on the combination of anti-PD-L1 antibodies with platinum-etoposide, the therapeutic standard in the first line treatment of metastasized SCLC has finally been improved for the first time in three decades; however, the overall survival benefit has been modest with an improvement of just 2-3 months. In advanced lines of treatment no new approaches could so far show improved outcome compared with established chemotherapy protocols, such as topotecan and combinations of anthracycline, cyclophosphamide and vincristine. The slow progress in SCLC compared to non-SCLC, has been attributed to the complex biology, the exceptionally high proliferation rate and rapid development of resistance to chemotherapy. Increasing knowledge on the molecular and immunological principles of SCLC is increasingly opening up novel treatment approaches.There has finally been a slow but clinically meaningful progress in the treatment of SCLC. Patients should be included in clinical trials at the latest after second line treatment, in order to accelerate the speed of the expansion of treatment options.HINTERGRUND: Während Therapie und Prognose anderer solider Tumorarten in der metastasierten Situation in den letzten 10 Jahren deutlich verbessert werden konnten, war in der Behandlung des kleinzellig-neuroendokrinen Karzinoms der Lunge (SCLC) lange Zeit kein signifikanter klinischer Fortschritt zu verzeichnen.Ziel dieses Beitrags ist es, den aktuellen Therapiestandard beim kleinzelligen Lungenkarzinom darzustellen und potenzielle Ansätze zu dessen Weiterentwicklung zu diskutieren.Es erfolgte eine selektive Literaturrecherche in PubMed sowie in den Abstractverzeichnissen relevanter Kongresse.Mit der Zulassung von 2 auf der Kombination von PD-L1-Antikörpern und Platin/Etoposid basierenden Immunchemotherapieregimen konnte der therapeutische Standard bei metastasierten SCLC erstmals seit 3 Jahrzehnten verbessert werden. Allerdings fallen die Vorteile im Gesamtüberleben mit 2 bis 3 Monaten moderat aus. In fortgeschrittenen Therapielinien konnte sich bisher kein neuer Therapieansatz gegenüber den etablierten Chemotherapieprotokollen (Topotecan oder Anthracyclin/Cyclophosphamid/Vincristin) durchsetzen. Der im Vergleich zum nichtkleinzelligen Lungenkarzinom langsame Fortschritt beim SCLC wird unter anderem durch dessen komplexe Biologie, die damit verbundene hohe Proliferationsrate sowie die schnelle Resistenzentwicklung gegenüber Chemotherapie erklärt. Ein zunehmendes Wissen über die molekularen und immunologischen Grundlagen des SCLC eröffnen aber zunehmend neue Therapiemöglichkeiten.Auch beim SCLC ist ein langsamer therapeutischer Fortschritt zu beobachten. Patienten sollten spätestens ab der zweiten Linie in klinische Studien eingebracht werden, um das Tempo der Erweiterung der therapeutischen Möglichkeiten zu beschleunigen.

Background: ICT01, an anti-BTN3A mAb, selectively activates γ9δ2 T cells resulting in remodeling of the tumor microenvironment by activated γ9δ2 T, CD8 T, and NK cells (EVICTION- NCT04243499; AACR 2022 CT188). Response to ICT01 depends on the baseline number of γ9δ2 T cells with many cancer patients having inadequate numbers due to prior chemotherapy and/or the underlying malignancy. ICT01 plus IL-2 induces selective expansion of γ9δ2 T cells with minimal Treg expansion in NHPs and is currently being tested in the EVICTION-2 Trial, a phase I/IIa, open-label study to characterize the safety, tolerability, pharmacodynamics, and antitumor activity of ICT01 in combination with low dose subcutaneous (LDSC) IL-2 in patients with advanced-stage solid tumors (NCT04243499). Methods: ICT01 (1, 5, 20 or 75 mg, IV Q3W) is given in combination with LDSC IL-2 (Proleukin®, 1 or 2 MIU/m2) on days 1-5 of the first 3 cycles and will be continued alone thereafter. Per dose combination two patients are enrolled for dose escalation based on the BOIN simulations to identify a safe and pharmacodynamically active dose combination(s) for Phase IIa expansion. Results: To date, 9 patients with colorectal (n=6), ovarian (n=2) or pancreatic cancer (n=1) with a mean/median of 6 prior lines of therapy have received at least their first cycle of ICT01 1, 5, 20 or 75 mg + IL-2 1MIU/m2 or ICT01 1mg + IL-2 2MIU/m2. Treatment-related adverse events (TRAE) were mainly infusion related reactions comprising fever and chills grade 1 and 2 in 8/9 patients, not different in severity from ICT01 or IL-2 monotherapy. No dose limiting toxicities were reported. By RECIST, Stable Disease was observed in 2/6 patients with a Week 8 assessment. In all patients, a 2-to-9-fold increase in γ9δ2 T cells was observed for each of the 3 combination cycles, which is accompanied by peripheral activation, mobilization, and proliferation of CD8 T cells, NKs and granulocytes, which is consistent with the expected contribution of IL-2. Increased IFNγ and IL-8 levels (2.4-to-140 fold and 2-to-94 fold respectively) were observed within 24h after each dose of ICT01/IL-2. Flow cytometry of Tregs in frozen PBMCs and IHC of tumor biopsies collected at baseline and on Day 28 are being analyzed to quantify tumor infiltration. Conclusions ICT01 plus LDSC IL-2 safely induced robust γ9δ2 T cell expansion leading to a broad immune response involving CD8 T cells, NKs, and granulocytes at lower doses than observed with ICT01 monotherapy. More patient data are needed to confirm that IL-2 potentiates the antitumor effects of ICT01 and that this leads to better clinical outcomes. Citation Format: Johann de Bono, Stéphane Champiat, Francois-Xavier Danlos, Martin Wermke, Volker Kunzmann, Aude De Gassart, Emmanuel Valentin, Marina Iche, Maelle Mairesse, Patrick Brune, Katrien Lemmens, Aurélien Marabelle, Daniel Olive, Paul Frohna. First-in-human study of ICT01, an anti-BTN3A activating monoclonal antibody in combination with low dose IL-2 in patients with advanced solid tumors (EVICTION-2 study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT179.

Objective Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. Materials and methods To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). Results EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1–2.3) and overall survival (OS HR 1.7–2.2), in combination defining patient subgroups with distinct outcome ( E GFR+ N SCLC risk S core, "ENS", p Conclusions EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Treatment outcome of relapsed or refractory AML patients remains dismal and new treatment options are needed. Adoptive cell therapy using CAR-T cells is a potentially interesting approach in this.Several potentially interesting AML targets are being investigated with CAR-T therapy with over 60 clinical trials listed on clinicaltrials.gov. The first clinical data are only just emerging with mixed results, once more proving that further research is needed.Adoptive cell therapy using chimeric antigen receptor T cells is being investigated in AML through many clinical trials. So far, no AML-specific antigen has been identified, requiring additional strategies to mitigate on-target off-tumor toxicity and to increase efficacy. Focus point is to acquire control over the CAR T cells once administered. Strategies to do so include biodegradable CARs, inducible CARs, suicide-switch containing CARs and two-component modular CARs. Limited and mixed results are available, confirming the risk of lasting toxicity for nonswitchable CARs. Initial results of modular CARs suggest toxicity can be mitigated whilst maintaining CAR activity by the use of modular CAR concepts that allows for 'ON' and 'OFF' switching.

Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell–mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 3 106 to 20 3 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade #2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcgRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37., Blood advances, 6 (12)

394 Background: In the dose-confirmation phase of this multicohort trial (NCT02720068), the anti-LAG-3 antibody favezelimab had a manageable safety profile and promising antitumor activity in patients (pts) with advanced solid tumors, confirming preliminary RP2D. Here we present results on the safety of favezelimab (fave) plus pembrolizumab (pembro) in all treated pts and efficacy in pts with advanced gastric cancer. Methods: In this phase 1b trial eligible pts aged ≥ 18 years were enrolled into 7 cohorts across 3 tumor types: Cohorts A (3L+ CRC), B (1L/2L CRC), C (PD-1 naïve HNSCC), D (PD-1 refractory HNSCC), E (PD-1 naïve gastric cancer), F (all solid tumors), and G (PD-1 naïve 3L CRC). Pts with gastric cancer in cohort E received either 200 mg fave + 200 mg pembro, or 700 mg fave + 200 mg pembro Q3W up to 35 cycles. Treatment continued until progression, unacceptable toxicity, or pt withdrawal. Primary endpoint was safety and tolerability of fave + pembro. Secondary endpoint was ORR per RECIST 1.1 by investigator assessment. Exploratory endpoints were PFS per RECIST 1.1, and OS. Data cutoff date was March 21, 2022. Results: At data cutoff, 397 pts were enrolled: 38 to fave, 368 to fave + pembro including 9 who crossed over from fave alone. Of these, 80 pts had gastric cancer; 50 (62.5%) of which had ≥2 lines of treatment, and 48 (60.0%) had PD-L1 CPS≥ 1. Among 368 pts treated with fave + pembro, treatment-related adverse events (TRAEs) occurred in 232 (63.0%) with fave + pembro. Grade ≥3 TRAEs occurred in 66 (17.9%) pts with fave + pembro. There were no grade 5 TRAEs. Immune-mediated adverse events (AEs) occurred in 121 (32.9%) pts with fave + pembro. Grade ≥3 immune-mediated AEs occurred in 27 (7.3%) pts with fave + pembro. No grade 5 immune-mediated AEs occurred. In pts with gastric cancer, the overall ORR was 11.3% (95% CI, 5.3-20.3 [3.8% CR; 7.5% PR]) with fave + pembro. In 2 arms, higher dose of fave (700mg) showed increased ORR and 12 months PFS rate. The table summarizes antitumor activity in the gastric cancer cohort. Conclusions: Favezelimab alone or in combination with pembrolizumab had an acceptable safety profile. The combination therapy showed antitumor activity in line with other checkpoint inhibitors in advanced gastric cancer though higher antitumor activity was seen in PDL1 CPS≥ 1 tumors, particularly at higher dose. Clinical trial information: NCT02720068 . [Table: see text]