favezelimab (MK-4280) / Merck (MSD), Agenus - LARVOL DELTA

KEYMAKER-U04 substudy 04B: First-line (1L) enfortumab vedotin (EV) plus pembrolizumab (pembro)-based immune checkpoint inhibitor (ICI) combinations for advanced urothelial cancer (UC). (ASCO-GU 2026) - P1/2 | " Adult pts without prior systemic therapy for la/mUC and an ECOG PS of 0-1 were randomized 1:1:1 to EV + coformulated favezelimab (fave; anti–LAG3)/pembro 800 mg/200 mg (arm A), EV + coformulated vibostolimab (vibo; anti-TIGIT)/pembro 200 mg/200 mg (arm B), and EV + pembro 200 mg (arm C). In pts with la/mUC, the addition of LAG3- or TIGIT-targeted ICIs to EV + pembro did not have a clinically significant impact on efficacy. No new safety signals were identified. Incidence of certain immune-mediated AEs was higher with pembro-containing coformulations compared to EV + pembro."

Checkpoint inhibition • Clinical • Metastases • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • TIGIT

KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and novel immunotherapy agents for advanced clear cell renal cell carcinoma (ccRCC). (ASCO-GU 2025) - P1/2 | "We present results from arms containing only immunotherapy regimens: arm B1 (quavonlimab [qmab; anti–CTLA-4] coformulated with pembro), arm B2 (favezelimab [fave; anti–LAG-3] coformulated with pembro), and arm B3 (pembro + MK-4830 [anti-ILT4]), and the reference (ref) arm (pembro + lenvatinib). Preliminary data from qmab/pembro (arm B1) and pembro + lenvatinib (ref arm) showed antitumor activity in pts with ccRCC that progressed on anti–PD-(L)1 and VEGF-TKI therapy. Fave/pembro (arm B2) and pembro + MK-4830 (arm B3) arms did not show clinical activity in this setting. The safety profile of each arm was manageable."

Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. (PubMed, Nat Med) - P2 | "Patients were categorized by T-cell-inflamed gene expression profile (TcellGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. These data demonstrate the feasibility of prospective TcellGEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981 ."

Biomarker • Combination therapy • IO biomarker • Journal • P2 data • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TMB

First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A (ESMO 2025) - P1/2 | "Methods Adults with advanced ccRCC and no prior systemic therapy were randomized 2:1 to open investigational arms or the reference (ref): coformulated quavonlimab (qmab; anti-CTLA-4)/pembro + lenvatinib (lenva; VEGFR-TKI); coformulated favezelimab (fave; anti-LAG-3)/pembro + lenva; pembro + lenva + belzutifan (bel; HIF-2α inhibitor); coformulated vibostolimab (vibo; anti-TIGIT)/pembro + bel; ref, pembro + lenva. Other regimens did not show improved ORR and PFS compared with pembrolizumab + lenvatinib, yet the duration of follow-up was insufficient to detect long-term contributions to OS. Safety profiles were consistent with the profiles of the individual drugs in each regimen."

Clinical • Late-breaking abstract • Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • EPAS1 • TIGIT

Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. (PubMed, Ann Oncol) - P1/2 | "Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase 3 LITESPARK-012 study."

Journal • P1/2 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

KEYNOTE-495/KeyImPaCT: updated analysis of a biomarker-directed, randomized, phase 2 trial of pembrolizumab-based combination therapy for non-small cell lung cancer (SITC 2022) - P2 | "Methods Patients with previously untreated stage IV NSCLC were categorized by Tcell inf GEP and TMB dual biomarker status (Tcell inf GEP low TMB non-high , Tcell inf GEP low TMB high , Tcell inf GEP non-low TMB non-high , Tcell inf GEP non-low TMB high ) then randomly assigned 1:1:1 to receive pembrolizumab (200 mg IV Q3W) plus the multikinase inhibitor (targeting VEGFRs 1-3, FGFRs 1-4, PDGFRα, RET, and KIT) lenvatinib (20 mg oral QD), CTLA-4 inhibitor quavonlimab (75 mg IV Q6W), or LAG-3 inhibitor favezelimab (initially 200 mg and then 800 mg IV Q3W). Although response in the pembrolizumab+favezelimab arm did not reach the efficacy bar, there was a trend toward improved ORR in the Tcell inf GEP non-low TMB high subgroup versus the other 3 biomarker-defined subgroups; median PFS and OS were also numerically longer in the Tcell inf GEP non-low TMB high subgroup compared with the other 3 biomarker-defined subgroups. Prospective assessment of dual biomarkers, as..."

Biomarker • Clinical • Combination therapy • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • LAG3 • PDGFRA • TMB

Phase 2 KEYNOTE-057 cohort C: Pembrolizumab (pembro) with vibostolimab or favezelimab for patients (pts) with high-risk (HR) bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). (ASCO-GU 2023) - P2 | "Efficacy will be evaluated in all pts who received ≥1 dose of study treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CT urography imaging. Clinical trial information: NCT02625961."

Clinical • P2 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • LAG3 • TIGIT

Favezelimab (anti–LAG-3) plus pembrolizumab in patients with anti–PD-1–naive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL): An open-label phase 1/2 study. (ASCO 2022) - P1/2 | "Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated a tolerable safety profile and effective antitumor activity in pts with anti–PD-1–naïve R/R cHL. Further studies will be useful to compare its activity to that of pembrolizumab alone."

Clinical • P1/2 data • Bone Marrow Transplantation • Endocrine Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Hepatology • Hodgkin Lymphoma • Immunology • Inflammation • Lymphoma • Musculoskeletal Pain • Oncology • Pain • Transplantation • LAG3

Updated Results from an Open-Label Phase 1/2 Study of Favezelimab (anti–LAG-3) Plus Pembrolizumab in Relapsed or Refractory Classical Hodgkin Lymphoma after Anti–PD-1 Treatment (ASH 2022) - P1/2 | "After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in pts with R/R cHL whose disease progressed following anti–PD-1 therapy. A phase 3 study is planned to further investigate the promising results found in this patient population."

Clinical • P1/2 data • Acute Graft versus Host Disease • Bone Marrow Transplantation • Cardiovascular • CNS Disorders • Endocrine Disorders • Fatigue • Graft versus Host Disease • Heart Failure • Hematological Disorders • Hematological Malignancies • Hepatology • Hodgkin Lymphoma • Immunology • Inflammation • Lymphoma • Melanoma • Metabolic Disorders • Migraine • Musculoskeletal Pain • Neutropenia • Oncology • Pain • Solid Tumor • Transplantation • LAG3

KEYMAKER-U02 substudy 02C: Neoadjuvant pembrolizumab (pembro) and investigational agents followed by adjuvant pembro for stage IIIB-D melanoma (ESMO 2024) - P1/2 | "We present initial results from arm 4 (pembro + MK-4830 [anti-ILT4]) and arm 5 (favezelimab [anti-LAG-3] coformulated with pembro [fave/pembro]) and updated results from arm 1 (pembro + vibostolimab [vibo; anti-TIGIT]), arm 2 (pembro + gebasaxturev [geba; coxsackievirus A21]), and arm 3 (pembro alone). Adults with resectable stage IIIB-D melanoma were randomly assigned to open arms. All arms had manageable safety in stage IIIB-D melanoma. With the promising antitumor activity observed in this study, further investigation of pembro + vibo and fave/pembro in this setting is warranted. RFS by major pathologic response will be presented."

Clinical • Melanoma • Oncology • Solid Tumor • TIGIT

Safety and Dose-Expansion Study of Combination Favezelimab (anti–LAG-3) Plus Pembrolizumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Refractory to Anti–PD-1 Treatment (ISHL 2022) - P1/2 | "Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in pts with R/R cHL and PD following anti–PD-1 therapy. This combination shows potential to reinduce a response in this pt population."

Clinical • Bone Marrow Transplantation • Endocrine Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Hepatology • Hodgkin Lymphoma • Immunology • Inflammation • Lymphoma • Oncology • Transplantation • LAG3

FAVEZELIMAB PLUS PEMBROLIZUMAB IN ANTI–PD-1–REFRACTORY CLASSICAL HODGKIN LYMPHOMA (CHL): ESTIMATING THE RELATIVE EFFICACY OF FAVEZELIMAB (ICML 2023) - "In this analysis, favezelimab + pembrolizumab was associated with a higher ORR and deeper responses than pembrolizumab alone in pts with anti–PD-1–refractory R/R cHL, indicating that favezelimab contributed substantially to the efficacy observed in MK-4280-003."

Clinical • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Oncology • LAG3

Pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Phase 2 KEYNOTE-057 cohort C. (ASCO-GU 2024) - P2 | "Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961."

Clinical • P2 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • LAG3 • TIGIT

Favezelimab plus pembrolizumab for anti-PD-1-refractory classic Hodgkin lymphoma: an open-label phase 1/2 study. (PubMed, Blood Neoplasia) - P1/2 | "Favezelimab plus pembrolizumab showed manageable safety and antitumor activity in heavily pretreated anti-PD-1-refractory cHL. This trial was registered at www.clinicaltrials.gov as NCT03598608."

Journal • P1/2 data • Autoimmune Hepatitis • B Cell Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Hodgkin Lymphoma • Immunology • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: An open-label phase 1/2 study. (ASCO 2022) - P1/2 | "Favezelimab 800 mg + pembro 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated pts with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these pts."

Clinical • P1/2 data • Bone Marrow Transplantation • Endocrine Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Hepatology • Hodgkin Lymphoma • Immunology • Inflammation • Lymphoma • Musculoskeletal Pain • Oncology • Transplantation • LAG3

KEYSTEP-008: Pembrolizumab (pembro)-based combinations for microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). (ASCO-GI 2026) - P2 | " Adults with stage IV colorectal adenocarcinoma, locally confirmed MSI-H/dMMR status and ECOG PS 0 or 1 were randomized 1:1 (cohort A) to coformulated quavonlimab (anti–CTLA-4; Qmab)/pembro (25 mg/400 mg) IV Q6W or pembro 400 mg IV Q6W or 1:1:1:1:1 (cohort B) to Qmab/pembro (25 mg/400 mg) IV Q6W, MK-4830 (anti-ILT4) 800 mg + pembro 200 mg IV Q3W, coformulated favezelimab (anti−LAG-3; fave)/pembro (800 mg/200 mg) IV Q3W, coformulated vibostolimab (anti-TIGIT; vibo)/pembro (200 mg/200 mg) IV Q3W, or pembro 400 mg IV Q6W. Pembro-based combinations evaluated in this study showed numerically higher ORR vs pembro alone, but the absolute improvement was modest, especially in the 1L setting. Despite manageable safety, these results do not support further clinical development of these combinations in pts with MSI-H/dMMR mCRC. NR, not reached."

dMMR • Metastases • Mismatch repair • MSI-H • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI • TIGIT

Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003) (clinicaltrials.gov) - P1/2 | N=137 | Terminated | Sponsor: Merck Sharp & Dohme LLC | Completed ➔ Terminated; Business Reason

Trial termination • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Population Pharmacokinetic, Exposure-Response Efficacy and Safety Analyses of Favezelimab in Patients With Solid Tumors. (PubMed, Clin Transl Sci) - "Favezelimab population pharmacokinetics (popPK) was evaluated using data from 2 trials; a Phase 1 study evaluating favezelimab across a range of doses (7 to 800 mg administered intravenously [IV] every 3 weeks [Q3W]) in patients with advanced solid tumors, and a Phase 3 study evaluating 800 mg IV Q3W favezelimab combined with pembrolizumab (200 mg Q3W) in patients with programmed death ligand 1 (PD-L1) positive colorectal cancer (CRC). No covariates were associated with ORR. This analysis was used to characterize variability in favezelimab pharmacokinetics and support the choice of Phase 3 dose."

Clinical • Journal • PK/PD data • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor • LAG3 • PD-L1

Final analysis of the biomarker-directed, randomized, phase 2 KEYNOTE-495/KeyImPaCT study of pembrolizumab (P)–based combination therapy for non–small cell lung cancer (NSCLC). (ASCO 2026) - P2 | "In interim analysis, ORR with P + lenvatinib (L) in the TcellinfGEPnon-lowTMBhigh subgroup met the prespecified efficacy threshold...Pts were assigned to 1 of 4 subgroups (TcellinfGEPlowTMBnon-high, TcellinfGEPlowTMBhigh, TcellinfGEPnon-lowTMBnon-high, and TcellinfGEPnon-lowTMBhigh) and adaptively randomized 1:1:1 to P (200 mg IV Q3W) + either L (20 mg PO QD), quavonlimab (Q; 25 mg IV Q6W), or favezelimab (F; 200 mg or 800 mg IV Q3W)... With longer follow-up, OS benefit was comparable across the 4 biomarker subgroups for the 3 combination therapies, with no new safety signals. These data continue to show the feasibility of prospective biomarker assessment to evaluate P-based therapies in advanced NSCLC. -, no pts enrolled."

Biomarker • Clinical • Combination therapy • P2 data • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TMB

KEYMAKER-U03 substudy 03B: Novel investigative regimens for previously treated advanced clear cell renal cell carcinoma (ccRCC). (ASCO-GU 2026) - P1/2 | " Adults with confirmed ccRCC and disease progression on or after PD-(L)1 inhibitor and VEGF-TKI were randomly assigned to open arms: pembrolizumab (pembro)/quavonlimab (qmab; anti–CTLA-4), pembro/favezelimab (fave; anti-LAG3), pembro + MK-4830 (anti-ILT4), pembro + belzutifan (bel; HIF-2α inhibitor), bel + lenvatinib (lenva; VEGF-TKI), and pembro + lenva. Bel + lenva continued to demonstrate the highest antitumor activity followed by pembro + lenva. Pembro + bel activity was similar to historical bel monotherapy. In the small pembro/qmab cohort, median OS was not reached."

Metastases • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • EPAS1

Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003) (clinicaltrials.gov) - P1 | N=134 | Not yet recruiting | Sponsor: Merck Sharp & Dohme Corp.

New P1 trial • New P1/2 trial • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hodgkin Lymphoma • Non-Hodgkin’s Lymphoma

Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003) (clinicaltrials.gov) - P1/2 | N=174 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Feb 2028 ➔ Oct 2027 | Trial primary completion date: Feb 2028 ➔ Oct 2027

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003) (clinicaltrials.gov) - P1/2 | N=174 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Dec 2026 ➔ Oct 2027 | Trial primary completion date: Dec 2026 ➔ Oct 2027

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003) (clinicaltrials.gov) - P1/2 | N=174 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

KeyImPaCT: A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495) (clinicaltrials.gov) - P2 | N=192 | Not yet recruiting | Sponsor: Merck Sharp & Dohme Corp. | Initiation date: Jul 2018 ➔ Dec 2018

Biomarker • Trial initiation date • Tumor mutational burden • Non Small Cell Lung Cancer • ALK • EGFR • ROS1