quavonlimab (MK-1308) / Merck (MSD), Akesobio - LARVOL DELTA

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

First-line pembrolizumab alone or with investigational agents for advanced melanoma: Updated results from the phase I/II KEYMAKER-U02 substudy 02B (ESMO 2025) - P1/2 | "Background Prior analysis of KEYMAKER-U02 substudy 02B (NCT04305054) showed promising activity for first-line vibostolimab (vibo) + pembrolizumab (pembro) and coformulated quavonlimab (qmab)/pembro in advanced melanoma. Manageable safety was observed across the first 4 arms (vibo + pembro, pembro alone, qmab/pembro; qmab/pembro + lenvatinib [len]). Updated results are presented, including from 2 previously unreported arms: coformulated favezelimab (fave; anti–LAG-3)/pembro and fave/pembro + all-trans retinoic acid (ATRA)...Conclusions Safety was manageable across arms. Moderate antitumor activity was observed with fave/pembro (arm 5); no additional benefit was observed with combining ATRA with fave/pembro (arm 6)."

Clinical • Metastases • P1/2 data • Melanoma • Oncology • Solid Tumor

KEYMAKER-U02 Substudy 02A: Substudy 02A: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents in Participants With Programmed Cell-death 1 (PD-1) Refractory Melanoma (MK-3475-02A/KEYMAKER-U02) (clinicaltrials.gov) - P1/2 | N=100 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | N=200 ➔ 100 | Trial completion date: Apr 2030 ➔ Aug 2025 | Trial primary completion date: Apr 2030 ➔ Aug 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor

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=245 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | Trial completion date: Nov 2025 ➔ Jun 2025 | Trial primary completion date: Nov 2025 ➔ Jun 2025

Biomarker • Trial completion • Trial completion date • Trial primary completion date • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1

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=318 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2025 ➔ Nov 2025 | Trial primary completion date: Jun 2025 ➔ Nov 2025

Biomarker • Trial completion date • Trial primary completion date • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1

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

KEYMAKER 02B: A randomized trial of pembrolizumab (pembro) alone or with investigational agents as first-line treatment for advanced melanoma (ESMO 2024) - P1/2 | "We present results from patients (pts) treated with pembro + vibostolimab (vibo; anti-TIGIT; arm 1), pembro alone (arm 2), quavonlimab (qmab; anti–CTLA-4) coformulated with pembro (qmab/pembro; arm 3), and qmab/pembro + lenvatinib (len; multitargeted TKI; arm 4). Pts were aged ≥18 y with previously untreated unresectable stage III or IV cutaneous melanoma who had measurable disease per RECIST v1.1 and an ECOG PS of 0 or 1, but no active brain metastases. Preliminary results from KEYMAKER-U02B showed promising antitumor activity for first-line pembro + vibo and qmab/pembro. Safety was generally manageable. Additional treatment arms will be reported when available."

Clinical • Metastases • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • TIGIT

Triplet combination treatments with pembrolizumab (pembro) for anti–PD-(L)1–refractory advanced melanoma: Preliminary results of the phase 1/2 KEYMAKER-U02A study. (ASCO 2024) - P1/2 | "We report results from arm 1 (pembro + quavonlimab [qmab] (anti-CTLA4) + vibostolimab [vibo] (anti-TIGIT)), arm 2 [pembro + qmab + lenvatinib [len] (TKI)), and arm 3 (pembro + ATRA [all-trans retinoic acid]) of KEYMAKER-U02A. Although objective responses were observed in some pts with anti–PD-(L)1–refractory melanoma, protocol-prespecified criteria for enrollment expansion were not met in any arm. The safety profile was manageable. Additional arms will be reported for this pt population with a high unmet need."

Metastases • P1/2 data • Melanoma • Nephrology • Oncology • Solid Tumor • TIGIT

Study of Quavonlimab (MK-1308) in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-1308-001) (clinicaltrials.gov) - P1/2 | N=413 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • CTLA4 • EGFR

KEYMAKER-U02 Substudy 02A: Substudy 02A: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents in Participants With Programmed Cell-death 1 (PD-1) Refractory Melanoma (MK-3475-02A/KEYMAKER-U02) (clinicaltrials.gov) - P1/2 | N=200 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Melanoma • Oncology • Solid Tumor

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma. (PubMed, Future Oncol) - P3 | "Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov)."

Journal • Metastases • Review • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CTLA4

KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer. (PubMed, Future Oncol) - P2 | "Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov)."

Journal • Metastases • P2 data • Review • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • CTLA4 • LAG3 • MSI • TIGIT

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

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

"Obv $MRK has its own CTLA-4, quavonlimab (MK-1308), in phase 3. Not sure why $PFE didn't take up the ONC-392 option." (@JacobPlieth)

P3 data • CTLA4

Updates in the Treatment of Renal Cell Carcinoma: Highlights from IKCS and ESMO 2022 : Episode 9: Phase III Trial of Lenvatinib, Pembrolizumab, and Belzutifan or Quavonlimab in Frontline Advanced RCC (Cancer Network) - "The panel continues their discussion of investigational triplet therapies in frontline RCC treatment."

Video

KEYNOTE-495/KeyImPaCT: interim analysis of a randomized, biomarker-directed, phase 2 trial of pembrolizumab-based combination therapy for non–small cell lung cancer (NSCLC) (SITC 2021) - P2 | "DNA and RNA were extracted from tumor tissue to determine TcellinfGEP and TMB; patients were assigned to one of four biomarker-defined subgroups (TcellinfGEPlowTMBlow, TcellinfGEPlowTMBhigh, TcellinfGEPhighTMBlow, TcellinfGEPhighTMBhigh) and randomly assigned 1:1:1 to receive pembrolizumab (200mg IV Q3W)+lenvatinib (20mg oral QD), pembrolizumab+quavonlimab (75mg IV Q6W), or pembrolizumab+favezelimab (200mg [n=30] or 800mg [n=34] Q3W; the initial prespecified dose was 200mg but changed to 800mg based on emerging data). Although sample sizes were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the biomarker subgroups for all three combination therapies; further validation is needed to determine additional signals and may be addressed as more mature data become available. Trial Registration ClinicalTrials.gov, NCT03516981"

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

KEYNOTE-495/KeyImPaCT: Phase 2 Biomarker-Directed Study of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (IASLC-WCLC 2019) - P2; "Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti–LAG-3), lenvatinib, or MK-1308 (anti–CTLA-4). Section not applicable"

Biomarker • IO biomarker • P2 data • PD(L)-1 Biomarker • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

KEYNOTE-495/KeyImPaCT: A randomized, biomarker-directed, phase II trial of pembrolizumab-based therapy for non–small cell lung cancer (NSCLC) (ESMO 2019) - P2; "Trial design:In this group-sequential, adaptive randomized trial, pts (N∼288) receive pembro 200 mg Q3W intravenously (IV) combined with MK-4280 (anti–LAG-3) 200 mg Q3W IV, lenvatinib (lenv) 20 mg PO QD, or MK-1308 (anti–CTLA-4) 25 mg Q6W IV for 35 cycles (∼2 years); pts in the lenv arm may receive lenv monotherapy until disease progression or toxicity. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA."

Biomarker • Clinical • IO biomarker • P2 data • PD(L)-1 Biomarker • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

Phase 1 Study of the CTLA-4 Inhibitor MK-1308 in Combination With Pembrolizumab in Patients With Advanced Solid Tumors (ESMO 2018) - P1; "Preliminary results suggest that the combination of MK-1308 and pembrolizumab shows promising responses in a 1L advanced NSCLC population and manageable toxicity in most tumor types evaluated. Enrollment is ongoing."

Clinical • Combination therapy • IO biomarker • P1 data • PD(L)-1 Biomarker • Tumor mutational burden • Non Small Cell Lung Cancer

Study of Quavonlimab (MK-1308) in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-1308-001) (clinicaltrials.gov) - P1/2 | N=348 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Oct 2023 ➔ Apr 2024 | Trial primary completion date: Oct 2023 ➔ Apr 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • CTLA4 • EGFR

Phase 3 study of pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib as first-line treatment for advanced renal cell carcinoma (SITC 2021) - P3 | "Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. Trial Registration Clinicaltrials.gov, NCT04736706"

Clinical • P3 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • EPAS1 • MRI

KEYNOTE-495/KeyImPaCT: interim analysis of a randomized, biomarker-directed, phase 2 trial of pembrolizumab-based combination therapy for non–small cell lung cancer (NSCLC) (SITC 2021) - P2 | "DNA and RNA were extracted from tumor tissue to determine Tcell inf GEP and TMB; patients were assigned to one of four biomarker-defined subgroups (Tcell inf GEP low TMB low , Tcell inf GEP low TMB high , Tcell inf GEP high TMB low , Tcell inf GEP high TMB high ) and randomly assigned 1:1:1 to receive pembrolizumab (200mg IV Q3W)+lenvatinib (20mg oral QD), pembrolizumab+quavonlimab (75mg IV Q6W), or pembrolizumab+favezelimab (200mg [n=30] or 800mg [n=34] Q3W; the initial prespecified dose was 200mg but changed to 800mg based on emerging data). View this table: View inline View popup Download powerpoint Abstract 457 Table 1 Confirmed ORR by Therapy and Biomarker Status Conclusions These data demonstrate the feasibility and clinical usefulness of prospective Tcell inf GEP and TMB assessment to study the clinical activity of three first-line pembrolizumab-based combination therapies in patients with advanced NSCLC. Although sample sizes were small, the Tcell inf GEP..."

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

Phase 3 study of first-line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib for advanced renal cell carcinoma (RCC). (ASCO-GU 2022) - P3 | "Antitumor activity has also been shown with the hypoxia-inducible factor 2a (HIF-2a) inhibitor belzutifan (MK-6482) in ccRCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The study is recruiting patients at sites across, Asia, Australia, Europe, North America, and South America."

Clinical • P3 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1