Pembrolizumab Combinations for Small Cell Lung Cancer
Recruiting in Palo Alto (17 mi)
+24 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Merck Sharp & Dohme Corp.
Must not be taking: RTK inhibitors, Anti-CTLA-4
Disqualifiers: Active CNS metastases, Autoimmune disease, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial tests a combination of pembrolizumab and new experimental drugs in patients with advanced lung cancer who did not respond to previous treatments. The goal is to see if this combination is safe and effective. Pembrolizumab helps the immune system attack cancer by blocking a protein that stops immune cells from working. Pembrolizumab has been widely studied and approved for the treatment of various cancers, including lung cancer.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received certain treatments like systemic anticancer therapy or radiotherapy shortly before starting the study. It's best to discuss your current medications with the study team to get specific guidance.
What data supports the effectiveness of the drug combination of pembrolizumab, lenvatinib, and quavonlimab for small cell lung cancer?
Research shows that pembrolizumab combined with lenvatinib has shown promising results in various solid tumors, including non-small cell lung cancer, with objective response rates (ORR) reaching up to 60% in certain groups. Additionally, the combination of pembrolizumab and quavonlimab has demonstrated encouraging antitumor activity in small cell lung cancer, with ORR ranging from 28% to 40%.
12345What safety data exists for pembrolizumab combinations in humans?
The combination of pembrolizumab with other drugs like lenvatinib has been studied in various cancers, showing a safety profile consistent with known effects of each drug. Common side effects include high blood pressure, low thyroid function, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss.
16789What makes the drug combination of pembrolizumab, favezelimab, lenvatinib, MK-4830, and quavonlimab unique for treating small cell lung cancer?
This drug combination is unique because it combines multiple immune checkpoint inhibitors (like pembrolizumab and quavonlimab) with other agents like lenvatinib, which targets blood vessel growth in tumors, potentially enhancing the immune system's ability to fight cancer. This approach is novel for small cell lung cancer, which traditionally has limited treatment options.
15101112Eligibility Criteria
This trial is for adults with Stage IV small cell lung cancer who need second-line therapy after not responding to first treatments including PD-1/PD-L1 inhibitors. They must have a life expectancy over 3 months, measurable disease, and be willing to use contraception. Exclusions include recent major surgery or radiation, active infections, other cancers within 3 years, severe allergies to study drugs, and certain heart or blood vessel problems.Inclusion Criteria
I have provided a sample of my tumor that has not been treated with radiation.
You are expected to live for more than 3 months.
I am a man and will not have unprotected sex or will use contraception during and for 7 days after my treatment, unless I'm receiving specific immunotherapies.
+12 more
Exclusion Criteria
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
I haven't had cancer treatment or experimental drugs in the last 4 weeks.
I have not had a serious wound, ulcer, or bone fracture that hasn't healed in the last 28 days.
+27 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Safety Lead-in
Initial safety lead-in to determine safety and tolerability for experimental combinations of investigational agents
3 weeks
Efficacy Evaluation
Efficacy evaluation of investigational agents as monotherapy or in combination with pembrolizumab
Up to approximately 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to approximately 60 months
Participant Groups
The study tests pembrolizumab combined with investigational agents (quavonlimab/lenvatinib/MK-4830/favezelimab) in two parts: initial safety assessment followed by efficacy evaluation for those with extensive-stage small cell lung cancer resistant to standard treatments. No hypothesis testing; focuses on determining safe dosages and observing effectiveness.
5Treatment groups
Experimental Treatment
Group I: R-DXdExperimental Treatment1 Intervention
Participants receive 5.6 mg/kg R-DXd via IV infusion every three weeks (Q3W) until progressive disease or discontinuation.
Group II: Coformulation Pembrolizumab/Quavonlimab + MK-4830Experimental Treatment2 Interventions
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS MK-4830 800 mg. Pembrolizumab/quavonlimab will be administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation. MK-4830 will be administered by IV infusion once every 3 weeks (Q3W) for up to 36 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Group III: Coformulation Pembrolizumab/Quavonlimab + LenvatinibExperimental Treatment2 Interventions
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation. Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation.
Group IV: Coformulation Pembrolizumab/QuavonlimabExperimental Treatment1 Intervention
Participants receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) administered by intravenous (IV) infusion once every 6 weeks (Q6W) for up to 18 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Group V: Coformulation Favezelimab/PembrolizumabExperimental Treatment1 Intervention
Participants receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) administered by intravenous (IV) infusion once every 3 weeks (Q3W) for up to 36 infusions (up to approximately 2 years) or until progressive disease or discontinuation.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Banner MD Anderson Cancer Center ( Site 0152)Gilbert, AZ
Georgia Cancer Specialists ( Site 0156)Atlanta, GA
Virginia Cancer Institute ( Site 0169)Richmond, VA
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Who Is Running the Clinical Trial?
Merck Sharp & Dohme Corp.Lead Sponsor
Merck Sharp & Dohme LLCLead Sponsor
Daiichi SankyoIndustry Sponsor
References
Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. [2023]Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a heterogenous tumor microenvironment. KEYNOTE-495/KeyImPaCT is an ongoing biomarker-directed, adaptively randomized phase 2 study investigating first-line pembrolizumab (200 mg every 3 weeks) + lenvatinib (20 mg daily), anti-CTLA-4 quavonlimab (25 mg every 6 weeks) or anti-LAG-3 favezelimab (200 mg or 800 mg every 3 weeks) in advanced NSCLC. Patients were categorized by T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. The primary outcome was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 using pre-specified efficacy thresholds for each biomarker-defined subgroup (>5% (TcellinfGEPlowTMBnon-high (group I)), >20% (TcellinfGEPlowTMBhigh (group II) and TcellinfGEPnon-lowTMBnon-high (group III)) and >45% (TcellinfGEPnon-lowTMBhigh (group IV))). Secondary outcomes were progression-free survival, overall survival and safety. At data cutoff, ORR ranges were 0-12.0% in group I, 27.3-33.3% in group II, 13.6-40.9% in group III and 50.0-60.0% in group IV. ORR with pembrolizumab + lenvatinib in group III met the pre-specified efficacy threshold. The safety profile of each treatment arm was consistent with the known safety profile of each combination. These data demonstrate the feasibility of prospective TcellinfGEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981 .
The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. Clinical trial registration: NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).
Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. [2023]The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy.
Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. [2021]Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.
Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer. [2021]This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.
Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]The combination of lenvatinib plus pembrolizumab demonstrated a relevant clinical benefit in patients with endometrial carcinoma. The safety profile was consistent with the established profiles of each drug in monotherapy, with the most frequent adverse events being hypertension, an on-target effect, hypothyroidism, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss.
Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. [2023]To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose.
Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]Both pembrolizumab and lenvatinib demonstrate antitumor activity and safety in cancers. However, whether their combination is safer and more effective than monotherapies remains unknown. A systematic review was performed to assess the safety and efficacy of pembrolizumab plus lenvatinib versus their respective monotherapies in solid cancers.
Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. [2023]Lenvatinib plus pembrolizumab showed significantly improved progression-free and overall survival outcomes compared with sunitinib in patients with advanced renal cell carcinoma in the CLEAR study (NCT02811861). Here, we used CLEAR data to characterize common adverse reactions (ARs; adverse-event preferred terms grouped in accordance with regulatory authority review) associated with lenvatinib plus pembrolizumab and review management strategies for select ARs.
Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. [2021]Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. [2021]Small-cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by a rapid initial response and early development of resistance to systemic therapy and radiation. The management of SCLC significantly changed for the first time in decades with the introduction of immune checkpoint inhibitors. Pembrolizumab, a humanized IgG4 isotype antibody, targets the programmed cell death protein 1 (PD-1) pathway to restore anti-tumor immunity. Prospective trials of pembrolizumab in patients with previously treated SCLC showed significant durability of responses. These results led to the U.S. Food and Drug Administration (FDA) granting pembrolizumab accelerated approval as second- or third-line monotherapy for patients with extensive-stage (ES) SCLC. In a recent clinical trial that included patients with previously untreated ES-SCLC, pembrolizumab in combination with platinum/etoposide met its progression-free survival endpoint, but overall survival (OS) did not cross the threshold for superiority. With the therapeutic landscape for SCLC rapidly evolving, we review prior experience and future directions of pembrolizumab in ES-SCLC.
The benefits and risks of pembrolizumab in combination with chemotherapy as first-line therapy in small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized control trials. [2023]Although pembrolizumab has shown clinical benefit in patients with small-cell lung cancer (SCLC), its actual efficacy in combination with a conventional chemotherapy drug has not been determined. We performed this study to discern the efficacy and risk of pembrolizumab in combination with chemotherapy as first-line therapy in SCLC patients.