Pembrolizumab Combinations for Small Cell Lung Cancer

Recruiting at 33 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: RTK inhibitors, Anti-CTLA-4

Disqualifiers: Active CNS metastases, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

110 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for people with small cell lung cancer (SCLC) that has worsened after initial therapy. It tests several experimental drugs, either alone or with pembrolizumab (an immunotherapy drug), to determine their safety and effectiveness as second-line treatments. Participants may qualify if they have stage IV SCLC, have previously received PD-1/PD-L1 therapy, and are experiencing progression. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive potentially groundbreaking therapies.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that the combination of pembrolizumab and quavonlimab is safe, with patients typically experiencing few serious side effects. Adding lenvatinib results in a safety profile similar to each drug individually.

Research on the combination of pembrolizumab, quavonlimab, and the investigational drug MK-4830 reveals no new safety concerns, with side effects aligning with those expected from similar treatments.

Favezelimab combined with pembrolizumab has also undergone testing. Results indicated that side effects were manageable and not severe or life-threatening.

These treatments remain under study, so new safety information may emerge. However, current data suggests that these combinations are generally well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for small cell lung cancer because they offer innovative combinations that may enhance the immune system's ability to fight cancer. Unlike standard chemotherapy, which attacks cancer cells directly, the coformulation of pembrolizumab and quavonlimab works by boosting the body's immune response to target cancer cells more effectively. Lenvatinib adds another layer by inhibiting the growth of blood vessels that feed tumors, potentially starving the cancer. Additionally, the combination with MK-4830 aims to block certain pathways that tumors use to evade the immune system. These fresh approaches could offer more powerful and targeted options compared to traditional treatments.

What evidence suggests that this trial's treatments could be effective for small cell lung cancer?

Research has shown that different combinations of pembrolizumab with other experimental drugs may help treat small cell lung cancer (SCLC). In this trial, participants may receive pembrolizumab combined with quavonlimab, which has shown promising results in patients with advanced SCLC. Another arm of the trial tests the addition of lenvatinib to this combination, which also appears effective in similar cases. Researchers are testing the addition of MK-4830 to pembrolizumab and quavonlimab in a separate arm, with early studies suggesting it might help patients who do not respond to other treatments targeting PD-1/PD-L1. Additionally, the trial includes an arm where participants receive ifinatamab deruxtecan (R-DXd), which demonstrated a 48.2% response rate in patients with advanced SCLC who have already received treatment, indicating potential benefits. These findings suggest potential benefits for patients seeking second-line treatments for SCLC. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Favezelimab
• Lenvatinib
• MK-4830
• Pembrolizumab
• Quavonlimab

Trial Overview 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.

How Is the Trial Designed?

Group I: R-DXd Experimental Treatment 1 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-4830 Experimental Treatment 2 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 + Lenvatinib Experimental Treatment 2 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/Quavonlimab Experimental Treatment 1 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/Pembrolizumab Experimental Treatment 1 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.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Published Research Related to This Trial

In a phase III study with 453 patients, pembrolizumab combined with etoposide and platinum significantly improved progression-free survival (PFS) compared to placebo plus etoposide and platinum, with a 12-month PFS of 13.6% versus 3.1%.

While pembrolizumab plus EP also prolonged overall survival (OS), the results did not meet the predefined significance threshold; however, the treatment showed a favorable safety profile with no unexpected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Rudin, CM., Awad, MM., Navarro, A., et al.[2021]

The ongoing KEYNOTE-495/KeyImPaCT study is evaluating the effectiveness of pembrolizumab combined with other therapies in advanced non-small cell lung cancer (NSCLC), with results showing varying objective response rates (ORR) based on tumor characteristics, ranging from 0-12% in low T-cell-inflamed groups to 50-60% in high T-cell-inflamed groups.

The study confirms that assessing T-cell-inflamed gene expression profiles (TcellinfGEP) and tumor mutational burden (TMB) can help identify which patients are more likely to benefit from pembrolizumab-based treatments, while the safety profiles of the combinations remain consistent with previous findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Gutierrez, M., Lam, WS., Hellmann, MD., et al.[2023]

In a study involving 137 patients with advanced solid tumors, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common side effects including fatigue, diarrhea, and hypertension.

The treatment demonstrated promising antitumor activity, with objective response rates at week 24 ranging from 25% to 63% across different cancer types, indicating its potential effectiveness in various advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. Taylor, MH., Lee, CH., Makker, V., et al.[2021]

In a meta-analysis of 6 studies involving 396 patients, the combination of pembrolizumab and chemotherapy showed a median overall survival of 9.6 months and a median progression-free survival of 4.2 months, indicating its efficacy as a first-line treatment for small-cell lung cancer (SCLC).

The treatment was associated with a manageable safety profile, with a 20.88% rate of grade 3-4 adverse effects, the most common being neutropenia and anemia, suggesting that while there are risks, the benefits may outweigh them for patients with SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Liu, Q., Zhang, Y., Liu, M., et al.[2023]

The combination of pembrolizumab and lenvatinib demonstrated significantly higher objective response rates (ORRs) and progression-free survival (mPFS) compared to their individual therapies in solid cancers, with ORRs reaching up to 70% in renal cell carcinoma.

Despite a high incidence of adverse events (68.0% for the combination therapy), the toxicities were manageable and no unexpected safety issues were reported, indicating that the combination therapy is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. Mo, DC., Luo, PH., Huang, SX., et al.[2021]

In the CLEAR study involving 352 patients, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common adverse reactions including fatigue (63.1%), diarrhea (61.9%), and hypertension (56.3%).

Most adverse reactions occurred within approximately 5 months of starting treatment, and effective management strategies such as monitoring and dose modifications were identified to ensure patient safety and support ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Motzer, R., George, S., Merchan, JR., et al.[2023]

In a phase 2 study involving 38 patients with pleural mesothelioma, the combination of pembrolizumab and lenvatinib resulted in a promising objective response rate of 58%, indicating significant anti-tumor activity after prior chemotherapy.

However, the treatment was associated with considerable toxicity, with 26% of patients experiencing serious treatment-related adverse events, including one death, highlighting the need for careful monitoring and supportive care during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. Douma, LH., Lalezari, F., van der Noort, V., et al.[2023]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

In a phase I study involving 40 patients with extensive-stage small cell lung cancer (SCLC), the combination of quavonlimab and pembrolizumab showed encouraging antitumor activity with an objective response rate (ORR) of 18%, indicating potential effectiveness in treating this aggressive cancer.

The treatment was generally well tolerated, with 80% of patients experiencing treatment-related adverse events, but only 10% facing dose-limiting toxicity, suggesting that the combination therapy has manageable safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Cho, BC., Yoh, K., Perets, R., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor targeting the PD-1 pathway, has shown significant durability of responses in previously treated patients with extensive-stage small-cell lung cancer (ES-SCLC), leading to its accelerated approval by the FDA for second- or third-line treatment.

In a recent clinical trial, pembrolizumab combined with platinum/etoposide improved progression-free survival in previously untreated ES-SCLC patients, although it did not demonstrate a significant improvement in overall survival compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. Riano, I., Patel, SR., Liu, SV., et al.[2021]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9832734/

A first-in-human study of the anti-LAG-3 antibody ... Favezelimab plus pembrolizumab vs pembrolizumab improved exploratory efficacy outcomes of survival and duration of response in MSS mCRC. •. The ...

2. merck.com merck.com/news/merck-provides-update-on-phase-3-keyform-007-trial-evaluating-investigational-fixed-dose-combination-of-favezelimab-and-pembrolizumab-for-patients-with-previously-treated-pd-l1-positive-microsatellite/

Merck Provides Update on Phase 3 KEYFORM-007 Trial ... The Phase 3 KEYFORM-007 trial evaluating the investigational fixed-dose combination of favezelimab, Merck's anti-LAG-3 antibody, and pembrolizumab (KEYTRUDA)

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05064059

NCT05064059 | A Study of Coformulated Favezelimab/ ... The primary study hypothesis is that coformulated favezelimab/pembrolizumab (MK-4280A) is superior to standard of care with respect to overall survival.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.LBA248

The phase 3, randomized KEYFORM-007 study. The phase 3 KEYFORM-007 study (NCT05064059) evaluated the efficacy and safety of co-formulated fave/pembro vs standard-of-care (SOC) in PD-L1–positive MSS/pMMR ...

5. aacrjournals.org aacrjournals.org/cancerres/article/84/7_Supplement/CT256/742469/Abstract-CT256-Results-from-KEYNOTE-B98-A-phase-1b

Abstract CT256: Results from KEYNOTE-B98: A phase 1b/2 ... The KEYNOTE-B98 study (NCT04938817) evaluated pembro in combination with investigational agents as 2L therapy for anti-PD-(L)1-refractory ES-SCLC.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37429923/

phase 2 KEYNOTE-495/KeyImPaCT trial interim results Biomarker-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results.

7. cancernetwork.com cancernetwork.com/view/vibostolimab-favezelimab-clinical-programs-in-nsclc-lymphoma-discontinued

Vibostolimab/Favezelimab Clinical Programs in NSCLC/ ... There were no concerns about the favezelimab/pembrolizumab combo's safety data ... pembrolizumab in patients with extensive- small cell lung ...

8. esmoopen.com esmoopen.com/article/S2059-7029(22)00273-3/fulltext

A first-in-human study of the anti-LAG-3 antibody ... Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was ...