Pembrolizumab Combinations for Small Cell Lung Cancer

Recruiting at26 trial 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%. ^{1 2 3 4 5}

What 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. ^{1 6 7 8 9}

What 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. ^{1 5 10 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility 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.

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.

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

Treatment Details

Interventions

• Favezelimab (PD-1/PD-L1 Inhibitor)
• Lenvatinib (Tyrosine Kinase Inhibitor)
• MK-4830 (Other)
• Pembrolizumab (PD-1/PD-L1 Inhibitor)
• Quavonlimab (PD-1/PD-L1 Inhibitor)

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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 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]

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]

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 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]

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]

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]

References

1. United States 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

3. England 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. [2023]

4. United States 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. [2021]

5. Ireland 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. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]

9. England 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. [2023]

10. United States 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. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. [2021]

12. England 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. [2023]