Pembrolizumab + Chemotherapy for Lung Cancer

Recruiting at 1239 trial locations

Overseen By Eric C. McGary

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Checkpoint inhibitors, Steroids

Disqualifiers: EGFR mutations, Auto-immune conditions, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 22

Duration: Up to 2 years

600 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed by pemetrexed and carboplatin with or without pembrolizumab after disease progression is superior to induction with pembrolizumab, pemetrexed and carboplatin followed by pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. It is not yet known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or without pembrolizumab works better in treating patients with non-squamous non-small cell cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before starting the trial treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of pembrolizumab and chemotherapy for lung cancer?

Research shows that combining pembrolizumab with chemotherapy, like carboplatin and pemetrexed, improves survival rates and delays cancer progression in patients with advanced non-small cell lung cancer compared to chemotherapy alone. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and chemotherapy safe for treating lung cancer?

The combination of Pembrolizumab with chemotherapy, including drugs like carboplatin and pemetrexed, has been studied for safety in treating advanced non-small cell lung cancer. Some studies report adverse events (side effects) such as kidney issues, but these are generally manageable and the treatment is considered safe for use in patients with adequate kidney function. ^{1 6 7 8 9}

What makes the drug pembrolizumab combined with carboplatin and pemetrexed unique for treating non-small cell lung cancer?

The combination of pembrolizumab with carboplatin and pemetrexed is unique because it enhances the immune system's ability to fight cancer by targeting specific proteins, leading to improved survival rates compared to chemotherapy alone, and is now a standard first-line treatment for advanced non-small cell lung cancer. ^{1 2 4 7 10}

Research Team

Hossein Borghaei

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

Adults with stage IV non-squamous non-small cell lung cancer, who have not had previous systemic chemotherapy for advanced disease. They must have a PD-L1 expression TPS of at least 1%, be in good physical condition (ECOG 0-1), and may have treated brain metastases if stable. Patients should not be pregnant or breastfeeding, must agree to use contraception, and cannot have certain serious illnesses or organ dysfunctions.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I took low-dose Methotrexate for a non-cancer condition and stopped at least 14 days ago.

My hepatitis B is under control or I am cured of hepatitis C.

Exclusion Criteria

My heart is healthy and I haven't had serious heart disease or treatments that could harm my heart.

I have NSCLC but haven't had checkpoint inhibitors for it. I've waited the required time after any previous treatments.

I haven't needed treatment for an autoimmune disease in the last 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive pembrolizumab, pemetrexed, and carboplatin in various combinations depending on the arm, with cycles repeating every 21 days

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular follow-up visits

Treatment Details

Interventions

• Carboplatin
• Pembrolizumab
• Pemetrexed

Trial Overview The trial is testing the effectiveness of pembrolizumab alone as an initial treatment followed by pemetrexed and carboplatin with/without continued pembrolizumab after disease progression versus starting with all three drugs together then maintaining with pembrolizumab and pemetrexed. It aims to see which method is better for treating patients.

Participant Groups

Group I: Arm B (pembrolizumab, pemetrexed, carboplatin) Experimental Treatment 7 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Within 6 weeks of disease progression, patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.

Group II: Arm A (pembrolizumab, pemetrexed, carboplatin) Experimental Treatment 7 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Within 6 weeks of disease progression, patients receive pemetrexed IV over 10 minutes and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then may receive pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.

Group III: Arm C (pembrolizumab, pembrolizumab, carboplatin) Active Control 7 Interventions

Patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed. Patients undergo MRI during screening, CT scan and blood sample collection throughout the study, and may undergo PET scan throughout the study.

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

Pembrolizumab, when combined with carboplatin and pemetrexed, significantly improves overall and progression-free survival rates in patients with non-small cell lung cancer (NSCLC), demonstrating its efficacy as a treatment option.

This case report highlights a unique instance of immune-mediated sarcoidosis developing in a patient with NSCLC after receiving pembrolizumab, indicating potential immune-related side effects of this therapy that require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. Fakhri, G., Akel, R., Salem, Z., et al.[2022]

In patients with metastatic non-small-cell lung cancer (NSCLC) expressing PD-L1 in ≥50% of tumor cells, pembrolizumab significantly improves progression-free and overall survival compared to traditional platinum-based chemotherapy.

Combining pembrolizumab with standard chemotherapy (pemetrexed and a platinum drug) enhances survival outcomes regardless of PD-L1 expression, indicating a broader efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. Wang, C., Kulkarni, P., Salgia, R.[2020]

Pembrolizumab, an immunotherapy for advanced non-small-cell lung cancer (NSCLC), significantly improves progression-free and overall survival compared to traditional chemotherapy, with fewer side effects, particularly in patients with high PD-L1 expression (≥50%).

In combination with pemetrexed and carboplatin, pembrolizumab also enhances treatment effectiveness and maintains manageable toxicity, leading to a shift in first-line treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck, M.[2018]

In a phase 2 study involving 216 patients with stage III non-small cell lung cancer (NSCLC), the combination of pembrolizumab and concurrent chemoradiation therapy (cCRT) showed a high objective response rate of approximately 70.5% in cohort A and 70.6% in cohort B, indicating strong antitumor activity.

The treatment was associated with manageable safety, with grade 3 or higher pneumonitis occurring in 8.0% of cohort A and 6.9% of cohort B, suggesting that while there are risks, the benefits of this treatment approach may outweigh them for patients with locally advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. Jabbour, SK., Lee, KH., Frost, N., et al.[2022]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a study of 100 patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, further stratification of PD-L1 tumor proportion score (TPS) beyond 50% did not significantly affect progression-free survival (PFS).

Smoking status was associated with improved PFS, while prior radiotherapy was linked to decreased PFS, indicating that these factors, along with performance status, may serve as important biomarkers for predicting response to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study. Mander, ES., Merrick, CB., Nicholson, HA., et al.[2023]

In a study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab and pemetrexed-carboplatin (PC) significantly improved the objective response rate (56.7% vs. 30.2% with PC alone) and progression-free survival (PFS) compared to PC alone, with a hazard ratio (HR) of 0.53.

The updated analysis showed a favorable overall survival (OS) hazard ratio of 0.56 for the pembrolizumab plus PC group, indicating a significant survival benefit, although 41% of patients experienced grade 3 to 5 treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. Borghaei, H., Langer, CJ., Gadgeel, S., et al.[2022]

In a study of 29 non-small-cell lung cancer patients treated with pemetrexed, 21% developed acute kidney injury (AKI) despite having an initial eGFR above the recommended threshold of 45 mL/min, indicating potential renal toxicity even in patients considered safe for treatment.

Patients with a baseline eGFR below 60 mL/min were more likely to experience AKI, suggesting that careful monitoring and management of renal function and risk factors are essential when administering pemetrexed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. Rombolà, G., Vaira, F., Trezzi, M., et al.[2021]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. [2022]

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

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. [2018]

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

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study. [2023]

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

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. [2022]

9. Italy pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. [2021]

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

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. [2022]