Pembrolizumab + Olaparib/Pemetrexed for Non-Small Cell Lung Cancer

Recruiting at 177 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Steroids, PARP inhibitors

Disqualifiers: Squamous NSCLC, CNS metastases, Autoimmune, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 35

1003 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is comparing two treatment combinations for a specific type of lung cancer. It aims to find out which combination helps patients live longer and keeps their cancer from getting worse. The treatments work by boosting the immune system, making it harder for cancer cells to repair themselves, or stopping their growth.

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 prior systemic treatment for their advanced/metastatic NSCLC.

What data supports the effectiveness of the drug combination Pembrolizumab and Pemetrexed for Non-Small Cell Lung Cancer?

Research shows that Pembrolizumab, when used with Pemetrexed and Carboplatin, significantly improved response rates and survival in advanced non-small cell lung cancer compared to chemotherapy alone, with manageable side effects. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and other drugs generally safe for humans?

Pembrolizumab, used in various cancer treatments, can cause side effects like rash, fatigue, and hypothyroidism (underactive thyroid), and in rare cases, pneumonitis (lung inflammation). However, some patients who experienced these side effects had better treatment outcomes. ^{1 3 5 6 7}

How is the drug Pembrolizumab + Olaparib/Pemetrexed unique for treating non-small cell lung cancer?

This treatment combines pembrolizumab, an immune system booster that helps the body attack cancer cells, with either olaparib or pemetrexed, which target cancer cell growth in different ways. This combination is unique because it uses both immune system activation and direct cancer cell targeting, offering a potentially more effective approach than using these drugs separately. ^{1 3 5 8 9}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with stage IV nonsquamous NSCLC who haven't had prior treatments. They must have a life expectancy of at least 3 months, be able to use contraception, and not be pregnant. Participants need good organ function and no severe allergies to the drugs being tested or their ingredients.

Inclusion Criteria

I haven't had systemic treatment for my advanced lung cancer.

My lung cancer is advanced (stage IV) and not squamous.

I have provided a biopsy sample of my tumor that has not been treated with radiation.

Exclusion Criteria

I have been treated for an autoimmune disease in the last 2 years.

You have had a serious allergic reaction (Grade 3 or higher) to pembrolizumab or any of its ingredients.

My lung cancer is mainly squamous cell type.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive pembrolizumab plus pemetrexed plus platinum chemotherapy for up to 4 cycles

12 weeks

4 visits (in-person)

Maintenance

Participants receive pembrolizumab plus maintenance olaparib or maintenance pemetrexed for up to 31 cycles

93 weeks

31 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Second Course (optional)

Eligible participants may receive a second course of pembrolizumab for up to 17 cycles

51 weeks

Treatment Details

Interventions

• Olaparib
• Pembrolizumab
• Pemetrexed

Trial Overview The study compares two treatments: pembrolizumab combined with olaparib versus pembrolizumab with pemetrexed after initial therapy. It aims to see which combination is better for extending patients' lives without cancer progression and overall survival.

Participant Groups

Group I: Pembrolizumab + Pemetrexed + Platinum Therapy + Olaparib Experimental Treatment 5 Interventions

For the Induction Phase, participants receive 4 cycles (up to \~12 weeks \[cycle = 3 weeks\]): pembrolizumab 200 mg intravenous (IV) on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m\^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin area under the curve (AUC) 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m\^2 IV on Day 1 of each cycle (Cycles 1 through 4). If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance oral olaparib 300 mg twice daily. The participant can continue to receive maintenance olaparib until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to \~35 cycles (up to \~2 years \[cycle = 3 weeks\]).

Group II: Pembrolizumab + Pemetrexed + Platinum Therapy + Pemetrexed Active Control 4 Interventions

For the Induction Phase, participants receive 4 cycles (up to \~12 weeks \[cycle = 3 weeks\]): pembrolizumab 200 mg IV on Day 1 of each cycle (cycles 1 through 4) PLUS pemetrexed 500 mg/m\^2 IV on Day 1 of each cycle (cycles 1 through 4) PLUS platinum chemotherapy, investigator's choice: carboplatin AUC 5 mg/mL/min IV on Day 1 of each cycle (Cycles 1 through 4) OR cisplatin 75 mg/m\^2 IV on Day 1 of each cycle (Cycles 1 through 4). If the participant has a complete/partial response or stable disease to induction therapy, the participant can enter the Maintenance Phase and receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 31 cycles PLUS maintenance pemetrexed 500 mg/m\^2 IV on Day 1 of each 3-week cycle. The participant can continue to receive maintenance pemetrexed until progressive disease or toxicity. Across both phases, participants can receive pembrolizumab for a total treatment duration of up to \~35 cycles (up to \~2 years \[cycle = 3 weeks\]).

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

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

Findings from Research

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a study of 97 non-small cell lung cancer patients treated with pembrolizumab, 40% experienced treatment-related adverse events (trAEs), with common ones being rash, fatigue, and hypothyroidism.

Patients who experienced trAEs had significantly better clinical outcomes, including a higher objective response rate (38.5% vs. 8.9%), longer progression-free survival (248 days vs. 60 days), and longer overall survival (493 days vs. 144.5 days), suggesting that trAEs may be indicative of a positive response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center. Lisberg, A., Tucker, DA., Goldman, JW., et al.[2022]

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]

In a study of 1,026 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) and PD-L1 expression of ≥50%, pembrolizumab showed an objective response rate of 44.5%, with median progression-free survival of 7.9 months and overall survival of 17.2 months.

Higher PD-L1 expression (≥90%) was linked to better treatment outcomes, while factors like poor performance status and the presence of bone or liver metastases were associated with worse clinical outcomes, indicating the importance of patient selection for pembrolizumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. Cortellini, A., Tiseo, M., Banna, GL., et al.[2020]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. [2022]

3. France pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. [2017]

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

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center. [2022]

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

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

9. Germany pubmed.ncbi.nlm.nih.gov

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. [2020]