Pembrolizumab + Chemoradiation +/- Olaparib for Stage III Lung Cancer

Recruiting at 214 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Small cell lung cancer, MDS/AML, 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: Unknown

Duration: 52 weeks

870 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the efficacy and safety of pembrolizumab in combination with concurrent chemoradiation therapy followed by either pembrolizumab with olaparib placebo (Arm 1) or with olaparib (Arm 2) compared to concurrent chemoradiation therapy followed by durvalumab (Arm 3) in participants with unresectable, locally advanced NSCLC. Arms 1 and 2 will be studied in a double-blind design and Arm 3 will be open-label. The primary hypotheses are: 1. Pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with olaparib is superior to concurrent chemoradiation therapy followed by durvalumab with respect to progression-free survival (PFS) and overall survival (OS) 2. Pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab is superior to concurrent chemoradiation therapy followed by durvalumab with respect to PFS and OS

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, specifically strong or moderate inducers or inhibitors of CYP3A4, and aspirin or NSAIDs above a certain dose. If you are on these medications, you will need to discontinue them for the duration of the study.

What data supports the effectiveness of the treatment Pembrolizumab + Chemoradiation +/- Olaparib for Stage III Lung Cancer?

Research shows that pembrolizumab, when combined with chemotherapy and radiotherapy, improves survival rates in non-small-cell lung cancer (NSCLC). Additionally, studies like KEYNOTE-189 have demonstrated that pembrolizumab with chemotherapy significantly enhances overall survival and progression-free survival in NSCLC patients. ^{1 2 3 4 5}

Is the combination of pembrolizumab, chemotherapy, and radiation generally safe for humans?

Studies have shown that the combination of pembrolizumab with chemotherapy drugs like carboplatin and pemetrexed is generally safe, though it can cause side effects such as kidney issues and blood-related problems. These side effects vary in severity, and safety has been confirmed in different cancer types, including lung and esophageal cancer. ^{6 7 8 9 10}

What makes the treatment with pembrolizumab, chemoradiation, and possibly olaparib unique for stage III lung cancer?

This treatment is unique because it combines pembrolizumab, an immunotherapy drug that helps the immune system fight cancer, with chemoradiation, and possibly olaparib, which may enhance the treatment's effectiveness. This approach is being studied to see if it improves outcomes for patients with stage III non-small cell lung cancer compared to standard treatments. ^{3 4 5 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with Stage III NSCLC who haven't had previous treatments for this stage, can't have surgery to cure it, and don’t have metastatic (Stage IV) disease. They should be expected to live at least 6 months, able to perform daily activities with little or no help (ECOG 0-1), and must agree to use contraception.

Inclusion Criteria

My lung cancer has not spread to other parts of my body.

My lung cancer is at stage IIIA, IIIB, or IIIC.

You are expected to live for at least 6 months.

Exclusion Criteria

Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

I have had radiation therapy to my chest area before.

I have been treated with specific immune therapy for cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation

Participants receive 3 cycles of platinum doublet chemotherapy with concurrent standard thoracic radiotherapy (60 Gy over 6 weeks)

6 weeks

Treatment

Participants receive pembrolizumab with or without olaparib or durvalumab for approximately 1 year

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

72 months

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Durvalumab
• Etoposide
• Olaparib
• Paclitaxel
• Pembrolizumab
• Pemetrexed
• Placebo for Olaparib
• Thoracic Radiotherapy

Trial Overview The study tests pembrolizumab combined with chemoradiation followed by either pembrolizumab plus olaparib placebo or just olaparib versus chemoradiation followed by durvalumab. It aims to see if the first two methods are better than the third in improving survival without cancer progression.

Participant Groups

Group I: pembrolizumab+chemoradiation→pembrolizumab+olaparib placebo Experimental Treatment 8 Interventions

Participants will receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) in combination with 3 cycles of the investigator's choice of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gray (Gy) over 6 weeks) followed by pembrolizumab plus olaparib placebo twice a day (BID) for approximately 1 year.

Group II: pembrolizumab+chemoradiation→pembrolizumab+olaparib Experimental Treatment 8 Interventions

Participants will receive pembrolizumab 200 mg IV Q3W in combination with 3 cycles of the investigator's choice of platinum doublet chemotherapy and concurrent standard thoracic radiotherapy (60 Gy over 6 weeks) followed by pembrolizumab plus olaparib 300 mg BID for approximately 1 year.

Group III: chemoradiation→durvalumab Active Control 7 Interventions

Participants will receive 3 cycles of the investigator's choice of platinum doublet chemotherapy with concurrent standard thoracic radiotherapy (60 Gy over 6 weeks) followed by durvalumab 10 mg/kg every 2 weeks (Q2W) for approximately 1 year.

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?

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

Cisplatin combined with other agents like vinblastine or etoposide shows promise as an effective pre-radiotherapy treatment for locally advanced non-small cell lung cancer (NSCLC), but optimal scheduling is still being researched.

In a study of 170 patients, concurrent chemotherapy with carboplatin and radiation led to increased toxicity, including significantly higher rates of neutropenia and thrombocytopenia, indicating that while this approach may improve treatment efficacy, it also raises safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. Bishop, JF.[2019]

In the phase III KEYNOTE-189 study, pembrolizumab combined with pemetrexed and platinum-based chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in patients with untreated metastatic nonsquamous non-small-cell lung cancer, with a hazard ratio of 0.56 for OS and 0.49 for PFS after a median follow-up of 31 months.

The treatment was associated with a high objective response rate (ORR) of 48.3% compared to 19.9% for the placebo group, and among patients who completed 35 cycles of pembrolizumab, the ORR was even higher at 85.7%, indicating strong efficacy with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Rodríguez-Abreu, D., Powell, SF., Hochmair, MJ., et al.[2022]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

In the KEYNOTE-189 study, first-line treatment with pembrolizumab combined with pemetrexed-platinum significantly improved overall survival (OS) to a median of 22.0 months compared to 10.7 months for the placebo group, indicating a strong efficacy in treating metastatic nonsquamous non-small-cell lung cancer (NSCLC).

The combination therapy also resulted in a median progression-free survival (PFS) of 9.0 months versus 4.9 months for placebo, with benefits observed regardless of tumor PD-L1 expression or the presence of liver/brain metastases, while maintaining a similar incidence of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. Gadgeel, S., Rodríguez-Abreu, D., Speranza, G., et al.[2021]

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]

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 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 a study of 42 lung cancer patients receiving pemetrexed plus carboplatin, 19% experienced severe hematologic toxicities during the first cycle of chemotherapy, highlighting the significant risk associated with this treatment regimen.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) was found to significantly increase the risk of severe hematologic toxicities, suggesting that drug interactions may play a critical role in the toxicity experienced by patients, rather than renal function alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study. Kawazoe, H., Yano, A., Ishida, Y., et al.[2022]

In a safety analysis of 6 patients with locally advanced esophageal cancer, the combination of pemetrexed, carboplatin, and radiation followed by surgery showed a favorable safety profile, with only one patient experiencing a severe adverse event (grade 4 neutropenia).

The treatment resulted in promising outcomes, with one patient achieving a complete pathologic response and three showing partial responses, indicating potential efficacy that warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed, Carboplatin, and Concomitant Radiation followed by Surgery for Locally Advanced Esophageal Cancer: Results of a Planned Interim Toxicity Analysis of North Central Cancer Treatment Group Study N044E. Katipamula, R., Jatoi, A., Foster, NR., et al.[2021]

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]

In a study involving 9 patients with resectable stage IIIA non-small cell lung cancer (NSCLC), the addition of pembrolizumab to neoadjuvant chemotherapy and radiotherapy resulted in a promising 67% overall response rate, with 4 patients achieving a pathologic complete response.

However, the trial faced significant safety concerns, with serious adverse events occurring in 7 patients, including 2 fatal events, leading to the study's closure due to higher-than-expected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC. Lemmon, CA., Videtic, GMM., Murthy, S., et al.[2022]

References

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

Scheduling of chemotherapy and radiotherapy in locally advanced non-small cell lung cancer. [2019]

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

Phase I/II Study of Cisplatin plus Nab-Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. [2022]

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

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

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

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. [2021]

6. 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]

7. 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]

8. 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]

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

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Pemetrexed, Carboplatin, and Concomitant Radiation followed by Surgery for Locally Advanced Esophageal Cancer: Results of a Planned Interim Toxicity Analysis of North Central Cancer Treatment Group Study N044E. [2021]

11. 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]

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

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC. [2022]