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

Not currently recruiting at 283 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new combinations of cancer treatments for individuals with Stage III lung cancer that cannot be surgically removed. Researchers aim to determine if combining pembrolizumab (an immune-boosting drug) with chemoradiation, and possibly adding olaparib (a DNA repair blocker), can extend the time patients live without cancer progression compared to the usual treatment with durvalumab. Participants diagnosed with Stage III non-small cell lung cancer (NSCLC) who have not yet received treatment may be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that the combination of pembrolizumab and olaparib has been tested for safety in lung cancer patients. In one study, serious side effects related to the treatment occurred in about 26.1% to 30.1% of patients, indicating that some experienced significant issues while others did not.

The safety of pembrolizumab has also been tested with chemoradiation. Pembrolizumab is already approved for treating many types of cancer, including lung cancer, suggesting that the treatment is generally safe, though some individuals might still experience side effects.

This trial is in a later stage, which usually indicates that the treatment has shown a reasonable safety profile in earlier tests. However, discussing any concerns with a doctor is crucial, as they can provide advice based on personal health needs. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab with chemoradiation and olaparib for stage III lung cancer because it brings new potential to boost the immune system's response to cancer. Unlike standard treatments that typically include chemotherapy and radiation, pembrolizumab is an immunotherapy that works by blocking a protein called PD-1, helping the immune system recognize and attack cancer cells more effectively. Additionally, olaparib, a PARP inhibitor, may help enhance the DNA damage in cancer cells caused by chemotherapy and radiation, potentially improving efficacy. This multi-pronged approach could offer improved outcomes by tackling cancer through different mechanisms, which standard treatments don't currently combine.

What evidence suggests that this trial's treatments could be effective for Stage III Lung Cancer?

Research has shown that using pembrolizumab with chemoradiation may effectively treat stage III non-small cell lung cancer (NSCLC). In this trial, one group of participants will receive pembrolizumab with chemoradiation followed by pembrolizumab plus olaparib, while another group will receive pembrolizumab with chemoradiation followed by pembrolizumab plus a placebo for olaparib. Studies have found that patients receiving pembrolizumab with chemoradiation tend to live longer than those receiving only chemotherapy. Additionally, pembrolizumab with radiotherapy appears to enhance the body's immune response against tumors. However, adding olaparib to pembrolizumab has not significantly improved progression-free survival or overall survival in some studies. Nonetheless, pembrolizumab alone remains a strong option due to its effectiveness in similar situations. ^{6 7 8 9 10}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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 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]

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]

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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39521434/

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus ... Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC.

2. jto.org jto.org/article/S1556-0864(24)02435-3/fulltext

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus ... We report the results of phase 3, randomized KEYLYNK-006 study, which evaluated maintenance therapy with pembrolizumab plus olaparib or ...

3. aacrjournals.org aacrjournals.org/cancerres/article/84/7_Supplement/CT034/742303/Abstract-CT034-Results-from-phase-3-KEYLYNK-008

Abstract CT034: Results from phase 3 KEYLYNK-008 ... Abstract. Introduction: 1L pembro + chemo significantly improved OS vs chemo for metastatic sqNSCLC in the KEYNOTE-407 study.

4. merck.com merck.com/news/merck-provides-update-on-phase-3-keylynk-006-trial-evaluating-keytruda-pembrolizumab-plus-maintenance-lynparza-olaparib-for-certain-patients-with-metastatic-nonsquamous-non-small-cell/

Merck Provides Update on Phase 3 KEYLYNK-006 Trial ... The safety profiles of KEYTRUDA and LYNPARZA in this trial were consistent with those observed in previously reported studies for the individual ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35618629/

Rationale and Design of the Phase III KEYLYNK-012 Study of ... Conclusion: KEYLYNK-012 will provide important information on the efficacy and safety of pembrolizumab combined with concurrent chemoradiotherapy and subsequent ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8446818/

Pembrolizumab Plus Concurrent Chemoradiation Therapy in ... This nonrandomized trial evaluates the treatment outcomes and safety of pembrolizumab plus concurrent chemoradiation therapy in stage III non–small cell lung ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03631784

Study Details | NCT03631784 | A Trial of Pembrolizumab in ... This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in ...

8. keytruda.com keytruda.com/

KEYTRUDA® (pembrolizumab) - Official Site TREATS 18 TYPES OF CANCER, INCLUDING CERTAIN EARLY-STAGE AND ADVANCED CANCERS. ONE OF THOSE CANCERS IS EARLY-STAGE NON—SMALL CELL LUNG CANCER (NSCLC).

9. merck.com merck.com/news/keytruda-pembrolizumab-demonstrates-long-term-survival-benefit-in-certain-patients-with-earlier-or-advanced-stages-of-non-small-cell-lung-cancer-nsclc/

KEYTRUDA® (pembrolizumab) Demonstrates Long-Term ... “The five-year benefit demonstrated across overall survival and event-free survival from KEYNOTE-671 supports the continued use of this ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S1470204525004620

Articles Radiotherapy-free pembrolizumab combined with ... This prospective, multicentre, single-arm, phase 2 study was conducted to evaluate the efficacy and safety of pembrolizumab combined with ...