Pembrolizumab + Chemoradiotherapy/Radiation for Small Cell Lung Cancer

Overseen By James Welsh

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Immunodeficiency, Active CNS metastases, Autoimmune, others

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

Compensation: Varies

Number of Visits: 46

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the new drug pembrolizumab works when combined with chemotherapy and radiation to treat small cell lung cancer. Pembrolizumab, an immunotherapy, helps the immune system fight cancer cells. The study aims to determine the safest and most effective dose when used with other treatments. It suits individuals diagnosed with small cell lung cancer who haven't recently received immunotherapy and are not currently battling other major illnesses.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or immunosuppressive therapy, you may need to stop these at least 7 days before starting the trial treatment.

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

Research has shown that pembrolizumab is generally safe for various types of cancer. A review of 31 clinical trials found that the side effects were manageable and consistent with previous reports. When combined with radiation therapy, studies indicated that most patients did not experience severe side effects.

In studies where pembrolizumab was used with both chemotherapy and radiation (chemoradiotherapy), the safety remained manageable. These studies found that adding pembrolizumab did not lead to unexpected or severe side effects compared to other treatments. The most common side effects included tiredness, nausea, and loss of appetite, which are typical for cancer treatments.

Overall, whether used alone, with radiation, or with chemoradiotherapy, pembrolizumab has demonstrated a manageable safety profile for most patients. While side effects can occur, they are usually not severe and can be controlled. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine pembrolizumab, an immunotherapy drug, with traditional chemoradiotherapy for small cell lung cancer (SCLC). Pembrolizumab works by unleashing the immune system to attack cancer cells, offering a new mechanism of action compared to standard treatments, which typically rely on chemotherapy alone. The combination with radiation and chemotherapy could potentially enhance the effectiveness of treatment by tackling the cancer from multiple angles, potentially improving outcomes for patients with both limited-stage and extensive-stage SCLC.

What evidence suggests that this trial's treatments could be effective for small cell lung cancer?

Research has shown that pembrolizumab, one of the treatments in this trial, yields promising results for treating small cell lung cancer (SCLC) when combined with chemotherapy. In earlier studies, patients with SCLC who received pembrolizumab experienced long-lasting responses, with their cancer either stopping growth or shrinking for a significant period. Specifically, 56% of patients who responded to pembrolizumab treatment experienced benefits lasting 18 months or more.

In this trial, some participants will receive pembrolizumab combined with chemoradiotherapy (a mix of chemotherapy and radiation), which previous studies have found to be well tolerated and effective. These findings suggest that pembrolizumab, especially when used with other treatments like radiation or chemotherapy, could effectively manage SCLC. ^{3 5 6 7 8}

Who Is on the Research Team?

James Welsh

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with small cell lung cancer or neuroendocrine tumors who are in good physical condition (ECOG 0-2), have adequate organ function, and can consent to the study. Women of childbearing age must test negative for pregnancy and agree to birth control; men must also agree to use contraception. Exclusions include HIV, hepatitis B/C, recent immunosuppressive treatments, other active cancers, CNS metastases, severe autoimmune diseases, lung disease like pneumonitis, live vaccines within 30 days before treatment start.

Inclusion Criteria

My kidney function is within the required range for the study.

Your blood counts must be within a certain range for white blood cells, platelets, and hemoglobin.

Your platelet count is at least 100,000 per microliter within 10 days of starting the treatment.

Exclusion Criteria

I have received treatment with specific immune-boosting drugs.

I have a known history of HIV or active hepatitis B or C.

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pembrolizumab and undergo radiation therapy, with chemotherapy for LS-SCLC, repeated every 3 weeks for up to 16 courses

48 weeks

16 courses, each with multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

Follow-up at 30 days, then every 12 weeks

Extension

Participants who achieve systemic disease control may receive 16 additional courses of pembrolizumab

48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cisplatin
• Etoposide
• Pembrolizumab
• Radiation Therapy

Trial Overview

The trial tests how safe pembrolizumab is when combined with chemoradiotherapy or radiation therapy alone in treating small cell lung cancer. Pembrolizumab is an immunotherapy drug that may boost the immune system's response against cancer cells. The combination aims to see if it improves outcomes compared to standard chemotherapy and radiation therapy.

How Is the Trial Designed?

Group I: Part B (ES-SCLC, pembrolizumab, radiation therapy) Experimental Treatment 3 Interventions

Beginning after the completion of chemotherapy, patients receive pembrolizumab IV over 30 minutes on day 1 and undergo radiation therapy BID 5 days a week for 3 weeks. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy) in the absence of disease progression or unacceptable toxicity.

Group II: Part A (LS-SCLC, pembrolizumab, chemoradiotherapy) Experimental Treatment 6 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 and undergo radiation therapy BID 5 days a week for 3 weeks. Patients also receive cisplatin IV over 2 hours or carboplatin IV over 30 minutes and etoposide IV over 4 hours on days 1, 2, and 3. Treatment repeats every 3 weeks for 16 courses (1 course for radiation therapy, 4 courses for chemotherapy) in the absence of disease progression or unacceptable toxicity. Patients who achieve systemic disease control and do not exhibit severe (grade \> 3) pembrolizumab related toxicity during/after completion of 16 courses may receive 16 additional courses of pembrolizumab in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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 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]

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 phase I trial involving 38 patients with extensive-stage small cell lung cancer, the combination of pembrolizumab and thoracic radiotherapy was found to be safe, with no dose-limiting toxicities observed in the first 35 days of treatment.

The median progression-free survival was 6.1 months and overall survival was 8.4 months, suggesting that while the safety profile is promising, further studies are needed to fully understand the efficacy of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. Welsh, JW., Heymach, JV., Chen, D., et al.[2023]

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 55 patients with limited-stage small cell lung cancer, the combination of paclitaxel, carboplatin, and etoposide showed promising efficacy, with 37.1% achieving a complete response and 51.4% a partial response.

The treatment was associated with moderate toxicity, primarily hematologic, but no life-threatening complications were reported, indicating that the regimen is tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel, carboplatin, and oral etoposide: a phase II trial in limited-stage small cell lung cancer. Gatzemeier, U., Jagos, U., Kaukel, E., et al.[2015]

In a study of 47 patients with limited disease small-cell lung carcinoma, the combination of carboplatin and etoposide followed by thoracic radiotherapy resulted in a 73% overall response rate, but the median survival time was only 13.7 months, indicating limited long-term efficacy.

The treatment was associated with significant adverse effects, including grade 3-4 neutropenia in 46% of patients and febrile neutropenia in 14%, highlighting safety concerns despite the initial response to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and etoposide followed by once-daily thoracic radiotherapy in limited disease small-cell lung cancer: unsatisfactory results. Yilmaz, U., Anar, C., Korkmaz, E., et al.[2022]

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 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]

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