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

83 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of pembrolizumab when given together with chemoradiotherapy or radiation therapy in treating patients with 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. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more cancer cells. Giving pembrolizumab with chemoradiotherapy or radiation therapy may be a better treatment for small cell lung cancer.

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.

What data supports the effectiveness of the treatment Pembrolizumab + Chemoradiotherapy/Radiation for Small Cell Lung Cancer?

The KEYNOTE-604 study showed that pembrolizumab, when combined with etoposide and platinum, has antitumor activity in patients with extensive-stage small-cell lung cancer. Additionally, pembrolizumab plus concurrent chemoradiation therapy has shown treatment benefits in patients with non-small cell lung cancer, suggesting potential effectiveness in similar settings. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Carboplatin, Etoposide, and Radiation Therapy safe for humans?

Pembrolizumab, when used with chemotherapy, has been generally safe but can cause serious side effects like pneumonitis (lung inflammation) in a small percentage of patients. The combination of Carboplatin and Etoposide has shown moderate toxicity, including blood-related side effects, but no life-threatening complications in small cell lung cancer patients. Radiation therapy is commonly used and generally safe, but it can have side effects depending on the dose and area treated. ^{6 7 8 9 10}

How is the treatment with pembrolizumab and chemoradiotherapy for small cell lung cancer different from other treatments?

This treatment is unique because it combines pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with chemoradiotherapy, which uses both chemotherapy and radiation to target cancer. This combination aims to enhance the effectiveness of traditional therapies by adding an immune-based approach, which has shown promise in improving outcomes for patients with extensive-stage small cell lung cancer. ^{1 2 3 11 12}

Research Team

James Welsh

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

I have received treatment with specific immune-boosting drugs.

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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 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]

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]

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]

References

1. United States 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. [2021]

2. Ireland pubmed.ncbi.nlm.nih.gov

A phase II study of pembrolizumab and paclitaxel in patients with relapsed or refractory small-cell lung cancer. [2020]

3. 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]

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

Carboplatin and etoposide followed by once-daily thoracic radiotherapy in limited disease small-cell lung cancer: unsatisfactory results. [2022]

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

Rationale and Design of the Phase 3 KEYLYNK-013 Study of Pembrolizumab With Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Limited-Stage Small-Cell Lung Cancer. [2022]

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

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

7. 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]

8. 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]

9. 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]

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

Paclitaxel, carboplatin, and oral etoposide: a phase II trial in limited-stage small cell lung cancer. [2015]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. [2021]

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

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. [2023]