Pembrolizumab + Radiation Therapy for Non-Small Cell Lung Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Autoimmune disease, Active infection, others

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

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: 45

126 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

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, unless it's for physiological replacement.

What data supports the effectiveness of the treatment Pembrolizumab + Radiation Therapy for Non-Small Cell Lung Cancer?

Research shows that combining pembrolizumab (a drug that helps the immune system fight cancer) with radiation therapy may enhance the body's ability to control non-small cell lung cancer. Studies have indicated that this combination can provide treatment benefits and improve disease control in patients with advanced stages of this cancer. ^{1 2 3 4 5}

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

Pembrolizumab, used in various cancers, can cause side effects like fatigue, cough, and more serious immune-related issues such as pneumonitis (lung inflammation) and thyroid problems. When combined with radiation therapy, there may be an increased risk of immune-related side effects, as seen in a case of severe thrombocytopenia (low platelet count) following treatment. ^{2 4 6 7 8}

How is the drug pembrolizumab combined with radiation therapy unique for treating non-small cell lung cancer?

Pembrolizumab is a unique drug because it is an immune checkpoint inhibitor that helps the body's immune system attack cancer cells by blocking the PD-1 pathway, which is different from traditional chemotherapy. When combined with radiation therapy, it may enhance the immune response against cancer, offering a novel approach for treating non-small cell lung cancer. ^{2 4 5 7 9}

What is the purpose of this trial?

This randomized phase I/II trial studies the side effects and best dose of pembrolizumab when given together with stereotactic body radiation therapy or non-stereotactic wide-field radiation therapy (conventional radiation therapy) and to see how well they work in treating patients with non-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 tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab together with radiation therapy may kill more tumor cells.

Research Team

James Welsh

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with non-small cell lung cancer, including those with Stage IV metastatic disease. Participants must have at least one measurable tumor and be in good physical condition (ECOG 0 or 1). They should not be pregnant or breastfeeding, agree to use contraception, and meet specific blood criteria. Those with brain metastases can join under certain conditions but cannot have autoimmune diseases, recent monoclonal antibody treatments, or other disqualifying medical issues.

Inclusion Criteria

I have had radiation therapy to areas other than the cancer site before joining this study.

Your blood and body chemistry need to meet certain standards.

My cancer is in stage IV and has spread to other parts of my body.

Exclusion Criteria

I have recently received a live vaccine.

Participation in other investigational studies within a specified timeframe

I have an immune system disorder or I'm taking steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase I

Patients receive pembrolizumab and either SBRT or WFRT. Treatment repeats every 21 days for up to 16 courses.

Up to 48 weeks

Every 21 days

Treatment Phase II

Patients are randomized to receive pembrolizumab with or without radiation therapy, depending on lesion characteristics.

Up to 48 weeks

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes CT scans every 3 months.

Up to 5 years

Every 3 months

Treatment Details

Interventions

• 3-Dimensional Conformal Radiation Therapy
• Intensity-Modulated Radiation Therapy
• Pembrolizumab
• Proton Beam Radiation Therapy
• Stereotactic Body Radiation Therapy

Trial Overview The trial is testing the combination of Pembrolizumab (an immunotherapy drug) with different types of radiation therapy: Stereotactic Body Radiation Therapy which targets tumors precisely over fewer sessions, or conventional wide-field radiation therapy. The goal is to determine the best dose and effectiveness in shrinking tumors by enhancing the body's immune response against cancer cells.

Participant Groups

Group I: Group V, Phase II (low dose radiation therapy) Experimental Treatment 7 Interventions

Patients with lesions amenable to SBRT or WFRT receive pembrolizumab IV as in Group I. Patients also receive either IMRT, PBRT, or 3D-CRT in 15 fractions to the primary lesions and low dose radiation therapy to other lesions on days 43-61 or SBRT in 4 fractions to primary lesions and low dose radiation therapy to other lesions on days 44-47.

Group II: Group IV, Phase II (pembrolizumab + XRT upon PD) Experimental Treatment 5 Interventions

Patients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I without XRT. The decision on when to start XRT will be assessed first at week 5 (after the second dose of pembrolizumab). If a patient has PD based on irRC then XRT will be delivered after the third dose of pembrolizumab, while patients with SD or PR will not start XRT and will continue to be followed. These patients will then have follow up CT scans 5 weeks after course 3 and then approximately every 3 months for the remainder of the trial; any patient at this point with PD will then have XRT delivered with the sixth dose of pembrolizumab.

Group III: Group III, Phase II (pembrolizumab + IMRT, PBRT, or 3D-CRT) Experimental Treatment 4 Interventions

Patients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I and IMRT, PBRT, or 3D-CRT on days 43-61.

Group IV: Group II, Phase II (pembrolizumab + XRT upon PD) Experimental Treatment 6 Interventions

Patients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV as in Group I without XRT. At the first planned efficacy evaluation (5 weeks), patients exhibiting PD are treated with SBRT concurrent with the remaining cycles of pembrolizumab. In the event that lesion size has progressed to the point where the attending physician no longer considers SBRT safe, then the patient will be salvaged with IMRT, PBRT, or 3D-CRT and analyzed as part of the fourth treatment group.

Group V: Group II, Phase I (pembrolizumab + IMRT, PBRT or 3D-CRT) Experimental Treatment 5 Interventions

Patients who exhibit a lung lesion of size or location not amenable to SBRT, but amenable to WFRT receive pembrolizumab as in Group I and either IMRT, PBRT, or 3D-CRT in 15 fractions total on days 1-19 concurrent with pembrolizumab administration.

Group VI: Group I, Phase II (pembrolizumab + SBRT) Experimental Treatment 3 Interventions

Patients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV on day 1 and SBRT on days 44-47 or IMRT, PBT, or 3D-CRT on days 43-61. Treatment with pembrolizumab repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

Group VII: Group I, Phase I (pembrolizumab + SBRT) Experimental Treatment 6 Interventions

Patients who exhibit a lung lesion of size and location amenable to SBRT receive pembrolizumab IV over 30 minutes on day 1. Patients also receive SBRT in 4 fractions daily on days 2-5 or either IMRT, PBRT, or 3D-CRT in 15 fractions total concurrent with pembrolizumab administration on days 1-19. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a study of 98 patients with advanced non-small-cell lung cancer (NSCLC), those who had previously received radiotherapy experienced significantly longer progression-free survival (4.4 months) and overall survival (10.7 months) when treated with pembrolizumab compared to those without prior radiotherapy.

The safety profile was acceptable, with similar rates of severe pulmonary toxicity between patients who had and had not received thoracic radiotherapy, suggesting that combining radiotherapy with pembrolizumab may be a beneficial treatment strategy for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Shaverdian, N., Lisberg, AE., Bornazyan, K., 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 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]

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 (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

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]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase I/II trial. [2021]

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

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. [2022]

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. 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]

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

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

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

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

8. Japan pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]