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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of pembrolizumab, an immunotherapy drug, with different types of radiation therapy to treat non-small cell lung cancer. Pembrolizumab helps the immune system target cancer cells, while radiation aims to shrink tumors. The trial tests various combinations to determine the best dose and assess their combined effectiveness. People with non-small cell lung cancer, particularly those with tumors treatable by radiation, might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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.

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

Research shows that pembrolizumab, a type of immunotherapy, is usually well-tolerated by patients with non-small cell lung cancer (NSCLC). Studies have found it to be generally safe, and it is already approved for treating various cancers, including advanced NSCLC, which provides some reassurance about its safety. However, like all treatments, it can have side effects.

The safety of pembrolizumab when combined with radiation therapy is still under investigation. Stereotactic body radiation therapy (SBRT), a precise form of radiation, causes minimal harm to nearby healthy tissues. Research indicates it is safe and effective for early-stage NSCLC, especially for patients who cannot undergo surgery.

Other radiation methods, such as intensity-modulated radiation therapy (IMRT), proton beam radiation therapy (PBRT), and 3-dimensional conformal radiation therapy (3D-CRT), are also considered safe. IMRT and PBRT are noted for causing fewer side effects, with PBRT being safer compared to some traditional radiation therapies. 3D-CRT has shown good long-term survival rates, indicating it is a safe option as well.

While the combination of these treatments is still under study, existing research supports the safety of both pembrolizumab and the radiation therapies involved. Participants might experience some side effects, but these treatments are generally considered safe based on past studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining pembrolizumab with radiation therapy for non-small cell lung cancer because this approach could enhance the immune system's ability to fight cancer. Pembrolizumab is an immunotherapy drug that blocks the PD-1 pathway, which tumors use to hide from immune cells. Unlike traditional chemotherapy, which directly attacks cancer cells, pembrolizumab works by unleashing the immune system. Adding radiation therapy, which can damage cancer cells and make them more visible to the immune system, potentially boosts pembrolizumab's effectiveness. This combination might offer a more potent attack on tumors with potentially fewer side effects than standard chemotherapy.

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

Research shows that pembrolizumab, a type of immunotherapy, helps the body's immune system fight non-small cell lung cancer. Studies have found that combining pembrolizumab with chemotherapy improves survival rates compared to chemotherapy alone. Specifically, some studies reported that about 19% of patients survived for 5 years. In this trial, participants will receive pembrolizumab with various forms of radiation therapy. One group will receive pembrolizumab with Stereotactic Body Radiation Therapy (SBRT), which precisely targets tumors while avoiding healthy tissue. Other groups will receive pembrolizumab with Intensity-Modulated Radiation Therapy (IMRT), Proton Beam Radiation Therapy (PBRT), or 3-Dimensional Conformal Radiation Therapy (3D-CRT). Combining pembrolizumab with these radiation therapies might enhance treatment effectiveness by boosting the immune system and directly killing cancer cells. ^{2 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 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

You have a history of mental health or drug problems.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2785930/

Treatment Outcomes of Three-Dimensional Conformal ... In summary, this study has demonstrated that increasing the radiation dose for NSCLC, using 3D-CRT, does not significantly increase the acute toxicities.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525730411707677

Three-Dimensional Conformal Radiation Therapy (3D-CRT ... The 2-year actuarial local control, overall survival, and cancer-specific survival rates were 43%, 54%, and 57%, respectively. The 5-year actuarial local ...

3. ro-journal.biomedcentral.com ro-journal.biomedcentral.com/articles/10.1186/s13014-016-0582-1

Patient outcomes of monotherapy with hypofractionated three ... In the present study, the 3-year survival period following 3D-CRT for localized lung cancer was comparable with, or better than, those of ...

4. jto.org jto.org/article/S1556-0864(15)30758-9/fulltext

Comparative Effectiveness of Intensity-Modulated Versus ... In a prior study, we found that adoption of 3D-RT, made possible by CT-based treatment planning, was associated with improved outcomes among patients with stage ...

5. bmjopen.bmj.com bmjopen.bmj.com/content/14/11/e090728

protocol for a systematic review and meta-analysis The combination of 3D-CRT with concurrent chemotherapy for unresectable stage III NSCLC may improve local tumour control and potentially prolong survival.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39515858/

protocol for a systematic review and meta-analysis We will conduct a meta-analysis to evaluate the efficacy and safety of 3D-CRT concurrent chemotherapy in unresectable stage III NSCLC.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02720614

Study Details | NCT02720614 | Hypofractionated Radiation ... The purpose of this study is to evaluate the safety of accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) concurrent ...

8. ajronline.org ajronline.org/doi/abs/10.2214/ajr.178.6.1781383

Radiation Injury of the Lung After Three-Dimensional ... The objective of this study is to describe the CT patterns of radiation injury in the lungs of patients who have undergone three-dimensional (3D) conformal ...