Chemoimmunotherapy + Radiation for Lung Cancer

(NEORADJUVANT Trial)

Recruiting at 3 trial locations

Overseen By Caitlin Eggleston, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Maryland, Baltimore

Must not be taking: Corticosteroids, Immunosuppressants, Anti-PD-(L)1

Disqualifiers: Metastatic disease, Brain metastases, Autoimmune, 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

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to find out if adding radiation prior to chemoimmunotherapy and surgery is effective for people with non-small cell lung cancer (NSCLC) who have the potential for surgery. Standard of Care Chemoimmunotherapy: For this study, standard of care chemotherapy will be used. This means this is the type of chemotherapy that is normal for your cancer. In addition to the chemotherapy, you will also receive the immunotherapy drug, nivolumab. This will be administered intravenously once every 3 weeks for up to 3 cycles (i.e. 9 weeks of total systemic therapy), prior to surgical resection assessment. This combination is made up of the chemotherapy drugs carboplatin or cisplatin along with pemetrexed, paclitaxel or gemcitabine, and the immunotherapy drug is nivolumab. The chemotherapy is used to kill cancer cells, and the immunotherapy enables your immune system to attack cancer cells. Stereotactic Body Radiation Therapy (SBRT) SBRT is when radiation is delivered at higher doses over a smaller period of time. For this study, you will receive three doses of radiation delivered every other day, for three total days. The final dose of radiation will happen within 7 days of starting chemoimmunotherapy. You will be followed for up to 100 days following your last chemoimmunotherapy dose to monitor for potential side effects. Following this you will continue with your standard follow up with your doctor. During the standard follow-up time, study staff will review your charts to see if there have been any new updates with your cancer following treatment so they can tell how this treatment affects how long patients live and whether it helps avoid recurrence of the cancer.

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 corticosteroids or other immunosuppressive medications, you may need to stop them 14 days before enrolling in the study.

What data supports the effectiveness of the treatment Chemoimmunotherapy + Radiation for Lung Cancer?

Research shows that combining radiation with nivolumab (an immune therapy drug) can improve survival in patients with advanced non-small cell lung cancer. Radiation may enhance the cancer-fighting effects of nivolumab, leading to better outcomes. ^{1 2 3 4 5}

Is the combination of chemoimmunotherapy and radiation safe for lung cancer patients?

The safety of combining chemoimmunotherapy and radiation for lung cancer is still being studied, with some reports of lung and heart-related side effects. More research and longer follow-up are needed to fully understand the risks. ^{6 7 8 9 10}

How is the treatment Nivolumab combined with radiation unique for lung cancer?

This treatment is unique because it combines Nivolumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with radiation therapy, which may enhance the immune response against the tumor. This combination aims to improve outcomes in lung cancer by potentially overcoming resistance and enhancing the effects of both treatments. ^{1 3 5 11 12}

Eligibility Criteria

This trial is for individuals with borderline resectable non-small cell lung cancer (NSCLC) who may be candidates for surgery. Participants should not have had prior treatments for NSCLC and must be able to undergo chemotherapy, immunotherapy with nivolumab, and stereotactic body radiation therapy (SBRT).

Inclusion Criteria

I don't have any major health issues that make surgery too risky.

I have confirmed I am not pregnant through a test in the last 30 days.

My case has been reviewed by a team of lung cancer experts.

Exclusion Criteria

I do not have an active autoimmune disease that prevents immunotherapy.

I am allergic to nivolumab or certain chemotherapy drugs.

History of allogeneic organ transplantation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive three doses of stereotactic body radiation therapy (SBRT) delivered every other day over three days

1 week

Chemoimmunotherapy

Participants receive standard of care chemotherapy and the immunotherapy drug nivolumab intravenously every 3 weeks for up to 3 cycles

9 weeks

Follow-up

Participants are monitored for potential side effects for up to 100 days following the last chemoimmunotherapy dose

14 weeks

Long-term follow-up

Participants continue with standard follow-up with their doctor, and study staff review charts for updates on cancer status

1 year post completion of accrual

Treatment Details

Interventions

• Chemotherapy
• Nivolumab
• SBRT

Trial Overview The study tests if adding SBRT before standard chemoimmunotherapy improves outcomes in NSCLC patients eligible for surgery. Patients receive three doses of SBRT followed by up to three cycles of chemotherapy combined with the immunotherapy drug nivolumab before a surgical assessment.

Participant Groups

Group I: SBRT+Chemoimmunotherapy +/-Surgery Experimental Treatment 4 Interventions

Standard of care chemotherapy along with nivolumab. Nivolumab will be infused every 3 weeks for up to 3 cycles. Chemotherapy options include: carboplatin or cisplatin along with pemetrexed, paclitaxel or gemcitabine. Concurrently patient will receive 3 fractions of SBRT. Patient will then be evaluated for possible surgical resection.

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

In a feasibility study involving six patients with advanced non-small-cell lung cancer, nivolumab was administered after stereotactic radiation therapy, showing good tolerance with only one case of Grade 3 pneumonitis and no other serious adverse events.

The combination treatment resulted in one complete response and two partial responses, indicating potential effectiveness, especially in patients with lesions outside the irradiated area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and stereotactic radiation therapy for the treatment of patients with Stage IV non-small-cell lung cancer. Miyamoto, S., Nomura, R., Sato, K., et al.[2022]

The RTOG 3505 study is investigating the effectiveness of combining concurrent chemoradiation with the immune checkpoint inhibitor nivolumab in patients with locally advanced non-small-cell lung cancer, aiming to improve overall survival and progression-free survival.

With a planned enrollment of 660 patients, the study is designed to have sufficient power to detect significant differences in survival outcomes, ensuring robust results regarding the efficacy of nivolumab compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). Gerber, DE., Urbanic, JJ., Langer, C., et al.[2018]

The combination of PD-1/PD-L1 blockade with thoracic radiotherapy is now the standard treatment for locally advanced non-small-cell lung cancer, but safety data is primarily from retrospective studies and small clinical trials.

There is a need for longer and more rigorous follow-up studies to better understand the pulmonary safety and potential toxicity of this combined therapy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy. Li, M., Gan, L., Song, A., et al.[2019]

In a study of 60 patients receiving combined immunotherapy and thoracic radiation therapy (iRT), no patients experienced severe grade ≥4 toxicities, indicating a favorable safety profile for this treatment approach.

While some patients did experience grade 3 toxicities, particularly pulmonary and hematologic issues, the overall short-term safety of iRT suggests it can be administered without significant risk of severe adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. Verma, V., Cushman, TR., Selek, U., et al.[2022]

Concurrent immunoradiotherapy, combining immune checkpoint inhibitors with radiotherapy, showed a 30% overall response rate in 16 patients with metastatic melanoma who had progressed on nivolumab, with a notable 68.8% response rate in lesions within the radiation fields.

Nivolumab combined with radiotherapy demonstrated a 100% response rate inside the radiation fields, suggesting it may be more effective than ipilimumab in this setting, although some patients experienced grade 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. Nomura, M., Otsuka, A., Yoshimura, M., et al.[2019]

Radiation therapy (RT) is crucial for controlling non-small cell lung cancer (NSCLC), but it often fails to prevent distant metastases, leading to poor patient outcomes.

Recent advancements in combining RT with immune checkpoint blockade immunotherapy show promise in enhancing systemic anti-tumor responses in NSCLC, similar to successful strategies seen in melanoma, with ongoing clinical trials exploring this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experiences of combining immunotherapy and radiation therapy in non-small cell lung cancer: lessons from melanoma. Kalbasi, A., Rengan, R.[2020]

References

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

Nivolumab and stereotactic radiation therapy for the treatment of patients with Stage IV non-small-cell lung cancer. [2022]

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

Radiotherapy and immune checkpoint blockade: potential interactions and future directions. [2020]

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

Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). [2018]

4. England pubmed.ncbi.nlm.nih.gov

Radiation therapy for augmenting the efficacy of immunotherapy in advanced non-small cell lung cancer: a case-controlled study. [2020]

5. Singapore pubmed.ncbi.nlm.nih.gov

Radiotherapy is an independent prognostic marker of favorable prognosis in non-small cell lung cancer patients after treatment with the immune checkpoint inhibitor, nivolumab. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy. [2019]

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

Safety of Combined Immunotherapy and Thoracic Radiation Therapy: Analysis of 3 Single-Institutional Phase I/II Trials. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. [2019]

9. Italy pubmed.ncbi.nlm.nih.gov

Benefit of ablative versus palliative-only radiotherapy in combination with nivolumab in patients affected by metastatic kidney and lung cancer. [2020]

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

PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. [2022]

11. China pubmed.ncbi.nlm.nih.gov

Locally-advanced non-small cell lung cancer: shall immunotherapy be a new chance? [2020]

12. China pubmed.ncbi.nlm.nih.gov

Clinical experiences of combining immunotherapy and radiation therapy in non-small cell lung cancer: lessons from melanoma. [2020]