Immunotherapy for Lung Cancer

(RIVAL Trial)

Recruiting at 6 trial locations

Overseen By Garth W Strohbehn, MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of a new treatment for individuals with unresectable Stage III NSCLC, a specific type of lung cancer. The treatment combines Nivolumab (an immunotherapy), chemotherapy, and radiation therapy. Researchers seek participants with this lung cancer type whose tumors express a marker called PD-L1. Participants should not have other health issues such as autoimmune diseases or HIV. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or corticosteroids, you may need to stop or adjust them, as these are part of the exclusion criteria.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that nivolumab, the treatment under study, has a safety record similar to that observed in other clinical trials. In patients with non-small cell lung cancer (NSCLC), nivolumab is usually well-tolerated, though some serious side effects have been noted. These include pneumonia in about 11% of patients and trouble swallowing in about 7% of patients.

This treatment has demonstrated an acceptable safety record in other lung cancer studies. This trial combines nivolumab with chemotherapy and radiation therapy, which could alter the presentation of side effects. It is important to discuss with the research team to understand what this might mean for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for lung cancer, which typically involves chemotherapy and radiation, Nivolumab (Opdivo) offers a unique approach by harnessing the body's immune system to fight cancer. This immunotherapy works by blocking the PD-1 pathway, which tumors often use to hide from immune cells. By doing so, Nivolumab enables the immune system to recognize and attack cancer cells more effectively. Researchers are excited about this treatment because it has the potential to improve outcomes and provide a more targeted approach with potentially fewer side effects compared to traditional chemotherapy.

What evidence suggests that this treatment might be an effective treatment for lung cancer?

Studies have shown that nivolumab, also known as Opdivo, effectively treats non-small cell lung cancer (NSCLC). Research indicates that patients receiving nivolumab, either alone or with chemotherapy, lived longer on average than those receiving only traditional chemotherapy. In this trial, participants will receive a combination of nivolumab with platinum-doublet chemotherapy followed by radiotherapy. Nivolumab, an immunotherapy, helps the body’s immune system fight cancer cells. Patients who took nivolumab had better responses to treatment and experienced fewer side effects compared to those who took treatments like docetaxel. Overall, nivolumab has improved survival and treatment response in both squamous and non-squamous types of NSCLC. ^{3 6 7 8 9}

Who Is on the Research Team?

Michael D Green

Principal Investigator

VA Ann Arbor Healthcare System, Ann Arbor, MI

Nithya Ramnath, MBBS

Principal Investigator

VA Ann Arbor Healthcare System, Ann Arbor, MI

Are You a Good Fit for This Trial?

This trial is for veterans with Stage III NSCLC that can't be removed by surgery. Participants should meet certain health standards, but specific inclusion and exclusion criteria are not listed.

Inclusion Criteria

My cancer shows PD-L1 expression of 1% or more.

Presence of measurable disease according to RECIST v1.1

My organs are working well.

Exclusion Criteria

Inability to provide informed consent

I have an autoimmune disease and have taken immunosuppressive drugs in the last year.

Presence of significant comorbidities precluding participation in a clinical study as determined by investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy and Immunotherapy

Participants receive Nivolumab (Opdivo) plus platinum-doublet chemotherapy

12 weeks

Radiotherapy

Participants undergo radiotherapy following chemotherapy and immunotherapy

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately two years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab

Trial Overview

The study tests the combination of chemotherapy and immunotherapy (Nivolumab), followed by radiotherapy to treat patients with advanced lung cancer that cannot be surgically removed.

How Is the Trial Designed?

Group I: Chemoimmunotherapy followed by radiotherapy Experimental Treatment 1 Intervention

Nivolumab (Opdivo) + plus platinum-doublet chemotherapy followed by radiotherapy

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Nivolumab, an immunotherapy for advanced non-small cell lung cancer (NSCLC), has shown promising anticancer effects but can lead to previously unknown side effects due to its impact on the immune system.

This case report highlights a rare instance of drug-induced myocarditis occurring after nine cycles of nivolumab treatment, emphasizing the need for awareness of potential cardiac side effects in patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-induced myocarditis after nivolumab treatment in a patient with PDL1- negative squamous cell carcinoma of the lung. Semper, H., Muehlberg, F., Schulz-Menger, J., et al.[2022]

Nivolumab (Opdivo) is the first PD-1 inhibitor approved for advanced-stage squamous cell non-small-cell lung cancer, showing improved overall survival and progression-free survival compared to docetaxel in the Phase III CHECKMATE 017 trial.

Nivolumab demonstrated better safety and tolerability, along with improved patient-reported outcomes, although PD-L1 expression did not predict treatment outcomes, indicating a need for further research on predictive biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. Ang, YL., Lim, JS., Soo, RA.[2020]

Nivolumab, a PD-1 receptor inhibitor, shows an objective response rate of 18% and a 1-year overall survival rate of 45% in patients with advanced non-small-cell lung cancer, based on a meta-analysis of 20 studies involving 3404 patients.

The presence of PD-L1 expression in patients is associated with a better response to nivolumab, indicating that PD-L1 status can help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The benefit and risk of nivolumab in non-small-cell lung cancer: a single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials. Zhao, B., Zhang, W., Yu, D., et al.[2019]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

In a meta-analysis of 4413 patients from 8 randomized controlled trials, PD-1/PD-L1 inhibitors showed a significantly lower risk of all-grade adverse events (66.20% vs. 86.08%) and high-grade adverse events (14.26% vs. 43.53%) compared to chemotherapy, indicating a better safety profile.

While PD-1/PD-L1 inhibitors are generally safer, they are associated with a unique set of immune-related adverse events (irAEs) that can be severe, such as pneumonitis and thyroid dysfunction, which clinicians need to monitor closely to manage patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. Luo, W., Wang, Z., Tian, P., et al.[2021]

In a study of patients with non-small cell lung cancer treated with nivolumab, those who experienced serious adverse events (grade ≥3) had significantly better overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared to those without such events.

The findings suggest that while serious adverse events are typically concerning, they may be associated with a more favorable treatment response in patients receiving nivolumab, indicating a complex relationship between adverse effects and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious Immune-related Adverse Events Are Associated With Greater Efficacy of Nivolumab Therapy Against Non-small Cell Lung Cancer. Blazek, J., Hosek, P., Hrabcova, K., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Monoclonal antibodies like nivolumab and pembrolizumab, which target PD-1, have shown a survival benefit and better tolerability compared to standard second-line chemotherapy in non-small cell lung cancer, as demonstrated in three phase III trials.

Patients receiving PD-1 inhibitors may experience unique immune-related adverse events that require early recognition and a multidisciplinary management approach, highlighting the need for ongoing education among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. O'Kane, GM., Labbé, C., Doherty, MK., et al.[2018]

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