Nivolumab Clinical Trials

What Is Nivolumab?

Nivolumab is an FDA-approved medication for several cancer types, including melanoma, non-small cell lung cancer (NSCLC), malignant pleural mesothelioma, renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head/neck, urothelial carcinoma, MSI-H colorectal cancer, hepatocellular carcinoma, and gastric cancer.

It is a human IgG4 kappa monoclonal antibody that works as an immune checkpoint inhibitor. Nivolumab functions by blocking the interaction between the PD-1 (programmed death-1) receptor on immune cells and its ligands, PD-L1 and PD-L2. This action helps prevent cancer cells from deactivating T cells, thereby allowing the immune system to recognize and attack the cancer.

Nivolumab is also being investigated in clinical trials for various other advanced and metastatic solid tumors and hematological malignancies. These studies aim to explore its safety and effectiveness, often in combination with other therapies, to improve patient outcomes.

Uses and Conditions Under Study

Nivolumab is being studied across a wide range of cancers, both as a single agent and in combination with other treatments.

• Melanoma: With 125 trials for melanoma and 59 trials for metastatic melanoma, this is a significant area of research. Nivolumab helps the immune system fight melanoma, including cases resistant to other immunotherapies or those with brain metastases. Studies are also exploring personalized vaccines with nivolumab for melanoma.
• Lung Cancer: Nivolumab is extensively studied for lung cancers, with 38 trials for Non Small Cell Lung Cancer and an additional 68 trials combining Non-Small Cell Lung Cancer and Non-small Cell Lung Cancer. Research focuses on advanced or metastatic NSCLC, including those with specific mutations or as neoadjuvant therapy before surgery.
• Kidney Cancer: There are 52 trials investigating nivolumab for renal cell carcinoma. Studies aim to improve outcomes for metastatic clear cell renal cell carcinoma, often in combination with other targeted therapies or after kidney removal.
• Liver Cancer: Nivolumab is being studied in 47 trials for hepatocellular carcinoma. Research explores its use in advanced or unresectable HCC, sometimes combined with loco-regional therapies like trans-arterial embolization.
• Gastric and Gastroesophageal Cancer: With 36 trials for gastric cancer, nivolumab is being evaluated for advanced or metastatic forms, often in combination with chemotherapy. Studies also include esophageal and gastroesophageal junction adenocarcinomas.
• Other Solid Tumors: Nivolumab is under investigation for a broad category of solid tumors (37 trials) and advanced cancers (36 trials). This includes head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, breast cancer, pancreatic cancer, neuroendocrine tumors, and biliary tract cancers.
• Hematological Malignancies: Clinical trials are also exploring nivolumab for blood cancers such as classical Hodgkin lymphoma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and myelodysplastic syndrome.

Dosing

Nivolumab has been studied in various dosage forms and administration routes, depending on the specific cancer and treatment regimen.

It is primarily administered as an intravenous (IV) infusion. Common investigational IV doses include 3 mg/kg every 2 weeks or 240 mg every 2 weeks, and 480 mg every 4 weeks. Some studies also explore fixed-dose combinations, such as nivolumab plus relatlimab 360 mg/360 mg.

Subcutaneous (SC) formulations of nivolumab are also being developed and studied to offer more convenient administration options for patients and healthcare systems.

In combination therapies, nivolumab has been investigated with other drugs, with varying doses. For instance, in some trials, it's combined with ipilimumab at doses like 3 mg/kg nivolumab plus 1 mg/kg ipilimumab, or 1 mg/kg nivolumab plus 3 mg/kg ipilimumab. Other routes of administration under investigation include intratumoral injections for localized effects and intrathecal administration for specific brain metastases.

For pediatric patients, including children, adolescents, and young adults (CAYA) with high-risk ALK+ Anaplastic Large Cell Lymphoma, nivolumab is being investigated, sometimes in combination with other agents, at weight-based doses like 0.006 mg/kg.

Side Effects

The most common side effect reported by patients taking Nivolumab was fatigue, experienced by 32.1% of patients, compared to 30.9% of patients on placebo. Other common side effects reported more frequently with Nivolumab than with placebo, based on data from 14 to 17 clinical trials involving up to 5500 patients in the Nivolumab arm, include:

• Diarrhea: 28.4% of patients on Nivolumab experienced diarrhea, compared to 24.4% on placebo.
• Pruritus (itching): 21.0% of patients on Nivolumab experienced pruritus, compared to 15.3% on placebo.
• Decreased appetite: 17.7% of patients on Nivolumab experienced decreased appetite, compared to 14.6% on placebo.
• Increased alanine aminotransferase (a liver enzyme): 17.3% of patients on Nivolumab experienced this, compared to 11.1% on placebo.
• Rash: 16.3% of patients on Nivolumab experienced a rash, compared to 12.9% on placebo.
• Increased aspartate aminotransferase (another liver enzyme): 15.5% of patients on Nivolumab experienced this, compared to 9.5% on placebo.

Some side effects were reported at similar or slightly lower rates with Nivolumab compared to placebo, such as nausea (27.3% on Nivolumab vs 29.3% on placebo), constipation (17.4% vs 18.5%), arthralgia (joint pain) (16.8% vs 17.3%), and headache (14.9% vs 15.3%).

Clinical Trial Results

Clinical trials have evaluated the effectiveness of Nivolumab in various cancer types, both as a single agent and in combination with other therapies.

Renal Cell Carcinoma (RCC)

In a study of advanced/metastatic clear-cell RCC (NCT01354431), patients received different doses of Nivolumab. The best overall response rate (BORR) ranged from 20.0% to 24.1% across the different dosing groups. The median overall survival (OS) ranged from 18.45 months to 25.46 months, and median progression-free survival (PFS) ranged from 2.63 months to 4.17 months.

Another study in metastatic RCC (NCT01472081, CheckMate 016) investigated Nivolumab in combination with other drugs. The objective response rate (ORR) varied significantly by combination:

• Nivolumab with Sunitinib (SUN + NIV2) showed an ORR of 85.7%.
• Nivolumab with Pazopanib (PAZ + NIV2) showed an ORR of 45.0%.
• Nivolumab with Ipilimumab (IPI1 + NIV3 or IPI3 + NIV1) showed an ORR of 40.4% for both combinations.

However, one combination of Nivolumab and Ipilimumab (IPI3 + NIV3) showed an ORR of 0%. The median progression-free survival (PFS) ranged from 7.2 months to 12.7 months across the different combination arms, with the highest PFS observed in the Sunitinib combinations. The median duration of response (DOR) ranged from 30.1 weeks to 88.7 weeks, with the longest durations seen in the Ipilimumab combinations.

Non-small Cell Lung Cancer (NSCLC)

The CheckMate 012 study (NCT01454102) explored Nivolumab as monotherapy and in various combinations for Stage IIIB/IV NSCLC.

• As a single agent (Arm F), Nivolumab had an objective response rate (ORR) of 23.1%, with a 24-week progression-free survival rate (PFSR) of 39.7%.
• In combination with chemotherapy, Nivolumab + Pemetrexed + Cisplatin (Arm B) achieved an ORR of 46.7% and a 24-week PFSR of 68.4%.
• Nivolumab + Paclitaxel + Carboplatin (Arm C5) showed an ORR of 50.0% and a 24-week PFSR of 59.3%.
• When combined with Ipilimumab (Arm P), the ORR was 47.4%, and the 24-week PFSR was 72.4%.

For patients with squamous histology NSCLC receiving Nivolumab monotherapy (Arm K), the ORR was 0%, while the 24-week PFSR was 50.0%.

Uveal Melanoma

In a study of metastatic uveal melanoma (NCT01585194), the combination of Nivolumab and Ipilimumab resulted in an overall response rate of approximately 8.6% (3 out of 35 evaluable participants). The median overall survival was 19.1 weeks, and the median progression-free survival was 5.5 weeks.

Multiple Myeloma

An investigational study (NCT01592370) evaluated Nivolumab in patients with multiple myeloma. For the specific Multiple Myeloma Group, the best overall response was very low, with 0% for Nivolumab + Ipilimumab and Nivolumab + Lirilumab, and 3.7% for Nivolumab monotherapy (Expansion). However, in a specific Nivolumab + Daratumumab cohort, the objective response rate ranged from 36.4% to 71.4% across different sub-cohorts. The median overall survival for Nivolumab monotherapy was 52.57 months, while for Nivolumab + Ipilimumab it was 30.39 months, and for Nivolumab + Lirilumab it was 14.95 months. Median progression-free survival ranged from 3.02 months to 6.93 months for Nivolumab monotherapy and combinations (excluding Daratumumab cohorts). For the Nivolumab + Daratumumab cohort, median progression-free survival ranged from 7.01 months to 16.95 months.

Currently Recruiting Trials

Nivolumab, an immunotherapy that helps your immune system fight cancer, is being explored in many ongoing clinical trials. These studies aim to understand how Nivolumab works alone or in combination with other treatments across a variety of cancers. Here are a few examples of trials currently seeking participants:

• A Phase 1/Phase 2 study, NCT07281924, is investigating the combination of Hepzato Kit™ with nivolumab and relatlimab (Opdualag™) for patients with metastatic melanoma that has spread to the liver. This trial, sponsored by the University of Wisconsin, Madison, plans to enroll 15 participants to assess safety, tolerability, and potential synergistic effects.
• For advanced renal cell carcinoma, a Phase 2 randomized trial, NCT07188896, is comparing different combinations, including standard ipilimumab/nivolumab, against fianlimab and cemiplimab, with or without ipilimumab. This study, sponsored by Brian Rini, aims to enroll 120 patients.
• The "Window Study of Intratumoral Mitazalimab in Breast Cancer (WINIT-BC),"