CHECKMATE-914 Phase 3 Dr. Brian Rini, MD [2022]

CHECKMATE-914 Phase 3 Dr. Brian Rini, MD [2022]

CHECKMATE-914 Trial

The purpose of this study is to determine if the use of Nivolumab on its own or in combination with Ipilimumab and Nivolumab, as opposed to the use of a placebo, is both safe and beneficial for postponing or preventing the recurrence of cancer in patients who have had a kidney removed.

 

The key outcomes of this study are measured in two different ways. The first principal completion date is anticipated to take place in July 2022. (DFS in Part A). The second primary completion date is anticipated to fall in the month of July 2024 (DFS in Part B). Prior treatment of anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or another antibody or medication targeting T-cell co-stimulation or checkpoint pathways.

 

Renal Cell Carcinoma (RCC)

Renal cell carcinoma (RCC) is the most prevalent form of kidney cancer in adults, accounting for around 431,000 new cases and 179,000 deaths annually across the globe. RCC (renal cell carcinoma) is around twice as prevalent in men compared to women, with the highest incidence rates in North America and Europe.

 

The five-year disease-free survival (compared) rate for patients diagnosed with metastatic or advanced kidney cancer (high risk) is 14%, while the five-year disease-free survival (DFS) rate for patients with resectable localized (renal cell carcinoma) disease is little over 50%.

 

The background of this study is that About a year or so ago, we had the first data for adjuvant immune therapy and kidney cancer, which was from the keynote study of adjuvant Pembrolizumab versus placebo and resected, high risk localized kidney cancer (localized renal cell carcinoma). That study and its follow up showed a significant disease-free survival advantage, a trend towards overall survival, but not yet significant. Brian Rini, MD from Vanderbilt University Medical Center

 

The EMOTION-010 study that was. Adjuvant Atezolizumab a PDL1 inhibitor versus placebo, and there was a US cooperative group study called prosper, which was a single dose of neoadjuvant nivolumab plus adjuvant nivolumab versus observation. Both those studies were similarly negative. No advantage in disease free or overall survival. Brian Rini, MD from Vanderbilt University Medical Center

 

Opdivo (Nivolumab(Nivo))

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor meant to harness the body’s immune system to restore antitumor immune response. Opdivo has become a significant therapy option for a variety of tumors by utilizing the body’s immune system to combat cancer.

Opdivo’s leading worldwide development program is based on Bristol Myers Squibb’s scientific expertise in immuno-oncology and encompasses a wide range of clinical trials spanning all phases, including Phase 3, in a number of kidney tumor types. The Opdivo clinical trial program has treated almost 35,000 patients to date. The Opdivo trials have contributed to a greater understanding of the potential significance of biomarkers in patient treatment, particularly in terms of how patients across the spectrum of PD-L1 expression may benefit from Opdivo.

Opdivo was the first PD-1 immune checkpoint inhibitor globally to get regulatory approval in July 2014. More than 65 nations, including the United States, the European Union, Japan, and China, have currently approved Opdivo. The Company’s Opdivo and Yervoy combination regimen received regulatory clearance for the treatment of metastatic melanoma in September 2015 and is currently approved in over 50 countries, including the United States and the European Union.

 

Yervoy (Ipilimumab (Ipi))

Yervoy is a human recombinant monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative T-cell activity regulator. Yervoy binds to CTLA-4 and inhibits its interaction with CD80/CD86 ligands. It has been demonstrated that blocking CTLA-4 increases T-cell activation and proliferation, including the activation and proliferation of T-effector cells that infiltrate tumors. Inhibition of CTLA-4 signaling can also impair the activity of T-regulatory cells, which may contribute to an increase in T-cell responsiveness, including the antitumor immune response. The Food and Drug Administration (FDA) of the United States authorized Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma on March 25, 2011. In almost 50 countries, Yervoy is licensed for unresectable or metastatic melanoma. There is an extensive, ongoing development program for Yervoy that encompasses numerous kidney tumor types.

What Are The Infusion-Related Adverse Events?

The most common side effects of Nivolumab are diarrhoea, fatigue, itching and skin rash. Ipi/Nivo’s (CHECKMATE-914 trial) most common side effects are:

• Appetite loss

• Diarrhoea

• Fatigue

• Fever

• Itching or skin rash

• Muscle pain

• A sick feeling

• Thyroid hormone levels were lower

• Liver and pancreas blood tests changed

 

The OS data’s still pending, but based on those data, The drug was FDA approved and is relatively commonly used in that circumstance of, again, resected high risk kidney cancer. On this background, several other studies were conducted. CHECKMATE-914 trial is one of those studies. The study gave 6 months of adjuvant Ipi/Nivo compared to placebo in a very similar high risk resected population.

Somewhat surprisingly, this study was negative. It did not show a disease free survival (DFS) advantage in patients who received Ipi/Nivo in that setting. It’s a little bit hard to explain. We know Ipi/Nivo is active in the advanced setting. It’s an approved regimen based on CHECKMATE-214. So the drugs are clearly active. Brian Rini, MD from Vanderbilt University Medical Center

 

More About the CHECKMATE-914 Trial

To treat kidney cancer, the entire or a portion of the kidney can be surgically removed. However, some individuals have an increased chance of cancer recurrence (of distant metastases). Therefore, researchers are investigating postoperative (prior) treatment.

In this trial (CHECKMATE-914 trial), the medicines nivolumab and ipilimumab are being evaluated. These medications are already administered to patients whose kidney cancer has spread to other organs.

Both nivolumab and ipilimumab belong to the immunotherapy category. They function in several ways to aid the immune system in locating and eliminating cancer cells.

In the CHECKMATE-914 study, everyone has surgery, and

• Some people have nivolumab and ipilimumab

• Some individuals just have nivolumab.

• Some people take a placebo or placebos.

The primary objectives of the experiment are to determine:

• How effectively treatment works to prevent or delay cancer recurrence of distant metastases.

• More data about the adverse effects.

• More on how therapy impacts life quality.

So the field is kind of taking a step back a little bit. I think Pembrolizumab is the results are still positive. It’s still a good drug and will be used in that setting, but I think when you have three negative studies, although we can explain it way each one, it certainly caused you to, to step back and get some perspective and maybe think about the benefit risk in a little different light than, than we did before.

And I do discuss this with patients when I’m talking about Pembrolizumab that, hey, just so you know, there are three studies that were negative and, you know, want to have that sort of more thorough benefit risk discussion with patients. So we’ll wait for that final study. We’ll see how these other data mature.

We’ll see the manuscripts which give more detail. But the field of adjuvant immune therapy and kidney cancer, I think is, is very much an evolution. Brian Rini, MD from Vanderbilt University Medical Center

 

With the Part B of the CHECKMATE-914 clinical trial open to recruitment, that leaves room for more data to come to fruition. Over the next ten years, new data will mature from the Part A arm of the study. And hopefully, shed more light on the Ipi/Nivo drug combination (CHECKMATE-914 trial) and continue to see disease free survival (DFS) and bring down the high risk of relapse bringing up overall survival, as well as, advancing cancer care.

 

Brian Rini, MD – About The Author, Credentials, and Affiliations

Dr. Rini is the Chief of Clinical Trials and Ingram Professor of Cancer Research at Vanderbilt Ingram Cancer Center.

Dr. Brian I. Rini was an associate professor of clinical oncology at Case Western Reserve University’s Cleveland Clinic Lerner College of Medicine. Rini studied medicine at Case Western Reserve. Dr. Rini’s research focuses in clinical oncology is genitourinary tumors as Associate Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute.

Dr. Rini attended Ohio State University College of Medicine in Columbus, Ohio. Dr. Rini completed his internal medicine residency and fellowship at the University of Chicago Hospitals in Illinois. Dr. Rini’s research is on (localized) renal cell carcinoma (RCC) and prostate cancer, with an emphasis on antiangiogenic therapy and immunotherapy.

By Stephanie Comello – OncologyTube

References

1. ClinicalTrials.gov – A Study Comparing Nivolumab, Nivolumab in Combination With Ipilimumab and Placebo in Participants With Localized Kidney Cancer Who Underwent Surgery to Remove Part of a Kidney (CheckMate 914). ClinicalTrials.gov, July 20, 2022

2. Cancer Research UK – A trial of nivolumab with or without ipilimumab after surgery for kidney cancer (CheckMate 914). Cancer Research UK, April 20, 2022

3. Bristol Myers Squibb – Bristol Myers Squibb Provides Update on CheckMate -914 Trial Evaluating Opdivo (nivolumab) Plus Yervoy (ipilimumab) as Adjuvant Treatment of Localized Renal Cell Carcinoma. Bristol Myers Squibb News Release, July 29, 2022