# Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary

Dean F. Bajorin, Johannes Alfred M. Witjes, Jürgen Erich Erich Gschwend, M. Schenker, Begoña Pérez Valderrama, Yoshihiko Tomita, A. T. Bamias, Thierry Lebret, Shahrokh F. Shariat, Se-Hoon Park, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Dean F. Bajorin, Johannes Alfred M. Witjes, Jürgen Erich Erich Gschwend, M. Schenker, Begoña Pérez Valderrama, et al. Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary. Future Oncology, 2023, 19 (6), pp.413-426. 10.2217/fon-2022-1294. hal-04195132

HAL Id: hal-04195132

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# Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary

Dean F Bajorin<fnref n="1" />, J Alfred Witjes², Jürgen E Gschwend³, Michael Schenker⁴, Begoña P Valderrama⁵,
Yoshihiko Tomita⁶, Aristotelis Bamias⁷, Thierry Lebret⁸, Shahrokh F Shariat⁹,¹⁰,¹¹,¹²,¹³, Se Hoon Park¹⁴,
Dingwei Ye¹⁵, Mads Agerbaek¹⁶, Deborah Enting¹⁷, Ray McDermott¹⁸, Pablo Gajate¹⁹, Avivit Peer²⁰, Matthew I Milowsky²¹,
Alexander Nosov²², João Neif Antonio Jr²³, Krzysztof Tupikowski²⁴, Laurence Toms²⁵, Bruce S Fischer²⁵, Anila Qureshi²⁵, Sandra Collette²⁵,
Keziban Unsal-Kacmaz²⁵, Edward Broughton²⁵, Dimitrios Zardavas²⁵, Henry B Koon²⁵ and Matthew D Galsky²⁶

First draft submitted: 22 December 2022; Accepted for publication: 30 January 2023; Published online: 15 March 2023

## Summary

### What is this summary about?

This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body.

The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment.

### What happened in the study?

In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment.

### What do the results mean?

The results showed that people who received nivolumab versus placebo:

* Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells.

* Survived longer before a secondary cancer outside of the urinary tract was detected.

* Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health).

* Had similar side effects to the people who received nivolumab in other studies.

### How to say (double-click on the icon to play sound)…

* **Adjuvant:** A-joo-vunt

* **Nivolumab:** nih-VOL-yoo-mab

* **Urothelial:** YOOR-oh-THEE-lee-ul

* **Immunotherapy:** IH-myoo-noh-THAYR-uh-pee

* **Chemotherapy:** KEE-moh-THAYR-uh-pee

* **Urethra:** yoo-REE-thruh

* **Ureter:** YER-eh-ter

<footnote n="1">¹Memorial Sloan Kettering Cancer Center, New York, NY, USA; ²Radboud University, Nijmegen, the Netherlands; ³Department of Urology, Technical University Munich, Munich, Germany; ⁴Nectarie Oncology Center, Craiova, Romania; ⁵Hospital Universitario Virgen del Rocío, Seville, Spain; ⁶Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; ⁷National and Kapodistrian University of Athens, Athens, Greece; ⁸Urology Department, Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Versailles, France; ⁹Weill Cornell Medical College New York, NY, USA; ¹⁰Medical University of Vienna, Vienna General Hospital, Vienna, Austria; ¹¹University of Texas Southwestern Medical Center, Dallas, TX, USA; ¹²Charles University, Prague, Czech Republic; ¹³Institute for Urology and Reproductive Health, IM Sechenov First Moscow State Medical University, Moscow, Russia; ¹⁴Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; ¹⁵Fudan University Shanghai Cancer Center, Shanghai, China; ¹⁶Aarhus University Hospital, Aarhus, Denmark; ¹⁷Guy's and St. Thomas's NHS Foundation Trust, London, UK; ¹⁸St. Vincent's University Hospital and Cancer Trials Ireland, Dublin, Ireland; ¹⁹Ramon y Cajal University Hospital, Madrid, Spain; ²⁰Rambam Health Care Campus, Haifa, Israel; ²¹University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; ²²Federal State Budget Institution NN Petrov National Medical Research Center of Oncology of the Ministry of Health Care of the Russian Federation, St. Petersburg, Russia; ²³Hospital de Amor de Barretos-Pio XII Foundation, Barretos, Brazil; ²⁴Subdivision of Urology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland; ²⁵Bristol Myers Squibb, Princeton, NJ, USA; ²⁶Icahn School of Medicine at Mount Sinai, New York, NY, USA</footnote>
## Who sponsored this study?

This study was sponsored by Bristol Myers Squibb and Ono Pharmaceutical. Bristol Myers Squibb would like to thank the people with muscle-invasive urothelial cancer who volunteered to take part in this study and their families, as well as the CheckMate 274 investigators and study teams. Nivolumab is licensed by Bristol Myers Squibb.

## Who is this article for?

This summary of the original article was written for people who want to learn more about clinical research in urothelial cancer and about the results of the CheckMate 274 study.

## Where can I find the original article on which this summary is based?

You can read the original article titled 'Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma', which was published in the *New England Journal of Medicine*, for free at: https://doi.org/10.1056/NEJMoa2034442

## What is muscle-invasive urothelial cancer?

Urothelial cancer is the 10th most common cancer in the world and is a type of cancer in the urinary tract. This includes the following body parts: the kidneys, renal pelvis, ureters, bladder, and the urethra (see diagram for further details). Muscle-invasive urothelial cancer happens when urothelial cancer has spread from the inner lining of the renal pelvis, ureters, bladder, or the urethra and into the nearby muscle wall. Without treatment, muscle-invasive urothelial cancer will spread to other parts of the body.

## What treatments are used for muscle-invasive urothelial cancer?

The standard treatment for muscle-invasive urothelial cancer is surgery to remove the affected body parts, such as the bladder, ureters, and/or kidneys and the surrounding lymph nodes. However, cells from the cancer can spread to other parts of the body before the surgery (known as metastases) and start to grow a new tumor. These metastases, or secondary cancers, can be difficult to find in the body at the time of surgery. A secondary cancer happens in more than half of people with urothelial cancer after they have had surgery.

Chemotherapy (medicines to slow the growth of or kill cancer cells) is often used along with surgery to kill remaining cancer cells and decrease the chance of the cancer coming back after the original tumor is removed. Chemotherapy given before surgery is called "neoadjuvant" chemotherapy. A commonly used neoadjuvant chemotherapy is a medicine called cisplatin (also called cisplatin-based neoadjuvant chemotherapy). Not all people are able to take or want to take cisplatin-based neoadjuvant chemotherapy, including almost half of the people in this study. Chemotherapy given after surgery is called "adjuvant" chemotherapy. Adjuvant therapy is given to people with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study was started, there was no standard adjuvant chemotherapy.

<figure><img src="image_4.png" /></figure>
The urinary system

<figure><img src="image_5.png" /></figure>
## What was the CheckMate 274 study?

In the CheckMate 274 study, researchers compared nivolumab with a **placebo**, as an adjuvant treatment for people with muscle-invasive urothelial cancer. They wanted to understand whether nivolumab worked to kill remaining cancer cells and reduce the chance of the cancer returning after surgery. The study also looked at the side effects people had with treatment.

<figure><img src="image_6.png" /></figure>

**Placebo:** (pluh-see-bo)

A substance that does not contain active medicine but is identical in appearance to a study drug that is being researched in a clinical trial.

## What is nivolumab?

Nivolumab is a type of cancer treatment called immunotherapy. Nivolumab works differently from chemotherapy. Chemotherapy is a chemical that is toxic to all cells, while nivolumab works in a more selective way. Some cancer cells have large amounts of a protein called programmed death ligand-1 (shortened to PD-L1). PD-L1 helps cancer cells to hide from the body's defense system by binding to a protein called programmed death receptor-1 (shortened to PD-1) on immune cells to inactivate them.

By binding to PD-1, nivolumab stops PD-L1 on the cancer cells from binding to immune cells. This helps the immune cells to identify and kill the cancer cells. This means that nivolumab can potentially reduce or stop cancer growth. Nivolumab has been studied in different types of cancer including urothelial cancer.

## How does nivolumab work?

<figure><img src="image_7.png" /></figure>
By binding to PD-1, nivolumab helps immune cells identify cancer cells that are hiding and kill them

<figure><img src="image_8.png" /></figure>

What did the CheckMate 274 study look at?

The aim of the study was to compare treatment with nivolumab or a placebo in adults with muscle-invasive urothelial cancer who had recently received surgery to remove the tumor. The goals of this study were to:

<figure><img src="image_9.png" /></figure>

Find out how long a person survived and was free of the urothelial cancer returning if they received adjuvant nivolumab compared to those who received placebo treatment. This is called disease-free survival (shortened to DFS) and was the main goal of the study.

Measure DFS in people whose cancer tested positive for PD-L1. In this study, the researchers counted a person's cancer as testing positive for PD-L1 if at least 1 of 100 or more of their cancer cells had PD-L1 on them.

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

Find out how long a person survived without developing a secondary cancer (also known as recurrence-free survival; shortened to RFS).

Determine the side effects people experienced with treatment, and the impact of the treatment on a person's mental and physical health (health-related quality of life).

<figure><img src="image_12.png" /></figure>
What did this study investigate?

<figure><img src="image_13.png" /></figure>

What patient
outcomes were
studied?

<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /></figure>

What was
measured?

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

What do the
results mean?

<figure><img src="image_18.png" /></figure>

Disease-free survival (DFS)

Time that a person
survived and was free from
the cancer returning after
starting the treatment

A longer time means that
the treatment is more likely
to stop the cancer from
returning

<figure><img src="image_19.png" /></figure>

DFS in people who had
PD-L1 protein on their
cancer cells

DFS in people who had
measurable amounts (1%
or more) of PD-L1 protein
on their cancer cells

Researchers wanted to
know if having lots of PD-L1
on their cancer cells made
people more likely to have a
longer DFS with novilumab
treatment

<figure><img src="image_20.png" /></figure>

Recurrence-free survival
(RFS) without developing
secondary cancers

Time that a person
survived and was free of
cancer returning outside of
the urinary tract

A longer time means that the
treatment is more likely to
stop secondary cancers from
developing

<figure><img src="image_21.png" /></figure>

Side effects

All side effects that
occured during the study
were recorded

Side effects can range in
severity; however, they
may or may not have been
caused by the treatments
people received during the
study

<figure><img src="image_22.png" /></figure>

Health-related quality of
life surveys

These questionnaires
are used to measure the
health-related quality of
life of adults with cancer

Health-related quality of
life measures the degree
to which an individual is
healthy, comfortable and
able to participate in or
enjoy life events
The study started with a screening period so doctors could check people's health to make sure they could take part in the study and were cancer-free following surgery to remove the affected body parts. After the screening period, people who could enter the trial were randomly assigned their treatment (this means that the treatment they received was decided by chance). Their treatment was given as an unlabeled 30-minute infusion into a vein through a needle so that they didn't know what their treatment was.

<figure><img src="image_23.png" /></figure>

## Who could take part in this study?

**Participants shared the following characteristics...**

Men and women

18 years +

<figure><img src="image_24.png" /></figure>

Muscle-invasive
urothelial cancer

<figure><img src="image_25.png" /></figure>

With or without cisplatin-based
neoadjuvant chemotherapy

<figure><img src="image_26.png" /></figure>
Had surgery to remove
the affected body
parts and nearby
lymph nodes within
the last 4 months

<figure><img src="image_27.png" /></figure>

Had a high risk of
cancer returning

<figure><img src="image_28.png" /></figure>

Also, they must have had tumor tissue from their surgery that could be tested for PD-L1. People were not allowed to take part in the study if they had surgery to remove only part of the bladder or part of the kidneys, or adjuvant chemotherapy or radiation therapy after surgery to remove the bladder.

Were cancer-free for at
least 4 weeks before
starting the trial

<figure><img src="image_29.png" /></figure>

Where did this study take place?

The study took place at hospitals in 30 countries across the world:

Argentina
Australia
Austria
Belgium
Brazil
Canada
Chile
China
Columbia
Denmark

France
Germany
Greece
Ireland
Israel
Italy
Japan
Republic of Korea
Mexico
Netherlands

Peru
Poland
Romania
Russian Federation
Spain
Sweden
Switzerland
Taiwan
United Kingdom
United States of America

<figure><img src="image_30.png" /></figure>
## Who participated in this study?

### People who took part in this study were....

<figure><img src="image_31.png" /></figure>

Adults with muscle-invasive
urothelial cancer

Average
age

65
years old

### Gender

<figure><img src="image_32.png" /></figure>

76%
male

### Race

<figure><img src="image_33.png" /></figure>

76%
White

### Prior treatment

<figure><img src="image_34.png" /></figure>

43%
had received
neoadjuvant
cisplatin
therapy

### Tumor location

<figure><img src="image_35.png" /></figure>

79%
of tumors
started in the
bladder

<figure><img src="image_36.png" /></figure>

24%
female

<figure><img src="image_37.png" /></figure>

22%
Asian

<figure><img src="image_38.png" /></figure>

57%
had not
received
neoadjuvant
cisplatin
therapy

<figure><img src="image_39.png" /></figure>

14%
of tumors
started in the
renal pelvis

<figure><img src="image_40.png" /></figure>

1%
Black

<figure><img src="image_41.png" /></figure>

7%
of tumors
started in the
ureter
# What were the results of the study?

## Disease-free survival (DFS) and recurrence-free survival (RFS)

Compared with those who received a **placebo**, people who received **nivolumab** had:

* A longer median cancer-free time (DFS)

<figure><img src="image_42.png" /></figure>

The median DFS is the time by which half the people in a clinical trial are alive and cancer free

* A longer median length of time without developing a secondary cancer (RFS) outside the urinary tract

<figure><img src="image_43.png" /></figure>

The median RFS is the time by which half the people in a clinical trial are alive and without signs or symptoms of a secondary cancer

People with PD-L1 protein on their cancer cells and who received nivolumab had a longer median cancer-free time (DFS) and a higher percentage of people who were cancer free at 6 months that those with the protein PD-L1 on their cancer cells who took a placebo.

<figure><img src="image_44.png" /></figure>

## Quality of life

No differences were observed in the health-related quality of life between people who received nivolumab and those who received a placebo.

* A higher percentage of people who were cancer-free at 6 months

<figure><img src="image_45.png" /></figure>

* More people free of a secondary cancer developing outside the urinary tract at 6 months

<figure><img src="image_46.png" /></figure>
## What were the most common side effects?

More people receiving nivolumab experienced side effects compared with those taking placebo. Side effects can range in severity and are classified as mild, moderate, severe or life-threatening. It is important to note that side effects may or may not be caused by the treatment people receive during the study.

<figure><img src="image_47.png" /><figcaption>Percentage of people who had to stop treatment because of any side effects:</figcaption></figure>

<figure><img src="image_48.png" /><figcaption>Percentage of people who experienced more severe side effects (requiring treatment, hospitalization and/or were life threatening):</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>Number of deaths due to treatment:</figcaption></figure>

<figure><img src="image_50.png" /></figure>
Pruritus (itching)

<figure><img src="image_51.png" /></figure>

23%

Nivolumab

12%

Placebo

Fatigue (extreme tiredness)

<figure><img src="image_52.png" /></figure>

17%

Nivolumab

12%

Placebo

Diarrhea (loose or watery bowel movements)

<figure><img src="image_53.png" /></figure>

17%

Nivolumab

11%

Placebo

Rash

<figure><img src="image_54.png" /></figure>

15%

Nivolumab

6%

Placebo

10%

Nivolumab

6%

Placebo

Increased lipase levels (digestive enzymes that the pancreas releases; increased levels can be a sign of pancreas inflammation)

Hypothyroidism (a condition where the thyroid gland doesn't make enough thyroid hormone to keep the body functioning normally)

<figure><img src="image_55.png" /></figure>

10%

Nivolumab

1%

Placebo

<figure><img src="image_56.png" /></figure>

What were the most common severe side effects?

Increased lipase
levels

5%

Nivolumab

3%

Placebo

Increased amylase
levels

4%

Nivolumab

1%

Placebo
## What do the results of this study mean?

The CheckMate 274 study showed that adjuvant nivolumab treatment increased the median cancer-free time in people with muscle-invasive urothelial cancer. Compared with people who received placebo:

* People who received nivolumab had a longer median DFS.

* People who received nivolumab and had the PD-L1 protein present on their cancer cells also had longer median DFS.

* People who received nivolumab had longer median RFS.

Overall, there were no differences in the health-related quality of life between people who received nivolumab and those who received placebo. The side effects reported by people receiving nivolumab in this study were similar to side effects reported by people receiving nivolumab in other studies.

## Key findings

<figure><img src="image_57.png" /></figure>

It is important to note that most people have only been taking part in this study for an average of 20 months, so the findings need to be further explored over a longer time. The CheckMate 274 trial is ongoing and will answer more questions, such as how long people survive after starting treatment with nivolumab and the placebo (also known as overall survival).
Where can I find more information on the study?

* Additional information on the CheckMate 274 study is available at: https://clinicaltrials.gov/ct2/show/NCT02632409

* And also at: EU clinical trials register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003626-40

Financial and competing interests

A full list of disclosures of the authors can be found at the end of the original article at:

https://www.nejm.org/doi/10.1056/NEJMoa2034442

Acknowledgments

Summary prepared by Lauren Ramsey, PharmD, Envision Pharma, Inc, and funded by Bristol Myers Squibb.