publication date: Jun. 12, 2020

Clinical Roundup

Keytruda fails to meet PFS, OS, in UCC trial

Keytruda in combination with chemotherapy for the first-line treatment of patients with advanced or metastatic urothelial carcinoma did not meet its pre-specified dual primary endpoints of overall survival or progression-free survival, compared with standard of care chemotherapy.

Keytruda is sponsored by Merck.

In the final analysis of the study, there was an improvement in OS and PFS for patients treated with Keytruda in combination with chemotherapy (cisplatin or carboplatin plus gemcitabine) compared to chemotherapy alone; however, these results did not meet statistical significance per the pre-specified statistical plan.

The monotherapy arm of the study was not formally tested, since superiority was not reached for OS or PFS in the Keytruda combination arm. The safety profile of Keytruda in this trial was consistent with previously reported studies, and no new safety signals were identified.

Keytruda has three FDA-approved bladder cancer indications across multiple types and stages of bladder cancer. Additionally, Merck has an extensive clinical development program in bladder cancer and is continuing to evaluate Keytruda as monotherapy and in combination with other anti-cancer therapies across several disease settings (i.e., metastatic, muscle invasive bladder cancer, and non-muscle invasive bladder cancer).


Inherited mutation associated with higher prostate cancer risk in African Americans

Researchers at the Keck School of Medicine have identified a variant in the genome that may explain why multiple men in the same family develop the disease—and could serve as a guide for screening,

For years, researchers have known that men of African ancestry are at greater risk of developing prostate cancer with research suggesting that inherited factors may contribute to their greater risk.

Now, a new USC study published in European Urology is the first to identify an inherited genetic variant associated with higher risk of prostate cancer in men of African descent that contributes to the clustering of prostate cancer cases within families.

“About 12% of men of African ancestry carry this particular variant in the genome, which increases their risk two-fold. The variant is not found in other populations,” Christopher Haiman, study author and professor of preventive medicine, Keck School of Medicine of USC, said in a statement. “But it’s even more common in families with a history of prostate cancer.”

One in six African American men develops prostate cancer in his lifetime. African American men are 1.8 times more likely to be diagnosed with—and 2.2 times more likely to die from—prostate cancer than white men. If a black man’s brother or father had prostate cancer, his risk will be even higher.

Until now, there has been no genetic mutation or biomarker doctors could look for to determine if a particular African American man was more likely to get the disease.

While a prostate specific-antigen blood test can detect prostate cancer, many of the cancers it detects may not cause harm, while treatment can cause life-altering side effects.

In the study, which is part of the RESPOND African American prostate cancer initiative, researchers looked at 9,052 prostate cancer cases among men of African ancestry. More than 23% had this specific genetic variant. The variant was strongly associated with a prostate cancer diagnosis at an earlier age, more aggressive disease, and men with a family history of prostate cancer. In fact, 32% of the men with prostate cancer who had a family history of the disease carried the variant.

This new information may eventually help clinicians identify men who could benefit from early prostate cancer screening and treatment.

“A man of African ancestry comes in and says, ‘Well, I have prostate cancer and I have a family history of the disease. Why?’ Well, now there’s a variant you can test to see if they and their family members carry it,” Haiman said. “This is a marker that down the road may be used to identify African-Americans and their family members who are at high risk and would benefit from more precise, targeted, and earlier PSA screening.”

Researchers believe this variant is one of the reasons why African American men are more likely to get prostate cancer and hope to find out more about the role genetic mutations play in their overall risk.


Many hospitalized people with advanced cancer struggle with daily tasks

New research from Mass General Cancer Center, published in JNCCNJournal of the National Comprehensive Cancer Network, found 40.2% of hospitalized patients with advanced, incurable cancer were functionally impaired at the time of admission, meaning they needed assistance with activities of daily living like walking, bathing, getting dressed, or other routine tasks.

Patients with functional impairment also had higher rates of pain, depression, and anxiety, and were more likely to have longer hospital stays and worse survival.

“Interventions addressing patients’ functional impairment and symptom management could help enhance care delivery and outcomes for the highly symptomatic population of hospitalized patients with advanced cancer,” lead researcher Daniel E. Lage, of Mass General Cancer Center, said in a statement. “This highlights the need for efforts to integrate functional assessments into the care of these patients to identify individuals who may benefit from physical therapy, palliative care, and/or other supportive services earlier in their hospital stay. Our finding that individuals with functional impairment experience worse survival could also help guide conversations about goals of care and hospice planning among hospitalized patients with cancer.”

“We are also actively exploring interventions to help patients transition from the inpatient to the outpatient setting, which we have identified as a key challenge for patients with functional impairment,” senior researcher Ryan D. Nipp, of Mass General Cancer Center, said in a statement.

The researchers studied 970 patients ages 18-and-older with advanced cancer—defined as those not being treated with curative intent—who experienced an unplanned hospital admission at Mass General Cancer Center between Sept. 2, 2014 and March 31, 2016. They measured functional impairment using nursing documentation collected at intake and stored in electronic health records, and also collected self-completed questionnaires from the patients. ADL impairment was defined as any need for assistance by another person. Overall, 390 patients (40.2%) had at least one ADL impairment with 14.8% having one or two, and 25.4% experiencing at least three areas of difficulty with daily tasks.

“Lage and colleagues highlight the important, often-missed, opportunity to routinely use hospitalization as a trigger for a careful assessment of symptoms and functional status,” Toby Campbell, MD, Chief of Palliative Care at the University of Wisconsin Carbone Cancer Center, and a member of the NCCN Guidelines Panel for Palliative Care, said in a statement.

“An unplanned hospitalization for an advanced cancer patient is a watershed moment and predicts higher symptoms and shorter survival in patients with and without impaired function. Hospitalization is a crucial opportunity to facilitate critical serious illness care, including comprehensive palliative care and advanced care planning, with the promise of improving the lives of our patients,” Campbell said.


NIH scientists develop blood test to help improve HCC screening

Scientists have developed a new test that can help identify people who are likely to develop hepatocellular carcinoma. The approach uses a simple blood test to check for the patient’s previous exposure to certain viruses.

A study of the new approach was led by researchers at NCI. The study also involved researchers from the National Institute of Diabetes and Digestive and Kidney Diseases and several academic centers. The findings were published June 10 in Cell.

“Together with existing screening tests, the new test could play an important role in screening people who are at risk for developing HCC. It could help doctors find and treat HCC early. The method is relatively simple and inexpensive, and it only requires a small blood sample,” study’s leader Xin Wei Wang, co-leader of the NCI Center for Cancer Research Liver Cancer Program, said in a statement

Certain factors increase a person’s chances of developing HCC, such as infection with hepatitis B or hepatitis C virus or cirrhosis of the liver. People who have risk factors are recommended to get screened for HCC every six months with an ultrasound with or without a blood test for alpha-fetoprotein.

But not everyone with risk factors for HCC will develop the disease. Although screening can lead to earlier detection, most patients are diagnosed when the cancer is advanced and often incurable. However, HCC that is caught early has a much better chance of being cured.

“We need a better way to identify people who have the highest risk for HCC and who should get screened more frequently,” said Wang, who is also part of NCI’s Translational Liver Cancer Consortium.

“A main focus of the NCI CCR Liver Cancer Program is to develop new methods for early detection, diagnosis, and treatment, with the goal of improving outcomes for patients with HCC,” Tim Greten, co-leader of the Liver Cancer Program and a collaborator of the study, said in a statement

Many screening tests detect features of cancer cells. But those features can change over time, and not all cancer cells in a tumor have the same characteristics. The NCI team took a different approach: detecting features of the cancer’s environment rather than cancer cells themselves.

More research is providing evidence that cancer development is influenced by interactions between viruses and the immune system. The team reasoned that certain interactions between viruses and the immune system may raise the risk of developing HCC.

To explore that possibility, the scientists scanned people’s blood for “footprints” left behind by past viral infections. Because these footprints are left in antibodies, proteins made by the immune system, they also reflect how the immune system reacted to the infection. The mixture of footprints each person has creates a unique pattern, which the researchers called a viral exposure signature.

The team checked for the footprints of more than 1,000 different viruses in blood samples from around 900 people, including 150 who had HCC. They identified a specific viral exposure signature that could accurately distinguish people with HCC from people with chronic liver disease and healthy volunteers. This signature contained footprints from 61 different viruses.

The researchers then tested the signature on blood samples from 173 people with chronic liver disease who were part of a 20-year study. During that time, 44 of the participants developed HCC. Using blood samples taken when the cancer was diagnosed, the signature correctly identified those who developed HCC (area under the curve, AUC=0.98). Importantly, the signature also worked when the researchers used blood samples taken at the beginning of the study, up to 10 years before diagnosis (AUC=0.91).

The signature appeared to be far more accurate than an alpha-fetoprotein test (AUC=0.91 vs. 0.62). An AUC of 0.5 indicates that a test is no better than chance in identifying disease, whereas an AUC of 1.0 represents a test with perfect accuracy.

The scientists are continuing to study their approach and plan to test it in clinical trials. They are collaborating with Katherine McGlynn, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics to test the approach in a prospective surveillance study of people with risk factors for HCC.

It’s possible that viral infections—even ones that don’t cause cancer—may change the immune system in ways that influence the development of other cancers. For example, certain infections may lessen the immune system’s ability to keep cancer cells in check. NCI scientists are testing the viral exposure signature in a study of prostate cancer, and others are considering applying the approach to a screening study for ovarian, esophageal, liver, and breast cancer in Africa.


Yale scientists develop experimental method to study infection and disease, including COVID-19

Yale Cancer Center scientists have developed a cell screening method for agents that alter biologic functions. This approach uses thousands of artificial proteins called “traptamers” and may help to answer research questions that are difficult to address with other cell screening methods, including the SARS-CoV-2 virus, COVID-19.

The data was published in Cell Reports.

“The traptamer screening approach identifies a molecular target required for human papillomavirus infection,” lead author Daniel DiMaio, deputy director of YCC, professor of genetics, molecular biophysics and biochemistry, and therapeutic radiology, said in a statement.

Traptamers are extremely short proteins designed to bind to transmembrane proteins. DiMaio’s lab developed the technology more than a decade ago, based on its discoveries about a bovine papillomavirus gene called E5, which provides a model for traptamer design.

In traptamer screening, researchers first generate many versions of the artificial proteins, each one being unique. The scientists then screen these artificial proteins for activity in a large number of cells. Any traptamer that binds to a cell transmembrane protein may activate or inactivate it, and thus can affect processes controlled by the protein.

Over the years, DiMaio and his collaborators have isolated traptamers tailored for specific transmembrane proteins that are crucial to cellular function, such as infection by HIV. More recently, DiMaio and his team wondered if traptamers could be used as a screening tool to block a process such as HPV infection, another main line of research in his lab, without designating a specific transmembrane protein beforehand.

To test this idea, the Yale team generated about 250,000 traptamers, expressed them in HeLa human cells, and added HPV. Researchers engineered a form of HPV expressing a gene that can stop the cells from growing, providing a selection for traptamers that block infection.

The screen allowed them to isolate a traptamer that inhibits a cellular protein called TBC1D5, thereby blocking HPV infection. Follow-up research demonstrated that TBC1D5 regulates a protein called Rab7, a key player in a biological pathway by which HPV enters cells. These findings in turn suggested that Rab7 may be a likely target for anti-HPV therapies.

DiMaio noted that HPV vaccines, which are effective and safe, are the first line of defense against the virus. Unfortunately, not everyone can or will be vaccinated, and there’s still a need for other treatments to defend against HPV or slow its spread.

Traptamer screening may also be a powerful tool to investigate other diseases. For instance, Jian Xie, a postdoctoral researcher in the DiMaio lab and the first author of the paper, has designed traptamer screens against the SARS-CoV-2 virus, in collaboration with Craig Wilen, assistant professor of laboratory medicine and immunobiology.

DiMaio says that the method may offer advantages over screening based on a widely adopted DNA-editing technology called CRISPR. In CRISPR screens, which have fueled many major recent advances in research, scientists “knock out” different single genes in a population of cells, which prevents the genes from expressing proteins, to see how that alters a given biological process.

Yale’s Erin Heim and Mac Crite are co-authors of the paper. Lead funding came from NCI and the National Institute of Allergy and Infectious Diseases.

Copyright (c) 2020 The Cancer Letter Inc.