publication date: Jun. 22, 2018

Clinical Roundup

Kymriah shows more than one-year durable responses in relapsed or refractory DLBCL

Novartis announced 14-month results from the pivotal JULIET clinical trial showing ongoing durable responses are achievable with Kymriah (tisagenlecleucel) when administered to adult patients with relapsed or refractory diffuse large B-cell lymphoma.  

The overall response rate was 52 percent (95 percent confidence interval [CI], 41 percent – 62 percent), among 93 evaluable patients who were followed for at least 3 months or discontinued earlier. A complete response was achieved in 40 percent of patients and 12 percent achieved a partial response.

Of the patients in CR at month 3, 83 percent remained in CR at month 12, and the median duration of response was not reached, indicating sustainability of response. These data will be presented in an oral presentation at the 23rd Annual Congress of the European Hematology Association. 

In the JULIET study, the relapse-free probability at 12 months after a patient’s first response (n=48) was 65 percent (95% CI, 49%-78%). In fact, 54 percent (13/24) of patients who had achieved a PR converted to CR, including two patients between months 9 and 12. 

Median overall survival was not reached for patients in CR (95% CI, 17.9-NE). The OS rate at 12 months was 49 percent and median OS was 11.7 months among all infused patients (n=111) (95% CI, 6.6-NE). The median time from infusion to data cutoff was 14 months with a maximum time from infusion of 23 months. At the time of data cutoff, no patients in response following treatment with Kymriah proceeded to stem cell transplant.

Within eight weeks of infusion with Kymriah, Grade III/IV cytokine release syndrome, as defined by the Penn Grading Scale, was reported in 22 percent of patients (14 percent grade III; 8 percent grade IV).  

Fifteen percent of patients received tocilizumab for treatment of CRS, including only 3 percent of patients with Grade II CRS and 50 percent of patients with Grade III CRS. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. No deaths due to cerebral edema were reported.

In this analysis, 12 percent of patients had grade 3/4 neurologic adverse events, which were managed with supportive care. Grade III/IV cytopenias lasting more than 28 days, grade III/IV infections and grade III/IV febrile neutropenia occurred in 32 percent, 20 percent and 15 percent of patients, respectively.

Analyses to better characterize and predict severe CRS and neurologic events, including relationships with baseline clinical and laboratory parameters, dose and cellular kinetics will also be presented.

Fifty patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status reflecting the acute and progressive nature of r/r DLBCL. Twelve out of 165 (7.3 percent) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells.

In May 2018, FDA approved Kymriah for the treatment of adult patients with r/r large B-cell lymphoma after two or more lines of systemic therapy including DLBCL, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma based on data from the JULIET study.

Kymriah is not approved for the treatment of patients with primary central nervous system lymphoma. The European Medicines Agency is evaluating the Marketing Authorization Application for Kymriah for the treatment of children and young adults with r/r B-cell acute lymphoblastic leukemia and for adult patients with r/r DLBCL.

JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only globally conducted study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.


Lonsurf improves OS in metastatic gastric cancer

Taiho Oncology Inc. and Servier announced clinical data from the pivotal phase III trial (TAGS) evaluating Lonsurf (trifluridine and tipiracil, TAS-102) plus best supportive care versus placebo plus BSC in patients with previously treated metastatic gastric cancer refractory to standard therapies.

This trial met its primary endpoint of overall survival and secondary endpoint measures of progression-free survival, and safety and tolerability, as well as quality of life. The data were presented as oral and poster presentations at the ESMO 20th World Congress on Gastrointestinal Cancer 2018 in Barcelona, June 20 to 23.

In the TAGS trial, patients treated with Lonsurf had a 31 percent risk reduction of death and a prolongation of their median survival by 2.1 months when compared with placebo (OS of 5.7 months compared to 3.6 months in the placebo group (hazard ratio [HR]: 0.69; 95 percent confidence interval 0.56, 0.85; one-sided p=0.0003); at 12-months, OS rates were 21.2 percent in the Lonsurf group and 13.0 percent in the placebo group. In addition, the risk for disease progression as measured by PFS, a key secondary endpoint, was reduced by 43 percent (HR: 0.57).

Any Grade 3 or higher adverse events (AEs) occurred in 80 percent of treated patients who received Lonsurf and in 58 percent of treated patients who received placebo. Grade 3/4 hematological AEs in patients treated with trifluridine and tipiracil included neutropenia (38 percent), leucopenia (21 percent), anemia (19 percent) and lymphocytopenia (19 percent). Of the 38 percent of patients who experienced grade 3/4 neutropenia when treated with Lonsurf, six (2 percent) experienced febrile neutropenia. No new safety signals were observed for Lonsurf in the TAGS study.

“We intend to include these data in an sNDA submission to FDA for consideration as a third-line treatment option for appropriate patients with metastatic gastric cancer,” said Martin Birkhofer, senior vice president and chief medical officer of Taiho Oncology.

Lonsurf is currently indicated in the United States for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy.


Greater levels of vitamin D associated with decreasing risk of breast cancer

Higher levels of vitamin D are associated with decreasing risk of breast cancer, according to researchers at University of California San Diego School of Medicine who conducted an epidemiological study published in the June 15 online issue of PLOS ONE. 

The study was conducted in collaboration with Creighton University, Medical University of South Carolina and GrassrootsHealth, an Encinitas-based nonprofit organization that promotes vitamin D research and its therapeutic benefits. 

Researchers pooled data from two randomized clinical trials with 3,325 combined participants and a prospective study involving 1,713 participants to examine the association between risk of female breast cancer and a broad range of serum 25-hydroxyvitamin D (25(OH)D) concentrations, which was chosen as the marker because it is the main form of vitamin D in blood.

The data were collected between 2002 and 2017—all women were age 55 or older, and the average age was 63. Participants were free of cancer at enrollment and were followed for a mean period of four years. Vitamin D levels in blood were measured during study visits.

Over the course of the combined studies, 77 new cases of breast cancer were diagnosed for an age-adjusted incidence rate of 512 cases per 100,000 person-years.

Researchers identified the minimum healthy level of 25(OH)D in blood plasma to be 60 nanograms per milliliter, substantially higher than the 20 ng/ml recommended in 2010 by the Institute of Medicine, now the National Academy of Medicine, a health advisory group to the federal government. Some groups, such as GrassrootsHealth, have advocated higher minimums for health blood serum levels of vitamin D, as much as 50 ng/ml. The matter remains hotly debated.

“We found that participants with blood levels of 25(OH)D that were above 60 ng/ml had one-fifth the risk of breast cancer compared to those with less than 20 ng/ml,” said principal investigator and co-author Cedric Garland, adjunct professor in the UC San Diego Department of Family Medicine and Public Health. Risk of cancer appeared to decline with greater levels of serum vitamin D.

Multivariate regression was used to quantify the association between 25(OH)D and breast cancer risk, with the results adjusted for age, body mass index, cigarette smoking and intake of calcium supplements, said first author Sharon McDonnell, an epidemiologist and biostatistician for GrassrootsHealth. “Increasing vitamin D blood levels substantially above 20 ng/ml appears to be important for the prevention of breast cancer.”

Garland, who has previously studied connections between serum vitamin D levels and several types of cancer, said the study builds upon previous epidemiological research linking vitamin D deficiency to a higher risk of breast cancer. Epidemiological studies analyze the distribution and determinants of health and disease, but it has been argued that they do not necessarily prove cause-and-effect.

“This study was limited to postmenopausal breast cancer. Further research is needed on whether high 25(OH)D levels might prevent premenopausal breast cancer,” Garland said. The population was also mainly white women so further research is needed on other ethnic groups.


Diabetes diagnosis later in life may signal early pancreatic cancer in African-Americans and Latinos

African-Americans and Latinos who are diagnosed with diabetes after age 50 are at increased risk of developing pancreatic cancer, according to a study from the Keck School of Medicine of USC.

Each year, more than one million Americans are diagnosed with adult-onset diabetes mellitus, also known as type 2 diabetes. The diagnosis comes with a long list of potential complications: high blood pressure, nerve damage, kidney disease, stroke, glaucoma and more. But for African-Americans and Latinos, a diagnosis of diabetes after age 50 may also come with a more than threefold risk for developing pancreatic cancer, according to a new study led by the Keck School of Medicine of USC published today in the Journal of the National Cancer Institute.

“There are very few studies on diabetes and pancreatic cancer that include Latinos and African-Americans,” said the study’s lead author V. Wendy Setiawan, associate professor of preventive medicine at the Keck School. “Both groups have a high rate of diabetes, and African-Americans, in particular, have a higher risk of developing pancreatic cancer relative to other racial/ethnic groups. Because most people with pancreatic cancer are diagnosed at a late stage, the five-year survival rate is low—about 8 percent. Identifying people who are at high risk early on could potentially save their lives.”

Symptoms of pancreatic cancer typically present when the disease is in its later stages, and no screening methods currently exist.

Using prospective data from approximately 49,000 African-Americans and Latinos, the researchers found that people who were diagnosed with diabetes between the ages of 65 and 85 were more likely to develop pancreatic cancer within three years as compared with people without diabetes.

The data showed that Latinos were four times more likely to develop pancreatic cancer within three years of a diabetes diagnosis, and African-Americans were three times more likely. The research team also looked at whether late-onset diabetes was associated with breast, prostate or colorectal cancer, and no association was found.

“What we found is that, yes, diabetes is associated with pancreatic cancer in African-Americans and Latinos, but we also discovered that there is a different type of diabetes here, a late-onset diabetes that’s associated with developing pancreatic cancer within 36 months. The evidence suggests that late-onset diabetes may be an early sign of pancreatic cancer,” Setiawan said.

Late-onset diabetes may be a useful marker for pancreatic cancer, she said, providing an opportunity to screen high-risk groups with new tools such as liquid biopsy, which is a test that looks for cancer cells or DNA from cancer cells in the blood.


Study finds emergency colon cancer surgery performed on weekends more likely to lead to complications

The likelihood of severe complications after emergency colon cancer surgery is significantly higher over the weekend, according to a study in the latest issue of JNCCN – Journal of the National Comprehensive Cancer Network.

The study examined 5,052 patients who underwent emergency colon cancer surgery at any Dutch hospital between 2012 and 2015, plus another 172 emergency rectal cancer surgery recipients. It found, after adjusting for case-mix, that weekend surgeries had a 66 percent higher mortality rate, and a 29 percent higher severe complication rate, compared to Monday surgeries.

The study, ”Weekend Effect in Emergency Colon and Rectal Cancer Surgery: A Prospective Study Using Data From the Dutch ColoRectal Audit,” was led by Perla Marang-van de Mheen of the Leiden University Medical Centre, Netherlands, and funded by the Dutch Cancer Foundation.

The researchers used data from the Dutch ColoRectal Audit, which contains a wide range of information on patient and tumor characteristics, treatment, and complications. Planned surgeries were omitted from the study, and weekends were defined as Saturday and Sunday, plus any national holidays. Severe complications were defined as any post-operative complication that led to a hospital stay of more than 14 days or required an additional operation. Of the 5,052 patients who underwent emergency colon cancer surgery during the study’s time period, 4,244 (84 percent) were carried out on a weekday, versus 808 (16 percent) during the weekend.

The published results include a call for more research, particularly regarding how care is organized across various hospitals during the weekend, not just for the pre-operative period, but also for post-operative care. These results are probably due to “a far more complex interplay between different factors, regarding both the patient and the organization, rather than simply the day of the initial surgery itself,” said Dr. Marang-van De Mheen.

“Allocating appropriate resources during weekends and holidays is critical to achieving outcomes that are just as good on the weekends as they are during the workweek,” said Steven Nurkin, associate professor in the Department of Surgical Oncology at Roswell Park Comprehensive Cancer Center, and a member of the NCCN Clinical Practice Guidelines in Oncology Panel for Colorectal Cancers. “The authors should be commended on a very timely study. These results are concerning, and need to be seriously considered. However, I think we need to be careful in extrapolating just from this study that surgical patients have significantly worse outcomes on the weekends. The weekend on-call teams are there for those true emergencies, and the ‘urgent, but not emergent’ surgeries may be delayed until the early workweek. Those that get operated on during weekends are frequently ‘the sickest of the sick’ and are therefore at higher risk of complications and worse outcomes.” 

“Regardless of whether surgery takes place on a weekend or during the week, it’s always important for patients to report any symptoms right away, to make sure that hospital staff has all the relevant information needed to catch complications early on,” Marang-van De Mheen said.

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