Trabectedin in Advanced Soft-Tissue Sarcoma

Priority Review Granted for Trabectedin in Advanced Soft-Tissue Sarcoma

By The ASCO Post
March 25, 2015, Volume 6, Issue 5



The U.S. Food and Drug Administration (FDA) has granted Priority Review for the New Drug Application (NDA) for trabectedin to treat patients with advanced soft-tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, who have received prior chemotherapy including an anthracycline. The NDA for trabectedin was submitted to the FDA on November 24, 2014.

Trabectedin is a novel, multimodal, synthetically produced antitumor agent—originally derived from the sea squirt Ecteinascidia ­turbinata—that prevents tumor cells from ­multiplying.

The filing is based on the phase III randomized, open-label study ET743-SAR-3007. This trial is evaluating the safety and efficacy of trabectedin vs dacarbazine for the treatment of patients with advanced liposarcoma and leiomyosarcoma. Results will be presented at a later date. ■

Role of Ramucirumab in Colorectal Cancer

Addition of Ramucirumab to Second-Line FOLFIRI Improves Overall Survival in Metastatic Colorectal Cancer

By Matthew Stenger
June 10, 2015, Volume 6, Issue 10

Josep Tabernero, MD, PhD

Role of Ramucirumab in Colorectal Cancer

Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments.
—Josep Tabernero, MD, PhD

In the phase III RAISE trial reported in The Lancet Oncology, Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall d’Hebron Institute of Oncology, Barcelona, and colleagues found that the addition of the antiangiogenic anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab (Cyramza) to second-line FOLFIRI (leucovorin, fluorouracil, irinotecan) improved overall survival in patients with metastatic colorectal cancer that had progressed on first-line bevacizumab, oxaliplatin, and fluoropyrimidine treatment.1

Study Details

In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab at 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after progression on first-line therapy. Randomization was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population.

The ramucirumab and control groups were generally balanced for age (mean, 62 years in both, 40% ≥ 65 years in both), sex (54% and 61% male), ethnicity (76% and 77% white, 21% and 19% Asian), region (Europe for 44% in both, North America for 27% in both), Eastern Cooperative Oncology Group performance status (0 for 49% and 48%, 1 for 50% and 51%), time to progression after start of first-line treatment (≥ 6 months for 77% and 76%), KRAS mutation status (mutant in 50% and 49%), carcinoembryonic antigen level (< 200/µg/L in 73% in both), number of metastatic sites (1 in 32% and 29%, 2 in 33% and 36%, ≥ 3 in 29% and 34%), and site of primary tumor (colon in 67% in both, rectum in 33% and 32%).
Improved Overall Survival

After study medication, subsequent systemic anticancer therapy was received by 54% of the ramucirumab group and 56% of the control group. Median follow-up was 21.7 months.

Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4–14.5 months) in the ramucirumab group vs 11.7 months (95% CI = 10.8–12.7 months) in the control group (hazard ratio [HR] = 0.844, P = .0219). Hazard ratios favored the ramucirumab group in all evaluated subgroups, including KRAS status, time to disease progression, and region subgroups.

Median progression-free survival was 5.7 months (95% CI = 5.5–6.2 months) vs 4.5 months (95% CI = 4.2–5.4 months; HR = 0.793, P < .0005), with hazard ratios favoring ramucirumab in all evaluated subgroups. Objective response rates were 13.4% vs 12.5%, (P = .63). Adverse Events

Grade ≥ 3 adverse events occurred in 79% of the ramucirumab group (grade 4 in 17%) vs 62% of the control group (grade 4 in 14%). The most common were neutropenia (38% vs 23%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). Febrile neutropenia occurred in 3% vs 2%.

Grade 5 adverse events consisted of bleeding/hemorrhagic events in three patients in the ramucirumab group and one in the control group, gastrointestinal (GI) hemorrhage in three and one, liver injury/failure in one and one, GI perforation in four and zero , arterial thromboembolic event in one and five, and congestive heart failure in one and two.

Serious adverse events occurred in 36% vs 31% of patients. Adverse events led to dose modification in 83% vs 75% and discontinuation in 11% vs 4%. Ramucirumab dose omission, dose reduction, and discontinuation occurred in 8%, 6%, and 4%, respectively.

The investigators concluded:

In view of our results, the combination of ramucirumab with FOLFIRI is an effective second-line treatment for patients with metastatic colorectal carcinoma. Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments. We have begun translational research of prespecified potential biomarkers to assist in selection of patients. ■

Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.

Physical Activity Protects Motor Function in Older Adults

From Medscape Education Clinical Briefs
Physical Activity Protects Motor Function in Older Adults CME/CE

News Author: Pauline Anderson
CME Author: Laurie Barclay, MD



Motor impairment in the elderly population is common and linked to morbidity. Public health strategies have therefore emphasized the need for older adults to increase their physical activity level.

White matter hyperintensities (WMHs) seen on brain imaging are common in elderly adults and are associated with level of motor function. The goal of this cross-sectional study by Fleischman and colleagues was to test the hypothesis that physical activity modifies the association between WMH burden and motor function in healthy older persons without dementia.

Study Synopsis and Perspective

Just as higher education and social connections seem to provide a cognitive reserve as people age, physical activity may build a motor reserve that protects against the harmful effects of WMHs in the brain on motor function, new research suggests.

The results point to a potential biological mechanism that may at least partly explain the well-established association between physical activity and motor function in healthy older adults, said lead author Debra A. Fleischman, PhD, professor, neurological sciences and behavioral sciences, Rush University Medical Center and Rush Alzheimer's Disease Center, Chicago, Illinois.

"The data suggest that physical activity may protect motor function from the untoward effects of small vessel disease," seen on magnetic resonance imaging (MRI) as WMHs.

The new findings emphasize the importance of an active lifestyle in protecting motor function from the adverse neurobiological effects of aging, Dr Fleischman said.

The study was published online March 11 and in the March 31 issue of Neurology.

Brain Volume

The study used data from 167 community-dwelling adults without dementia who were participants in the Rush Memory and Aging Project, an ongoing longitudinal clinical pathologic study of aging and dementia. Their mean age was 80 years, and approximately 21% were men.

Researchers used a composite measure of global cognition from 19 individual computer-scored cognitive tests. To assess motor function, they created a composite measure from 11 individual motor tests that included both upper- and lower-extremity motor performance.

Using actigraphs, the investigators measured total daily activity, including all exercise and nonexercise physical activity. Participants wore a watch-like monitor on the nondominant wrist for 24 hours per day for up to 11 days. The data were then downloaded to a computer for analysis. Researchers also calculated intensity of activity.

To assess WMH burden, they used a well-established, automated computer program that measures the total volume of brain tissue affected by WMHs as shown on fluid-attenuated inversion recovery MRI. Dr Fleischman noted that although studies suggest that WMHs on MRI reflect small-vessel disease, more studies are needed to characterize the pathologic bases of WMH.

After adjustment for age, gender, and education, total daily activity was not associated with WMH burden (P = .169).

As did previous research, this study showed that a higher level of WMH burden was associated with poorer motor function, but it also found that the harmful effects of WMHs disappeared in active people.

Comparing participants in different percentiles of total daily activity, they showed that in those with the highest activity (90th percentile) WMH burden did not affect motor function. In contrast, those at the 50th percentile of physical activity showed a negative effect of WMH burden on motor function, and this effect was even stronger for those in the 10th percentile of activity.

The difference between the 90th and 50th percentiles is roughly an additional 1.5 hours of walking per day at 2.5 miles per hour, Dr Fleischman noted. And the difference between the 50th and 10th percentiles translates to just less than 1 hour of additional walking per day.

This interaction persisted after controlling for various potential confounding variables, including depressive symptoms, body mass index, vascular diseases, functional status, and interactions with WMH burden.

"Together these findings suggest that higher levels of physical activity may provide reserve against the effects of brain pathology on motor function in older age," the authors conclude.

Dr Fleischman stressed that the association was significant when 2 different actigraphic measures were used: total daily activity and intensity of daily activity. There was no association when physical activity was measured by self-report.

Neural Reserve

That physical activity was not associated with WMH burden suggests that the benefit on motor function is through a neural reserve mechanism rather than through a direct association with WMH. Dr Fleischman suggested possible candidate mechanisms, including increases in various trophic factors that promote tissue survivability and genesis. However, she said, more work needs to be done to examine the potential mechanisms underlying motor reserve.

The concept of reserve has been frequently used in relationship to cognition. Studies show that older patients with higher levels of education, social networks, and purpose in life have better cognitive function despite significant Alzheimer disease pathology burden.

The same concept may be at play here: physically active people may have the same amount of brain damage as physically inactive people, but this damage does not seem to affect their motor function. Unlike education, however, physical activity is a modifiable behavior at any age.

The motor reserve provided by physical activity may have an influence at multiple sites along motor pathways. Although in the current study, the brain proxy measure was limited to WMH burden, further studies that examine a wider array of central nervous system abnormalities and other components of the motor pathways "will be crucial for defining the neurobiological basis of reserve provided by physical activity," said the authors.

The new findings underscore the importance of facilitating a more active lifestyle to prevent late-life motor impairment, improve survivability, and maintain independence and well-being, said the authors.

For people older than 65 years, the US Centers for Disease Control and Prevention recommends that older adults get at least:

2 hours and 30 minutes of moderate-intensity aerobic activity (eg, brisk walking) every week plus muscle strengthening activities on 2 or more days per week that work all major muscle groups; or
1 hour and 15 minutes of vigorous-intensity aerobic activity (eg, jogging or running) every week and muscle-strengthening activities on 2 or more days per week that work all major muscle groups; or
An equivalent mix of moderate- and vigorous-intensity aerobic activity and muscle-strengthening activities on 2 or more days per week that work all major muscle groups.

As for the type of exercise, that is an individual choice that considers existing medical conditions and leisure-time preferences, said Dr Fleischman. "I think that the important message, and the one that I give to my patients, is that they do not have to be marathon runners to maintain cognitive and motor function through physical activity as they age."

Other studies by Dr Fleischman and her research group showed that participants with the highest level of total daily activity, no matter how this is accumulated, are at the lowest risk for cognitive and motor impairment and decline as they age. "So the message is to just keep moving in any way that is safe and enjoyable."

This is particularly important because, unlike many age-related conditions that impair motor function, such as Parkinson disease and arthritis, age-related motor impairment is usually left untreated, said Dr Fleischman.

"Until we have a more complete understanding of the biological mechanisms underlying chronic late-life motor impairment, and have developed effective pharmacological treatments to lessen the effects of brain pathology on motor function, efforts to encourage and facilitate an active lifestyle in older adults will be a critical element in meeting this public health challenge."

The research group is acquiring longitudinal scans that will allow them to measure changes in all the primary variables and compare them with baseline, said Dr Fleischman.

Physical Activity a "Panacea"?

The study is yet another example of how physical activity is a kind of "panacea" in medicine, commented Glen Finney, MD, assistant professor, neurology, University of Florida College of Medicine, Gainesville, and a member of the American Academy of Neurology.

"We have seen similar effects for cognitive function and now they have found it in the motor domain. This supports the idea that physical activity is good for everything."

He noted that the motor function in this case is determined by the brain. "The research clearly shows that lower levels of physical activity are correlating with brain disease burden, so clearly this is brain-driven motor function. But once you get to a high level of physical activity, it actually helps to overcome and sort of negate that white matter burden."

Although the authors speculate that this is because of a motor reserve, Dr Finney said he would like to see a prospective study look at whether it is really a reserve or an actual treatment effect. "At this point, it's correlation; it's not causation. It's a definite possible way this works," he said.

According to an accompanying editorial, the "pooled approach" of using a composite motor score and a range of cognitive tests is statistically powerful but needs further development to be accessible in routine clinical practice.

The editorial writers, Richard Camicioli, MD, Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada, and Joe Verghese, MB BS, MS, Departments of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, New York, noted that the 167 participants were more educated and cognitively healthy although slightly older than the overall sample of 1545 persons originally recruited for the study.

They also commented that because the study was cross-sectional, it cannot determine causality. In addition, they note, actigraphy measures total activity, so it is difficult to know which aspects of the activities were protective.

"The nature (aerobic or resistance), complexity (dancing), or frequency of the physical activity may all have a role," they said.

Measuring WMHs by fluid-attenuated inversion recovery imaging may not completely reflect white matter damage, they said. Diffusion tensor imaging or magnetization transfer imaging may better depict white matter damage, might provide complementary measures, and may be related to physical activity.

The study was supported by the National Institute on Aging, National Institute of Minority Health and Health Disparities, Illinois Department of Public Health, and Rush Translational Science Consortium. The study authors and editorial writers have disclosed no relevant financial relationships.

Neurology. 2015;84:1294-1300, 1288-1289. Abstract, Editorial