Depth of Response to Therapy May Be a New Way to Measure Drug Success


CME NUGGETS

Ed Susman

Mr. Susman is a freelance medical writer based in Florida, USA. He travels worldwide to report from medical conferences, writing regularly for wire services, internet websites, and medical journals such as the Journal of the National Cancer Institute and AIDS.

For comments, edwardsusman@cs.com


CHICAGO, Illinois – Since the 1980s, success of a cancer treatment has been measured by using RECIST (Response Evaluation Criteria in Solid Tumors) to evaluate response to therapy, but now a study authored by researchers from the U.S. Food and Drug Administration suggest there could be a better method.

RECIST has two levels: A partial response defined as a 30 percent reduction in tumor burden and a complete response, 100 percent reduction of tumor burden, said Christy Osgood, MD, a pediatric oncologist and medical officer with the Food and Drug Administration, Silver Spring, Maryland.

“RECIST does not provide any granular response between 30 percent reduction and 100 percent,” she said in her oral presentation at the 55th annual meeting of the American Society of Clinical Oncology. “Thus, the current system may not capture the full spectrum of benefit derived for more recently developed targeted kinase inhibitors or immunotherapies.”

In her study, Dr. Osgood reported that advanced melanoma patients who were treated in clinical trials with immunotherapies, the CD-1 or CTLA inhibitors, about 95 percent of patients who had achieved a complete response were alive at 36 months; about 90 percent of the patients who had achieved a 76 percent to less than 100 percent reduction in tumor burden were alive at 36 months and about 80 percent of the patients who achieved a 51 percent to 75 percent reduction in tumor burden were alive at 3 years.

But patients who achieved less reductions in tumor burden fared worse: Those who reduced tumor burden by 26 percent to 50 percent had a 3-year survival of about 60 percent; those with a reduction of 25 percent of less had a 3-year survival of about 50 percent, and those who did not show any reduction in tumor burden had a 3-year survival of less than 25 percent, Osgood illustrated.

“Depth of response correlates with a longer progression-free survival and overall survival regardless of therapy type,” she said.

For targeted agents, BRAF and MEK inhibitors, a greater than 75 percent depth of response was associated with greater chance of 2-year survival compared with patients who achieved lower levels of success in eliminating tumor burden, Osgood reported. A complete response with the agents translated to 80 percent survival at 2 years; a 76 percent or greater response translated to a 70 percent survival. Less of a reduction in tumor burden resulted in 2-year survival that was 50 percent of less, with lower reduction resulting in lower chance of being alive at 2 years, she reported.

Osgood and colleagues gathered randomized trial data in marketing applications to the FDA between 2011 and 2018 evaluating drugs in patients with previously untreated advanced or metastatic melanoma. They identified 10 randomized trials that included 4,826 patients. After culling patients with incomplete data or those who did not receive trial drugs, the researchers evaluated outcomes in 4,278 patients.

The researchers stratified treatments by targeted kinase inhibitors, immunotherapy, and chemotherapy, mainly dacarbazine and paclitaxel.

The depth of response was stratified by those patients in whom no decrease in tumor burden occurred; those with a 25 percent of less response; those with a 26 percent to 50 percent response; those with a 51 percent response to a 75 percent response; those with a 76 percent to less than 100 percent response; and those patients who achieved a 100 percent or complete response.

About 59 percent of the patients in the studies were men. The average age of the patients was 57, but ranged from 17 to 93; about 95 percent of the patients were white; about 72 percent were in ECOG stage 0; 93 percent were diagnosed as Stage IV disease; 34 percent were found to have elevated lactase dehydrogenase levels, a sign of cancer-mediated cell damage; BRAF mutations were found in 68 percent of patients.

Minimal surgery equal to open procedure

In another study, researchers reported that patients who undergo minimally-invasive laparoscopic surgery to excise colorectal cancer metastases to the liver appear to have similar outcomes to undergoing open surgery.

Asmund Fretland, MD, a surgeon at Oslo University Hospital in Norway, reported that after 5 years, 57 percent of the 147 patients who were treated with open surgery in the intention-to-treat population were still alive compared with 56 percent of the 133 patients who were treated with laparoscopy (p=.91).

The one-year results were similar with 93 percent of the open surgery patients surviving after 12 months and 94 percent of laparoscopic surgery patients alive after 12 months, he said. In both groups, 71 percent of patients were alive after 2 years, Dr. Fretland reported.

He and colleagues enrolled 280 patients in the study conducted from 2010 through 2016, allowing for at least 3 years of follow-up. “Laparoscopy liver surgery not only had a lower rate of post-operative complications, an improved quality of life and was cost-effective, compared to open liver surgery, it also had life expectancies that are similar to open surgery,” he said.

In the per protocol population, of the 133 patients undergoing open surgery, 31 percent of the patients achieved recurrence free survival after 5 years compared with 29 percent of 120 patients who underwent laparoscopy (p=.73), Fretland reported.

In the study, the surgeons involved in performing the minimally-invasive procedure had previous done more than 400 liver surgery laparoscopic operations, Fretland said.

He said that 19 percent of the laparoscopic patients experienced postoperative complications compared with 31 percent of the patients who had open surgery. Patients undergoing the laparoscopic procedure spent about 2 days in hospital; the open surgery patients spent about 4 days in hospital. About 93 percent of resected tumors removed through open surgery had clear margins compared with 94 percent of the tumors resected through laparoscopic surgery, he reported.

“Laparoscopic surgery was better for the patients,” Fretland said, “and it required no additional cost. More hospitals should establish a laparoscopic liver surgery program. Training programs are vital.”

Combination treatment beneficial in breast cancer

The cyclin dependent kinase (CDK) 4/6 inhibitor ribociclib was associated with a statistically significant overall survival benefit in combination with endocrine therapy when compared with endocrine therapy alone among women with advanced breast cancer, researchers said.

After 42 months of follow-up, 70.2 percent of women who were assigned to treatment that included ribociclib were alive compared with 46 percent of women who had received only endocrine therapy, a 29 percent reduction in overall survival (p=.00973), reported Sara Hurvitz, MD, medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit and Director of the Breast Cancer Clinical Trials Program at the University of California at Los Angeles.

She also reported that the median overall survival has not yet been reached for patients receiving ribociclib in the study, compared with 40.6 months median overall survival for patients who did not receive ribociclib.

“The unique feature of this study is that all the 672 women enrolled were all premenopausal younger women, all under the age of 59,” Dr. Hurvitz said. “We evaluated whether a CDK 4/6 inhibitor ribociclib improves outcomes for women – improves the length of their disease control and overall survival.”

She said that in the randomized MONALEESA 7 trial, all patients received endocrine therapy, either an aromatase inhibitor or tamoxifen – which was selected in consultation with their physicians; they all received goserelin to turn off their ovaries and then half received placebo and the others received ribociclib.

The primary end point of MONALEESA 7, published in 2018, was an improvement in progression free survival, Hurvitz said, and that endpoint was met, showing that treatment with ribociclib was associated with about a 10-month median progression free survival advantage compared with patients who were in the placebo arm of the study. “Women were able to live with their disease controlled about 23.8 months,” she said.

“The use of a CDK 4/6 inhibitor in metastatic breast cancer that is hormone receptor positive and HER2-negative is absolutely the standard of care now,” she said. “This particular agent was FDA approved for premenopausal and peri-menopausal women based on the MONALEESA 7 data published in 2018. It is already available to patients who are already taking this as standard of care. What we have done now is demonstrated that this therapy they are receiving and have access to extend survival.

“I think one of the great things about these data is that it may improve access worldwide where overall survival needs to be demonstrated in order for governments and institutions to provide this type of drug to patients,” she said.

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