SAN ANTONIO ― Older women with hormone receptor–positive, HER2-negative breast cancer experience a similar clinical benefit when treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as younger women with the disease, the results of a pooled analysis indicate.
Progression-free survival (PFS) was similar for patients aged ≥70 years as for those aged <70 years when given these drugs.
However, older women were more likely to experience serious adverse events than younger women and were more likely to have adverse events leading to drug discontinuation.
The results were reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017 by researchers from the US Food and Drug Administration (FDA).
They conducted a pooled, retrospective subgroup analysis of data from prospective randomized controlled trials in which the CDK4/6 inhibitors were used with an aromatase inhibitor for the initial treatment of hormone receptor–positive breast cancer.
Three CDK4/6 inhibbitors have been approved by the FDA for breast cancer ― palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis), and abemaciclib (Verzenio, Lilly).
Lead researcher Harpreet Singh, MD, scientific liaison for cancer in older adults and a medical officer in the Center for Drug Evaluation and Research at the FDA, said in a release: “As we approve new drugs to treat cancer, it is important to try to improve our understanding of the efficacy and safety of these drugs in our older patients.
“Our findings suggest that there is no treatment difference across age subgroups in terms of efficacy of CDK4/6 inhibitors,” she said.
This is an important piece of information as healthcare providers and patients weigh their treatment options.
“This is an important piece of information as healthcare providers and patients weigh their treatment options as new therapies are approved,” she added
Coauthor Lynn Howie, MD, a medical officer in the FDA, underlined that the increased severity of adverse events means that any potential benefits should be weighed against the risk for toxicity.
“Healthcare providers should counsel each patient individually on the potential benefit of these therapies, as well as the potential risks, taking into account the patient’s disease characteristics, performance status, comorbidities, social support, and treatment preferences,” she said.
Breast Cancer in Older Women
Dr Singh noted that breast cancer “is a disease of aging.” She highlighted that there are 72,000 new breast cancer cases in the United States every year among women aged ≥70 years and that more than 40% of breast cancer deaths are in women in this age group.
Older patients, especially those aged ≥70 years, have typically been underrepresented in breast cancer clinical trials, meaning that the safety and efficacy of treatments in this population is less well characterized.
Dr Singh explained that although women aged <65 years account for 57% of new breast cancer cases, they make up 80% of study participants. In contrast, women aged ≥75 years represent 19% of new cases but only 4% of trial participants.
Because there are few data on outcomes with CDK4/6 inhibitors in older women, the researchers turned to a subgroup analysis of clinical data that were already available.
From the prospective, randomized controlled trials in which the drugs were used with an aromatase inhibitor for the initial treatment of hormone receptor–positive breast cancer, they collected data on 1992 women, of whom 716 were aged <65 years, 555 were aged ≥65 years, and 329 were aged ≥70 years.
Women aged ≥70 years were less likely than those aged <65 years to have an ECOG performance status of 0 and were less likely to have received (neo)adjuvant chemotherapy or endocrine therapy.
There were no significant differences in the median PFS between the three age groups. The median PFS was not reported among women aged ≥70 years and was 23.75 months in those aged <70 years.
In women treated with an aromatase inhibitor only, the median PFS was 16.8 months in those aged ≥70 years vs 13.8 months in those aged <70 years.
Dr Singh said that similar results were obtained when using different age cutoffs, such as 65 years and 75 years.
Safety and Tolerability Analysis
The safety and tolerability analysis was conducted in 1106 women, of whom 627 were aged <65 years, 479 were aged ≥65 years, and 280 were aged ≥70 years. Adverse events were recorded up to 30 days after the last dose.
Overall adverse event rates were similar between the three age groups, regardless of whether the analysis was restricted to events of grades 1/2, 3/4, or 5.
Rates of adverse events leading to dose reduction and/or interruption were more common in women aged ≥65 years and ≥70 years than in those aged <65 years, at 75% and 77%, respectively, vs 66%.
The difference was even greater for adverse events leading to discontinuation, at 16% and 17%, respectively, vs 8%, and for serious adverse events, at 31% and 33% vs 16%.
Overall, rates of individual adverse events were similar between the patient groups, although Dr Singh noted that “the proportion of patients with infection, fatigue, and diarrhea appeared to trend slightly upwards with age.”
Speaking at a press conference, Dr Singh noted that there are a number of limitations to the study, including that the researchers pooled data for three different agents with similar but distinct safety profiles and that there were few women aged >75 years.
She said that there is potential to increase enrollment of older patients into studies, with the eligibility criteria “a good place to start.”
“Currently, they do tend to have very stringent requirements in terms of performance status and organ dysfunction that may not particularly relate to the drug, and so I think taking a rational approach to those with each drug…may at least allow for more older adults to be enrolled,” Dr Singh explained.
“The next step is the physician barrier: Do we have a bias in not enrolling these patients on a trial? I think that, as we become more flexible and dynamic in the oncology space and in the regulatory environment, it’s really important that we become more flexible in ways to obtain these data.”
Multiple Factors to Consider
Asked whether, on the basis of this evidence, CDK4/6 inhibitors could now be used in older patients, Joseph A. Sparano, MD, Montefiore Medical Center, Albert Einstein College of Medicine, New York City, who was not involved in the study, said that “there are multiple factors that weigh into a decision to use a CDK4/6 inhibitor as a component of initial therapy.”
He noted, “In general, the patients that we tend to treat with these agents in addition to standard endocrine therapy would be patients who may have a somewhat higher disease burden, shorter disease-free interval, are younger and more fit, so age does enter into it.”
Dr Sparano also said that there are barriers other than fitness that may prevent the drugs from being used in older patients, such as whether patients reside at home and, if so, whether they are independent, have help, or have family looking out for them. There are also financial ramifications.
“Having said that, I think this information does provide some reassurance about the safety and, perhaps more importantly, the efficacy of CDK4/6 inhibitors in this population, but also reinforces what we already know and have concerns about, which is that there are more adverse events in this population,” he commented.
Dr Sparano also pointed out that the patients in the analysis “don’t necessarily reflect the patients that we see in actual clinical practice.” He suggested that one way around the issue is prospectively to include subcohorts in larger trials to assess safety in patients who may be less fit and who are typically excluded.
Rowan Chlebowski, MD, PhD, research professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California, who also was not involved in the study, agreed, adding, that the issue of greater toxicity in older patients will have to be addressed in how the data are used.
“I would think that agencies that sponsor trials would be very reluctant to accept toxicity that they’re going to have to include on their label,” he said.
“So to be able to have a subcohort, say, that the FDA won’t count or will consider toxicity separately in this group vs the other group would greatly relieve the burden for investors,” he said.
In reply, Dr Singh said that the FDA is “certainly open to these types of proposals” and noted that this issue was discussed at a recent public meeting held in conjunction with the American Society of Clinical Oncology.
The study was run by the FDA. The authors have disclosed no relevant financial relationships.
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS5-06, presented December 8, 2017.
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