Good morning, thank you for this opportunity to present our work from the FDA. I have no disclosures. Breast cancer is a disease of aging, and nearly 72,000 breast cancers occur annually in women over 70. Although most breast cancers in older women are lower risk tumours, and most older patients with breast cancer die of other causes, approximately 40% of breast cancer-related deaths are in women over 70. Accrual of older patients to clinical trials has been a persistent challenge.

In our own review of FDA registration trials over a ten-year period, we found this classic U-shaped curve when we look at geriatric enrolment in clinical trials. While less than 60% of new cases of breast cancer are diagnosed in women under age 65, they make up about 80% of the clinical trial population. If you look at patients over age 75, up to 20% of new cases of breast cancer are diagnosed in women over 75, however they make up only about 4% of the clinical trial population. The FDA has several guidances which encourage investigators but do not require them to enrol adequate numbers of older adults onto clinical trials.

CDK 4/6 inhibitors are an active area of investigation in breast cancer and currently have indications in combination with an aromatase inhibitor as initial endocrine base therapy for hormone receptor positive, HER2 negative advanced or metastatic breast cancer, as well as for disease progression following endocrine therapy. However, we know very little about the safety and efficacy of these agents in older adults.

We conducted a pooled retrospective analysis of patients enrolled on randomised controlled studies which were submitted to the FDA for CDK 4/6 inhibitors in combination with an aromatase inhibitor as initial endocrine based therapy. The pooled efficacy population included close to 2,000 patients. Using Kaplan-Meier estimates and Cox proportional hazard models, we explored the effect of progression free survival and age. Demographic characteristics of the ITT population are shown here. There are 329 patients in the group over 70, you’ll note that most of the patients in the older age categories are ECOG performance status 1, as opposed to the younger cohort, you’ll see many of them have ECOG performance status 0. In terms of site of disease, this is well-balanced across age groups in terms of visceral and bone only. Only 22% of patients over 70 received neo-adjuvant or adjuvant chemotherapy compared to close to 50% of the younger patients under 65. Most patients presented with metastatic disease at presentation.

For patients over 70 treated with a CDK 4/6 inhibitor and an aromatase inhibitor, as depicted by the red dotted line, median progression free survival was not reached. For those under age 70, as depicted by the black dotted line, the median PFS was 23.8 months. For those in the control arm treated with an aromatase inhibitor alone, median PFS was 16.8 months in those over 70 and 13.8 months in those under 70. We looked for differences in treatment across age subgroups and there appears to be a similar benefit whether a patient is 70 or under. Also, we looked at alternative age cut-offs, like 65 and 75, and the results are similar.

We evaluated safety as well as measures of tolerability in all patients who received at least one dose of a CDK 4/6 inhibitor; approximately 25% of these patients were over 70. You’ll know that there are very few patients in the older age categories over 75, over 80, etc. Adverse events which occurred up to 30 days after the last dose of study drug were included. Here you see that rates of low-grade adverse events were similar across age groups, however patients over 65 and over 70 experienced higher rates of grade 3 and 4 adverse events, at 80-82%, compared to 66% in the lower age categories. In terms of measures of tolerability, we looked at adverse events leading to dose reduction and/or interruption, they were similar across age groups, though slightly higher in over age 65 and over age 70. Adverse events leading to discontinuation were higher at 16% and 17% in patients over 65 and over 70 compared to their younger counterparts, and serious adverse events were also higher, 31% and 33% in the older age categories compared to 16% in patients under 65. Selected adverse events which are typical of this class of agents were evaluated. Rates of neutropenia and hepatotoxicity were essentially unchanged across age groups. The proportion of patients with infection, fatigue and diarrhoea appeared to trend slightly upward with age, however were similar overall.

Based on our analysis, it appears that older patients derive similar benefit from treatment with CDK4/6 inhibitors as initial endocrine-based therapy for hormone receptor positive, HER2 negative metastatic breast cancer. The severity of events, as well as rates of dose modification and interruption, does appear higher in older patients, however, rates of selected adverse events appear generally similar across these pooled trials.

There are several limitations to this type of analysis. While the toxicity profile of these agents is generally well-known, we pooled data from three different agents. This analysis was powered to study the class of drugs as a whole in older adults and providers and patients are encouraged to refer to FDA labelling for specific drug information. There were very few patients in older age groups, especially those over 75, so the availability of prospective data in these patients is limited. By pooling data across trials we were able to gain some insight into the efficacy and safety of this class of agents in older adults.

We know that older adults enrolled on clinical trials are often more fit and with a better performance status than those seen in clinical practice. Perhaps by using assessment tools to determine physiologic age, as opposed to just chronologic age, we can better characterise our older patients.

There are many signs of progress. For example, there are ongoing efforts to modernise eligibility criteria which will promote greater inclusion of older adults. Specifically, taking a rational approach to organ dysfunction, such as requirements for renal function as well as prior malignancies in eligibility criteria, directly affect many older adults when being considered for clinical trials.

The use of patient reported outcomes is a critical adjunct which could help provide further information on tolerability of therapy in all patients but may be particularly valuable in our older patients. Also, the acquisition of real-world data from a more diverse oncology practice setting will help inform efficacy and safety of novel therapies in older adults. We are looking forward to further progress and efforts to increase the evidence base for treating older adults with cancer.
Thank you.