PI3K Inhibitors for HR+ MBC


The relevance of PIK3CA mutations in terms of the pathophysiology of HR-positive metastatic breast cancer, and lessons learned in practice and via clinical studies in terms of sequencing therapy with PI3K inhibitors.

Gabriel N. Hortobagyi, MD, FACP: The PI3 gene is a critical gene that is centrally located in multiple metabolic processes. Mutations of this gene, the PIK3CA] occur in about 40% of patients with hormone receptor-positive breast cancer. Some of the mutations occur in the activating sequences, some of them do not, but this is a frequent mutation—a frequent event, in a fairly large gene sequence. The presence of mutations in PIK3CA is associated with endocrine resistance and because of that, there has been much effort in developing strategies to prevent or perhaps reverse endocrine resistance in this setting. The presence of PIK3CA mutations is associated with a more limited progression-free and overall survival in hormone receptor-positive metastatic breast cancer but the benefits from CDK4/6 inhibitors are still present in both the mutated and the wild-type groups. There have been efforts to develop inhibitors of PIK3CA and alpelisib is an inhibitor of the alpha isoform of this gene, and has been shown in the SOLAR-1 clinical trial [NCT02437318] to have a significant effect in prolonging progression-free survival, as well as showed a numerical superiority in overall survival. We now have an agent that inhibits mutated PIK3CA tumors and is a treatment of choice for those patients who have progressed on frontline endocrine therapy and who are carriers of this mutation.

Alpelisib and other PI3 kinase inhibitors have somewhat significant adverse events associated with their use and to a large extent, because of their central location in various metabolic pathways; perhaps the most common occurrence when using alpelisib is the development of hyperglycemia. This is actually an on-target effect of alpelisib and it occurs in about 75% of patients with still a significant fraction of patients experiencing grade 3 and 4 hyperglycemia. This adverse effect requires, first of all, the selection of patients. The patients with diabetes, for instance, are probably not good candidates for alpelisib treatment, and those who have inherent or baseline glucose intolerance. Those who are eligible for treatment on the other hand need to be educated properly and monitored closely during the first 2 or3 cycles so that the occurrence of hyperglycemia can be detected early and managed appropriately. Appropriate management consists of dietary modifications to minimize hyperglycemia, the use of oral hyperglycemics for grade 1 and grade 2 hyperglycemia, and the addition of insulin as needed for higher levels. In the case of more serious events with hyperglycemia, a treatment interruption and in the extreme situation treatment discontinuation is appropriate. Other important adverse effects related to alpelisib include a rash, which can be maculopapular, or it can be acne form. It usually appears within the first 2 or t3 months of treatment and can range and grade from 1 to 3. It is rare to experience a higher-grade skin rash. The skin rash can be pruritic in nature and it requires again, appropriate education for patients and preventive interventions. Baseline antibiotic therapy has been recommended to reduce the incidents of this adverse effect and collaboration with the dermatologist is often beneficial in the management of these patients. In the higher grade situations or in recurring events the interruption of treatments, a dose reduction, and again, in more advanced grade skin rash, discontinuation of treatment results in complete reversal. Other adverse effects are managed similarly but in the management of the treatment with alpelisib it is critically important to educate your patient well to be proactive in eliciting symptoms or laboratory abnormalities and following standardized approaches to managing symptoms or toxicity to be able to continue treatment to the benefit of your patients without affecting adversely the quality of life.

Sara A. Hurvitz, MD: The SOLAR-1 study, looked at the addition of alpelisib to fulvestrant in a phase 3 clinical trial in patients whose disease had progressed on prior endocrine therapy and whose tumors contained a PIK3CA mutation. Alpelisib, of course, showed an improved progression-free survival in this study. And so, investigators from SOLAR-1 wanted to look at an analysis of postprogression therapy and see whether being on the alpelisib arm or the placebo arm impacted the type of postprogression therapy and the benefit from postprogression therapy. In this study, they showed that the median duration of chemotherapy, hormone therapy, and targeted therapy as the next line regimen was fairly similar when looking at the alpelisib arm and the placebo arm. They also showed that chemotherapy-based treatment tended to be more frequent as the next postprogression therapy in those patients in the alpelisib arm who had a shorter progression-free survival of 6 months or less compared with those patients whose PFS [progression-free survival] was greater. This, of course, makes sense, a shorter PFS would indicate more aggressive disease biology, perhaps instigating a physician to choose chemo as the next partner. In summary, this study indicated that alpelisib and fulvestrant doesn't seem to diminish the potential for benefit for subsequent antineoplastic therapy compared to placebo plus fulvestrant in the SOLAR-1 study. This thus further supports the use of alpelisib in this particular disease setting.

Transcript edited for clarity.

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