Alpelisib Arrives as New Targeted Option for Breast Cancer Subgroup

Dejan Juric, MD

In May 2019, the FDA approved alpelisib (Piqray) in combination with fulvestrant for the treatment of postmenopausal women and men with hormone receptor (HR)—positive, HER2-negative PIK3CA-mutated advanced or metastatic breast cancer, making it the first targeted therapy in this setting with a predictive biomarker.

Overall, approximately 70% of breast cancers are classified as HR positive/HER2 negative. Approximately 40% of patients with estrogen receptor (ER)—positive metastatic breast cancer harbor a PIK3CA mutation.¹

In an interview with OncologyLive^®, Dejan Juric, MD, an investigator in the phase III SOLAR-1 trial that led to the approval of alpelisib and director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center in Boston, discussed the significance of the alpelisib approval and the importance of developing a plan for the management of adverse events (AEs).

OncologyLive: Can you discuss the efficacy data that led to the approval of alpelisib?

Juric: SOLAR-1 enrolled a total of 572 patients and divided these patients into 2 cohorts based on their tissue mutation status for PIK3CA.² The mutated cohort had 341 patients, and the trial met its primary endpoint of progression-free survival [PFS], with prolongation of median PFS going from 5.7 months with fulvestrant and placebo to 11.0 months for patients treated with fulvestrant and alpelisib. The hazard ratio for that cohort was 0.65. The difference was both statistically significant and, most important, clinically meaningful. What is particularly interesting is that the PIK3CA wild-type cohort did not meet the prespecified criteria and the hazard ratio was 0.085.

This trial shows us 2 things: It shows the utility of alpelisib in prolonging median PFS in a subset of patients, but it also demonstrates the utility of using the PIK3CA mutation status as a predictive biomarker.

Please describe the mechanism of action.

Alpelisib, previously called BYL719, is an oral agent, a small molecule inhibitor blocking PI3K α isoform. PI3K is a very important regulator of cell survival and growth, and it plays a major role in cell signaling by connecting the growth factor receptors with downstream regulators controlling the cell cycle.

What is unique about [alpelisib] is that it selectively blocks just 1 isoform, the α isoform, and is able to block it 50 times more strongly than any other isoform. That is important because PIK3CA, the alteration of which we are using as a predictive biomarker, encodes the PI3K α and allows us to selectively block this oncogenic protein without necessarily affecting other isoforms that have bigger roles in normal tissues. By using this isoformselective inhibitor, we are able to improve the therapeutic window of this drug and its tolerability compared with older PI3K inhibitors that are simply too toxic for patients.

What else do we know about alpelisib’s tolerability?

The most frequent [AE] caused by alpelisib is hyperglycemia, with 36.6% [104 of 284] of patients in the alpelisib/fulvestrant arm experiencing grade ≥3 hyperglycemia. Only 0.7% of [2 of 287] patients receiving placebo experienced hyperglycemia. This is not surprising.

PI3K α is important for the function of insulin, and when you block it, insulin resistance is developed. Hyperglycemia is an on-target [AE] that is inextricably linked with the very action of the drug, and it is very important for practitioners who use alpelisib to understand this and learn how to manage hyperglycemia adequately using dietary measures and metformin and insulin sensitizer.

If the glucose cannot be controlled with these interventions, there is always the option to adjust the dose of the drug, and 2 dose reductions are permitted to improve the tolerability of this agent. If the drug is stopped, it has a relatively short half-life, and glucose [levels will] normalize on their own, usually within a day or two.

Overall, I think there will be a learning curve in using this agent; however, the [AEs] are fairly predictable, and with attention to some of these details, I suspect, patients will be able to tolerate this well. In my practice I’ve had patients who have been on alpelisib for more than 7 years, so certainly long-term tolerability can be achieved with these measures.

How does alpelisib fit into the current treatment paradigm?

Patients with ER-positive metastatic breast cancer have several treatment options, including hormonal therapies with CDK4/6 inhibitors, everolimus [Afinitor], an mTOR inhibitor, and cytotoxic chemotherapy. Although these treatments are active in ER-positive metastatic breast cancer, there is no current patient selection strategy for them. Alpelisib is the first targeted therapy treatment in this setting with a predictive biomarker, so only patients who have a PIK3CA mutation are candidates for the drug.

And that’s where knowing about the mutation and testing for it as early as possible will be critically important because without these results, patients are candidates for chemotherapy or everolimus-based therapy, which has its own [AEs], including stomatitis, pneumonitis, and fatigue.

What is really important, as well, and is a part of the approval of alpelisib, is that both tissue-based testing and circulating tumor DNA testing are allowed.

I suspect that in the first-line setting, patients would be treated with a CDK4/6-based hormonal therapy either in combination with an aromatase inhibitor or fulvestrant, and then in the second-line setting, if they [have a mutation], they would get alpelisib-based treatment. This is a very active area of research. There are a number of sequencing trials under way.

What are the next steps for alpelisib?

I think the question is whether alpelisib can be used in other subtypes of breast cancer, such as PIK3CA-mutated triple-negative or HER2-positive breast cancer. These mutations happen in those subtypes, and it will be important to define the role of alpelisib in those subsets of patients. I think there is plenty of work to be done to characterize both the role of PIK3CA mutations in those cancers and, additionally, the role of alpelisib in various drug combinations for those diseases.

In breast cancer, the interplay between the estrogen receptor and the PI3K inhibitor [is what] matters, and the combination of alpelisib and fulvestrant performs well in this setting. I think we will have to perform similar analyses across other diseases to develop specific combinations for those malignancies.

References

1. Juric D. New agents and markers for endocrine therapy resistance. Presented at: 18th Annual PER® Future of Breast Cancer East®; July 19-20, 2019; New York, NY.
2. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK- 3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.