PIK3CA mutation + HR positive

BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

At current drug prices, alpelisib plus fulvestrant is not cost effective for patients with PIK3CA-mutated, HR+/HER2- ABC from a US payer perspective. Given the considerable progression-free survival (PFS) and overall survival (OS) benefits observed with alpelisib in this setting, further discussion and negotiation of the price of alpelisib are warranted to provide more favorable economic outcomes and thereby increase the value of the alpelisib plus fulvestrant regimen in patients.

The sonographic features of PIK3CA-mutated breast cancers were strongly associated with extensive and liquefied necrosis. The ability to predict molecular subtypes, particularly using US to detect the triple-negative subtype, may play an important role in early management and treatment.

Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer.

PIK3CA status is most often assessed in this group of pts and combination of alpelisib - PIK3CA inhibitor and fulvestrant is second-line treatment option in PIK3CA mutated pts. There was no relevant difference in TTF between two groups. However, PIK3CA mutated subgroup had more aggressive clinical features - more often presented with bone marrow infiltration and de novo aBC, statistically relevant OR 5.158 and 2.323 respectively, which is related to lower quality of life and highlights the importance of treatment improvement for this subgroup of pts. >*Statistically significant p<0.05.

Alpelisib (ALP), an α-selective PI3K inhibitor and degrader, is indicated in combination with fulvestrant (FUL) for pts with HR+, HER2− ABC following progression on/after endocrine therapy (ET)-based treatments (tx)... Cohort A (ALP + FUL) comprised 127 pts whose immediate prior tx was CDK4/6i + aromatase inhibitor (AI); Cohort B (ALP + letrozole) enrolled 126 pts whose immediate prior tx was CDK4/6i + FUL... After ≥18 mo follow-up, with mature data, ALP + ET demonstrated clinical activity in BYLieve Cohorts A, B, and C. Within the trial, ALP + ET showed median OS between 20.7 mo and 29.0 mo following prior CDK4/6i, chemotherapy, or ET. AEs associated with ALP were well defined and manageable, with no new safety signals observed in any cohort. Clinical trial information: NCT03056755.

While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.

Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.