Same pathway, different profile: clinical considerations with apelvis, capisetide, and inaliset

Alpelisib (Alpelisib)-Piqray is a first-in-classPIK3CA-targeted kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) Approved in combination with fulvestrant (Fulvestrant; Falsodex; AstraZeneca) for the treatment of patients with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated metastatic breast cancer. Post-approval, the U.S. Food and Drug Administration approved capivasertib (Truqap; AstraZeneca) for use with fulvestrant in the same population as apelvist, but with 1 or more mutations in the PIK3CA/AKT/PTEN pathway in 2020. Palbociclib (Ibrance; Pfizer Inc.) and fulvestrantare in the same population as apelix and carpizatin with PIK3CA mutations. Each drug has a unique place in the treatment of patients with the mutation, but their similarities and differences should be considered before initiating treatment.

PIK3CA, AKT and PTEN mutations represent some of the most common genetic alterations in cancer, present in about one-third of cases. Mutational activity of the PIK3CA gene encoding the PI3K catalytic subunit p110a results in constitutive activation of P13K, resulting in HR-positive endocrine resistance in cancer. This appears to be a negative prognostic and predictive factor for chemotherapy treatment in patients with estrogen receptor/progesterone receptor-positive and HER2-negative disease. Inhibits the PI3K/AKT pathway by dephosphorylating PIP3, thereby limiting AKT activation. Loss of PTEN leads to increased AKT activation and uncontrolled growth. Apelvis inhibits PI3K-α, which blocks signaling that leads to cell death and causes PI3K degradation to cause cell death. This allows Apelix to overcome resistance to older PI3K inhibitors. In contrast, carpisetin is a pan-AKT inhibitor that blocks all major forms of AKT (1, 2, and 3) and stops downstream signaling of PI3K.

Apelix was studied in postmenopausal women and men with HER2-negative and HR-positive breast cancer in a Phase 3, randomized, double-blind, placebo-controlled trial (NCT02437318). According to tumor mutation status, patients were divided into 2 cohorts (PIK3CA mutations and non-PIK3CA mutations). In each cohort, patients were randomly assigned in a 1:1 ratio to receive apelvis, 300 mg daily, fulvestrant or placebo, fulvestrant. The primary endpoint of the trial isProgression-free survival (PFS) in the PIK3CA mutation cohort, secondary endpoints were overall survival (OS) and response rate. Median PFS (mPFS) was 11.0 months in the apelvis group compared with 5.7 months (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001). In the trial, the exploratory median OS (mOS) of apelvis plus fulvestrant was 39.3 months.

Following this trial, a phase 2 trial based on the most recent treatment had 3 different cohorts (NCT03056755). Cohort a included patients previously treated with CDK4/6 inhibitors and aromatase inhibitors; among these, 50.4% of patients remained progression-free after 6 months of treatment with apelvis and fulvestrant. Cohort B included patients who progressed on a CDK4/6 inhibitor plus fulvestrant and subsequently received aclivib plus letrozole, with an mPFS of 5.7 months. Cohort C included patients who had received other treatments and had an mOS of 5.6 months.

Carpisetin was studied in a Phase 3, double-blind, placebo-controlled trial (NCT04305496) evaluating patients with HR-positive/HER2-negative locally advanced breast cancer. Inclusion criteria included patients with aromatase inhibitor progression with or without CDK 4/6 inhibitors. In this trial, carpisetin was used in combination with fulvestrant. The primary endpoint was PFS in the PIK3CA, AKT, or PTEN-altered population and the overall population. In the overall population, mPFS was 7.2 months (HR 0.60, 95% CI 0.51-0.71 P<.001) and in those with altered AKT pathways, mPFS was 7.3 months (HR 0.50, 95% CI 0.38-0.65, P<.001). The objective response rate to carpisetin was 22.9% in the overall population and 28.8% in those with AKT pathway alterations. This study also assessed health-related quality of life, showing that the median time to deterioration was 24.9 months and OS had not yet been reached.

A Phase 3, double-blind, placebo-controlled study investigated inalisek plus palbociclib and fulvestrant in patients with HR-positive/HER2-negative, PIK3CA-mutated breast cancer (NCT05646862) who progressed within 12 months of completion of adjuvant endocrine therapy (NCT05646862). The primary endpoint was PFS at 15 months compared with 7.3 months (HR 0.43 95%CI 0.32-0.59 P<0.001). The objective response rate was 58%, and the median duration of response was 19.2 months. Based on a median follow-up of approximately 34 months, mOS was 34 months. Ongoing chemotherapy for 35.6 months and preferred to receive chemotherapy

Most common adverse reactions (AEs) reported in pivotal trials. Apelvis is most commonly associated with hyperglycemia; however, discontinuation rates are significantly reduced through early intervention strategies, including initiating metformin at the first signs of hyperglycemia, using prophylactic antihistamines to prevent rash, and administering loperamide during episodes of diarrhea. CarpisetiHyperglycemia Rate2.3%. No grade 3 or 4 rash was reported with inariside, but 26% of patients experienced rash of all grades.

PIK3CA inhibitors greatly expand the options for patients with HR-positive cancers. Although all 3 drugs act on the AKT pathway, each drug has differences in efficacy and side effects. Apelvis has clinically meaningful benefits but appears to have a higher rate of adverse events, such as hyperglycemia and dermatological reactions. Carpisetin includes broader biomarker-based patient selection and is a good alternative for patients at risk for hyperglycemia. Inaliset is highly selective for PI3K and provides good results, but neutropenia and stomatitis can occur when combined with palbociclib.

In clinical practice, the selection of these agents should be guided by molecular profiles, previous lines of treatment, comorbidities, and patient preferences. Ongoing direct comparisons are currently lacking, but real-world data and future trials will be critical to refine the sequencing and optimal integration of these targeted agents in the evolving therapeutic setting.

References:https://www.pharmacytimes.com/view/same-pathway-different-profiles-clinical-considerations-for-alpelisib-capivasertib-and-inavolisib