What is the potential role for inavolisib in the treatment of locally advanced or metastatic breast cancer?
- Inavolisib is an orally available inhibitor of phosphatidylinositol 3-kinase (PI3K) with inhibitory activity predominantly against the alpha isoform of PI3K (P13Kα).
- Inavolisib has been shown in vitro to induce the degradation of mutated P13K catalytic alpha subunit p110α and induce apoptosis in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated breast cancer cell lines.1
- Activating mutations in P1K3CA are present in approximately 35-40% of hormone receptor (HR)-positive breast cancers and are a poor prognostic factor in patients with advanced breast cancer as well as serving as a predictive biomarker for response to P13K inhibitors.
- Previous clinical trials have demonstrated the benefit of regimens targeting key oncogenic drivers in HR-positive breast cancer, including endocrine therapy combined with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors or with inhibitors of nodes in the PI3K–protein kinase B–mammalian target of rapamycin (PI3K–AKT–mTOR) signaling pathway.
- However, treatment resistance and treatment-related side effects resulting from targeting all three signaling pathways (estrogen receptor, CDK4/6, and P13K) remain a major challenge.2
- Inavolisib is FDA approved as a treatment option with palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, HR-positive, human epidermal growth-factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer. The FDA also provides guidance on approved tests to assess for alterations, including FoundationOne Liquid CDx assay.3
- Approval was based on INAVO120 (NCT04191499), a phase III international, multicenter, randomized, double-blind, placebo-controlled trial, evaluating premenopausal, perimenopausal, or postmenopausal women or men with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who had not received prior systemic therapy for locally advanced or metastatic disease.2,3
- INAVO120 enrolled 325 patients who were randomly assigned in a 1:1 ratio to receive inavolisib (at a dose of 9 mg, administered orally, once daily on days 1 to 28 of each 28-day cycle) or placebo (once daily). Each group was given palbociclib (at a dose of 125 mg orally once a daily on days 1 to 21 of each 28-day cycle) and fulvestrant (at a dose of 500 mg, administered intramuscularly, on days 1 and 15 of cycle 1 and approximately every 28 days after).
- Included premenopausal, perimenopausal, or postmenopausal women or men with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer with disease recurrence or progression during or within 12 months after the completion of adjuvant endocrine therapy.
- Excluded patients with de novo metastatic breast cancer.
- Additionally, men and pre- or perimenopausal women received a luteinizing hormone–releasing hormone agonist for the duration of the trial intervention.
- The primary endpoint was progression-free survival (PFS). The median PFS was 15 months in the inavolisib-palbociclib-fulvestrant group vs 7.3 months in the placebo-palbociclib-fulvestrant group (stratified hazard ratio (HR) for disease progression or death: 0.43; 95% confidence interval [CI]: 0.32 to 0.59; P<0.001).
- Additionally, in the landmark survival analysis, the probability of PFS was 82.9% at 6 months, 55.9% at 12 months, and 46.2% at 18 months in the inavolisib group, and 55.9% at 6 months, 32.6% at 12 months, and 21.1% at 18 months in the placebo group.
- Secondary endpoint included overall survival (OS); confirmed objective response, best overall response, clinical benefit, and response duration, as assessed by the investigator according to RECIST, version 1.1; and patient-reported outcomes.
- At the time of the interim analysis of OS, the landmark survival analysis revealed that the survival probability at 6, 12, and 18 months was 97.3%, 85.9%, and 73.7%, respectively, in the inavolisib group and 89.9%, 74.9%, and 67.5%, respectively, in the placebo group (stratified HR for death: 0.64; 95% CI: 0.43 to 0.97; P=0.03, which did not cross the predefined boundary for significance of <0.0098).
- Objective response occurred in 58.4% of patients in the inavolisib group and in 25% of those in the placebo group (difference: 33.4 percentage points; 95% CI: 23.3 to 43.5).
- Median response duration was 18.4 months in the inavolisib group and 9.6 months in the placebo group (HR: 0.57; 95% CI: 0.33 to 0.99).
- In the intervention group, the most common adverse effects of any grade that occurred in at least 20% of patients were neutropenia (88.9%), hyperglycemia (58.6%), stomatitis and mucosal inflammation (51.2%), and thrombocytopenia (48.1%).2
- Alpelisib, another selective PI3Kα inhibitor, in combination with fulvestrant is a National Comprehensive Cancer Network (NCCN) Category 1 recommendation as a preferred second- or subsequent-line therapy for recurrent or stage IV breast cancer in HR-positive, HER2-negative, and postmenopausal patients with PIK3CA-mutated tumors and was added in 2019 based on results from the phase III SOLAR −1 study.4,5,8
- PI3Kα inhibitors are known to have frequent and difficult-to-treat side effects and attempts to combine alpelisib with a CDK4/6 inhibitor and endocrine therapy have been unsuccessful, mainly due to toxicity.
- A low percentage of patients discontinued treatment due to adverse events in the INAVO120 study (6.8% of the patients in the inavolisib group, of which 6.2% of the patients discontinued inavolisib; 4.9%, palbociclib; and 3.1%, fulvestrant), whereas in the SOLAR-1 trial, treatment discontinuation because of adverse events occurred in 25% of patients within the alpelisib group.2
- There is currently an ongoing head-to-head phase III, randomized, open-label study that aims to evaluate inavolisib and fulvestrant vs alpelisib and fulvestrant in patients with HR-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer (INAVO121).6
- For patients that harbor one or more PIK3CA/AKT serine/threonine kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, capivasertib is another oral treatment option. There is no comparative efficacy to compare the use of inavolisib vs capivasertib. Assessment of the risks, benefits, and incidence of adverse effects of each treatment should guide therapeutic selection.7
What role can the pharmacist play in the management of patients on inavolisib?
- Pharmacists can play a role in the management of patients on inavolisib by ensuring appropriate dosing and dose reductions, management of side effects, adherence, and accessibility.
- Dosing and Administration
- The standard starting dose of inavolisib is 9 mg by mouth once daily (in combination with palbociclib and fulvestrant). This medication should be continued until disease progression or unacceptable toxicities.
- There are dose adjustments for renal impairment. For an estimated glomerular filtration rate (eGFR) of 30 to <60 mL/minute, it is recommended to reduce the initial dose to 6 mg by mouth once daily. There is no dosage adjustment provided in the manufacturer’s labeling for an eGFR<30 mL/minute as it has not been studied.
- There are no dosage adjustments provided for hepatic impairment.
- There are recommended dose adjustments for toxicity. The first dose reduction level is to 6 mg by mouth once daily. The second dose reduction level is to 3 mg by mouth once daily. If the patient is unable to tolerate the second dose reduction level, it is recommended to permanently discontinue inavolisib.
- Inavolisib is available as a 3 mg and 9 mg tablet.
- For administration, inavolisib can be given without regard to food at approximately the same time each day and should not be chewed, crushed or split.
- If a patient misses a dose by more than 9 hours, advise the patient to skip the dose and administer the next dose at the scheduled time.6
- Adverse effects1,6
- Based on results from the INAVO120 trial, serious adverse reactions occurred in 24% of patients who received inavolisib with palbociclib and fulvestrant. Serious adverse reactions in ≥ 1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%).1,6
- Gastrointestinal adverse events: Stomatitis (all grades: 51%; grade 3: 6%), diarrhea (all grades: 48%; grade 3: 3.7%), nausea (all grades: 28%; grade 3: 0.6%), and vomiting (all grades: 15%; grade 3: 0.6%).1,6
- Hematologic adverse events: Decreased hemoglobin (all grades: 88%; grades 3: 8%), decreased neutrophils (all grades: 95%; grades 3/4: 82%), decreased platelet count (all grades: 84%; grades 3/4: 16%), lymphocytopenia (all grades: 72%; grades 3/4: 9%).1,6
- Baseline monitoring
- Genetic testing to assess for PIK3CA mutation status.
- Complete blood count (CBC).
- Fasting glucose levels.
- Hemoglobin A1C (HbA1c) levels.
- Pregnancy status.
- Regular monitoring
- Fasting glucose levels once every 3 days for the first week, then once every week for the next 3 weeks, then once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated.
- HbA1c levels every 3 months during treatment and as clinically indicated.
- CBC.
- Signs and symptoms of diarrhea, hematologic toxicities, hyperglycemia, and stomatitis.
- Adherence.
- Inavolisib is a substrate of BCRP/ABCG2 and P-glycoprotein/ABCB1 (minor).6
Clinical Pearls
- The INAVO120 trial excluded patients with type 1 or type 2 diabetes mellitus that required ongoing treatment. Inavolisib increases the risk of hyperglycemia. Thus, clinicians should carefully consider the risks and benefits associated with use of inavolisib in patients receiving treatment for diabetes mellitus.
- Few patients in the INAVO120 trial had previously received adjuvant CDK4/6 inhibitors, as recruitment primarily occurred before adjuvant CDK4/6 inhibitors were available. Thus, it remains to be seen whether previous exposure to CDK4/6 inhibitors as adjuvant therapy compromises the efficacy of a CDK4/6 inhibitor as a component of therapy for advanced disease.
- The INAVO120 trial showed that inavolisib appeared to have led to little improvement as compared with placebo in patients older than 65 years of age and those who had previously received both an aromatase inhibitor and tamoxifen. However, the patients in these subgroups were small.2
- Inavolisib should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).1
- Genentech provides a program called “The Genentech Patient Foundation” to give free Genentech medicine to people living in the United States who meet their guidelines. Additionally, Genentech provides a program called “The Genentech Oncology Co-pay Assistance Program” if eligible commercially insured patients need assistance with their out-of-pocket costs.7
References
1.Itovebi (Inavolisib) [package insert]. Genentech USA, Inc: South San Francisco, CA. 2024.
2.Turner NC, Im SA, Saura C, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med. 2024;391(17):1584-1596. doi:10.1056/NEJMoa2404625
3.U.S. Food and Drug Administration. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. October 2024. Accessed November 02, 2024.
4.Juric D, Kalinsky K, Im S-A, et al. INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (ful) vs. alpelisib (ALP) + ful in patients (PTS) with hormone receptor-positive, HER2-negative (HR+, HER2–), pik3ca-mutated (MUT) locally advanced or Metastatic Breast Cancer (LA/MBC). Journal of Clinical Oncology. 2024;42(16_suppl). doi:10.1200/jco.2024.42.16_suppl.tps1136
5.Truqap (Capivasertib ) [package insert]. AstraZeneca Pharmaceuticals LP: Wilmington, DE. 2023.
6.Inavolisib [monograph]. In: LexidrugUptoDate[online database]. Hudson, OH: Lexidrug UptoDate. Accessed November 05, 2024.
7.Itovebi (inavoslib) – Information for Patients. https://www.gene.com/patients/medicines/itovebi. Accessed November 05, 2024.
8.National Comprehensive Cancer Network. Breast Cancer (Version 6.2024). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed November 14, 2024.
