By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has approved inavolisib, a phosphatidylinositol 3-kinase (PI3K) inhibitor, for the treatment of advanced hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with a PIK3CA mutation. Inavolisib was granted a priority review and Breakthrough Therapy Designation.1 It is used in combination with palbociclib and fulvestrant. Inavolisib is distributed by Genentech as Itovebi.
Indications
Inavolisib is indicated in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test (FoundationOneLiquid CDX), following recurrence on or after completing adjuvant endocrine therapy.2
Dosage
The recommended dose is 9 mg orally once daily with or without food at approximately the same time each day.2 It is given in combination with palbociclib 125 mg orally once daily for 21 consecutive days, followed by seven days off treatment (for a cycle of 28 days) along with fulvestrant 500 mg given intramuscularly on cycle 1, days 1 and 15, and then on day 1 of every 28-day cycle.
This regimen is administered until disease progression or unacceptable toxicity. Dose reduction is recommended for moderate renal impairment (estimated glomerular filtration rate 30 mL/min to < 60 mL/min) and dose modification for adverse reactions (e.g., hyperglycemia, stomatitis, diarrhea, hematologic toxicities, or other grade ≥ 2 adverse reactions). Inavolisib is available as 3 mg and 9 mg tablets.
Potential Advantages
Inavolisib, in combination with palbociclib and fulvestrant, doubles the median progression-free survival, objective response rate and the duration of response compared to placebo, palbociclib, and fulvestrant.2 It may be better tolerated than alpelisib, a PI3K inhibitor (e.g., 12% grade 3 hyperglycemia vs. 32.7%).2,3
Potential Disadvantages
Severe hyperglycemia, stomatitis, and diarrhea can occur with inavolisib.2 It also can decrease neutrophils, platelets, lymphocytes, and hemoglobin as well as lower calcium, potassium, sodium, and magnesium levels.2 Inavolisib can cause embryo-fetal toxicity.
Comments
The efficacy of inavolisib was evaluated in a randomized, double-blind, placebo-controlled trial in participants with endocrine-resistant PIK3A-mutated, hormone receptor-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.2 Participants had a median age of 54 years, 39% were pre/perimenopausal, 59% were white, 38% were Asian, and they had an Eastern Cooperative Oncology Group (ECOG) performance state of 0 (63%) or 1 (36%). Of the participants, 83% had received prior chemotherapy in the neo/adjuvant setting. Participants were randomized to inavolisib/palbociclib/fulvestrant (n = 161) or placebo/palbociclib/fulvestrant (n = 164) until disease progression or unacceptable toxicity.
The primary efficacy outcome measure was investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumor version 1.1. Other measures were overall survival, objective response rate, and duration of response. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum also must demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions also was considered progression.4
At the time of PFS analysis, overall survival data were not mature, with 30% deaths in the overall population. The median time to progression-free survival was 15 months (95% confidence interval [CI], 11.3-20.5) vs. 7.3 months (95% CI, 5.6-9.3) for placebo. The objective response rates (complete or partial response) were 94% vs. 41%, respectively, and the median duration of response was 18.4 months vs. 9.6 months, respectively.
Clinical Implications
The PI3K gene mediates processes that promote cell transformation, tumor initiation/proliferation, and resistance to apoptosis. PIK3CA-mutated, hormone receptor-positive/HER2-negative metastatic breast cancer is less sensitive to chemotherapy and has a poorer overall survival than PIK3CA wild-type breast cancer.5,6 Current American Society of Clinical Oncology guidelines recommend alpelisib in combination with fulvestrant for postmenopausal women and male patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer with or without a cyclin-dependent kinase 4/6 inhibitor (e.g., palbociclib).7 Inavolisib provides another option for this prevalent breast cancer subtype. The cost for inavolisib is $22,867 for a 28-day cycle.
References
- Genentech. FDA approves Genentech’s Itovebi, a targeted treatment for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. Published Oct. 10, 2024. https://www.gene.com/media/press-releases/15039/2024-10-10/fda-approves-genentechs-itovebi-a-target
- Genentech USA, Inc. Itovebi prescribing information. Revised October 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219249s001lbl.pdf
- Rugo HS, André F, Yamashita T, et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol 2020;31:1001-1010.
- Hoffmann-La Roche. A study evaluating the efficacy and safety of inavolisib + palbociclib + fulvestrant vs. placebo + palbociclib + fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (INAVO120). Updated Oct. 9, 2024. https://clinicaltrials.gov/study/NCT04191499?term=nct04191499&rank=1&tab=results
- Reinhardt K, Stückratheth K, Hartung C, et al. PIK3CA-mutations in breast cancer. Breast Cancer Res Treat 2022;196:483-493.
- Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol 2020;31:377-386.
- Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO Guideline update. J Clin Oncol 2021;39:3959-3977.
The U.S. Food and Drug Administration (FDA) has approved inavolisib, a phosphatidylinositol 3-kinase (PI3K) inhibitor, for the treatment of advanced hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with a PIK3CA mutation. Inavolisib was granted a priority review and Breakthrough Therapy Designation.
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