Rationale for Requested Change: Note: This updated submission is a follow-up to support the change requested to the NCCN Breast Cancer Guidelines in a previous submission. Data from the Phase 3 INAVO120 study was published in the New England Journal of Medicine on October 30, 2024. The publication is enclosed for your review and consideration.
HR-positive/HER2-negative breast cancer is the most common female breast cancer subtype, accounting for approximately 70% of cases. [3] Within this subtype, PIK3CA is one of the most commonly mutated genes and found in approximately 35-40% of these patients. [4-7] As these patients face a poor prognosis, [8] the identification of PIK3CA mutations via biomarker testing early can help inform treatment decisions.
Endocrine resistance is associated with poor prognosis in HR-positive breast cancer. [9] In an analysis of patient-level data from four randomized clinical trials, patients with primary endocrine resistance (1ER), secondary endocrine resistance (2ER), and endocrine sensitive (ES) breast cancer had a median overall survival (OS) of 27.2, 38.4 and 43.2 months, respectively (P=0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1ER (adjusted [aHR]=1.54; 95% CI, 1.03-2.30) and 2ER (aHR=1.17; 95% CI, 0.87-1.56) (P=0.11).
The FDA approval is based on a Phase 3, randomized, double-blind, placebo-controlled study (INAVO120) described in more detail below. [1,10] The study demonstrated that the addition of first-line inavolisib to palbociclib and fulvestrant significantly improved progression-free survival (PFS) in patients with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, with a manageable safety profile.
Study Design [1,10,11]:
INAVO120 is a Phase 3, randomized, double-blind, placebo-controlled study that evaluated inavolisib in combination with palbociclib and fulvestrant vs. placebo with palbociclib and fulvestrant in patients with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease recurrence or progression during or within 12 months of completed adjuvant endocrine therapy.
PIK3CA mutation status was prospectively determined in a central laboratory using the FoundationOne® LiquidCDx assay on plasma-derived circulating tumor DNA (ctDNA) or in local laboratories using various validated polymerase chain reaction (PCR) or next-generation sequencing (NGS) assays on tumor tissue or plasma. All patients were required to provide both a freshly collected pre-treatment blood sample and a tumor tissue sample for central evaluation and determination of PIK3CA mutation(s) status.
A total of 325 patients were randomized 1:1 to receive either inavolisib 9 mg or placebo orally once daily, in combination with palbociclib 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days, and fulvestrant 500 mg administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle.
The primary endpoint was investigator-assessed PFS.
Overall survival (OS), investigator-assessed objective response rate (ORR), and investigator-assessed duration of response (DOR) were among the secondary endpoints.
Additional endpoints included time to end or discontinuation of next-line treatment, or death from any cause (proxy for PFS2), and time to first subsequent chemotherapy after treatment discontinuation.
Efficacy Results [10,11]:
INAVO120 met its primary endpoint with a statistically significant improvement in PFS.
- At the primary analysis, the median PFS was 15.0 months vs. 7.3 months in the inavolisib and placebo groups, respectively (stratified HR 0.43 [95% CI, 0.32-0.59]; P<0.001]. The median follow-up was 21.3 months in the inavolisib group and 21.5 months in the placebo group.
An interim analysis of OS was performed, but the prespecified boundary for statistical significance of P<0.0098 was not crossed. Follow-up is ongoing. The results below are descriptive.
- OS event-free rates (inavolisib group vs. placebo group) at 6, 12, and 18 months were 97.3% 85.9%, and 73.7% vs. 89.9%, 74.9%, and 67.5% (stratified HR 0.64 [95% CI, 0.43-0.97]; P=0.03).
Other secondary endpoints results:
- ORR was 58.4% and 25% in the inavolisib and placebo groups, respectively (difference, 33.4 percentage points; 95% CI, 23.3 to 43.5).
- Median DOR was 18.4 months and 9.6 months, respectively (stratified HR 0.57 [95% CI, 0.33-0.99]).
Additional endpoint results:
- Time from randomization to end or discontinuation of next-line treatment, or death from any cause (proxy for PFS2) was 24 months vs.15.1 months, in the inavolisib group vs. placebo group, respectively, with a difference of 8.9 months (HR 0.54 [95% CI, 0.38-0.77]).
- Time to first subsequent chemotherapy after treatment discontinuation was not evaluable vs.15 months, in the inavolisib group vs. placebo group, respectively (unstratified HR 0.54 [95% CI, 0.37-0.78]).
Safety Results [10]:
The safety analysis included 162 patients in each treatment group.
The most common (occurring in at least 20%) all-grade adverse events (AEs) in either group (inavolisib vs. placebo) were:
- Neutropenia (88.9% vs. 90.7%); thrombocytopenia (48.1% vs. 45.1%); stomatitis/mucosal inflammation (51.2% vs. 26.5%); anemia (37.0% vs. 36.4%); hyperglycemia (58.6% vs. 8.6%), diarrhea (48.1% vs. 16.0%); nausea (27.8% vs. 16.7%); rash (25.3% vs. 17.3%); decreased appetite (23.5% vs. 8.6%); fatigue (23.5% vs. 13.0%); COVID-19 (22.8% vs. 10.5%); headache (21.0% vs. 13.6%); leukopenia (17.3% vs. 24.7%); and ocular toxic effects (22.2% vs. 13.0%).
Key Grade 3 and 4 AEs in both groups (inavolisib vs. placebo) were:
- Neutropenia (80.2% and 78.4%), stomatitis/mucosal inflammation (5.6% and 0%), hyperglycemia (5.6% and 0%), diarrhea (3.7% and 0%), and nausea (0.6% and 0%). No Grade 3 or 4 rash was reported in either arm.
Grade 5 AEs were reported in 6 (3.7%) patients in the inavolisib group and 2 (1.2%) patients in the placebo group, but none were reported as being related to study treatment by the investigators.
AEs led to the discontinuation of treatment in 6.8% of patients in the inavolisib group and 0.6% in the placebo group.
Thank you for your review and consideration of this request.
References:
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1. Itovebi™ [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2024. https://www.gene.com/download/pdf/itovebi_prescribing.pdf
2. FDA Approves Genentech’s Itovebi, a Targeted Treatment for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer With a PIK3CA Mutation [Press Release]. South San Francisco, CA; Genentech, Inc. October 10, 2024. Accessed from: https://www.gene.com/media/press-releases/15039/2024-10-10/fda-approves-genentechs-itovebi-a-target
3. SEER cancer stat facts: female breast cancer subtypes. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed August 5, 2024.
4. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature. 2012 Oct 4;490(7418):61-70. https://pubmed.ncbi.nlm.nih.gov/23000897/
5. Chen JW, Murugesan K, Newberg JY, et al. Comparison of PIK3CA mutation prevalence in breast cancer across predicted ancestry populations. JCO Precis Oncol. 2022 Nov:6:e2200341. https://pubmed.ncbi.nlm.nih.gov/36446041/
6. Martínez-Sáez O, Chic N, Pascual T, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020 May 13;22(1):45. https://pubmed.ncbi.nlm.nih.gov/32404150/
7. Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. Int J Breast Cancer. 2020 Jun 20;2020:3759179. https://pubmed.ncbi.nlm.nih.gov/32637176/
8. Fillbrunn M, Signorovitch J, André F, et al. PIK3CA mutation status, progression and survival in advanced HR?+?/HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022 Sep 21;22(1):1002. https://pubmed.ncbi.nlm.nih.gov/36131248/
9. Lambertini M, Blondeaux E, Bisagni G,et al. Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies. EClinicalMedicine. 2023 May 12;59:101931. https://pubmed.ncbi.nlm.nih.gov/37256095/
10. Turner NC, Im SA, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer [supplementary appendix appears online]. N Engl J Med. 2024;391(17):1584-1596. https://www.nejm.org/doi/10.1056/NEJMoa2404625
11. Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 Phase III randomized trial additional analyses. Oral presentation at the American Society of Clinical Oncology (ASCO) in Chicago, IL, USA; May 31-June 4, 2024. https://medically.gene.com/global/en/unrestricted/oncology/annual-meeting-2024/oncology-annual-meeting-2024-presentation-juric-first-l.html
