Is there clinical data supporting the use of inavolisib in metastatic hormone‑receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative breast cancer with a phosphoinositide 3‑kinase (PI3K)α (PIK3CA) mutation?

Inavolisib in Metastatic Breast Cancer: Strong Clinical Evidence Supports Use

Yes, there is robust clinical data supporting inavolisib use in metastatic HR-positive, HER2-negative breast cancer with PIK3CA mutations, specifically after progression on or within 12 months of completing adjuvant endocrine therapy. The FDA approved inavolisib in combination with palbociclib and fulvestrant based on the phase 3 INAVO120 trial, which demonstrated both significant progression-free survival and overall survival benefits 1, 2, 3.

Key Efficacy Data

The INAVO120 trial provides the strongest evidence for inavolisib:

• Median overall survival: 34.0 months with inavolisib versus 27.0 months with placebo (HR 0.67; 95% CI 0.48-0.94; P=0.02), representing a 7-month survival advantage 2
• Median progression-free survival: 15.0 months versus 7.3 months (HR 0.43; 95% CI 0.32-0.59; P<0.001), more than doubling the time to progression 4
• Objective response rate: 58.4% versus 25.0% in patients receiving inavolisib versus placebo 4
• Median duration of response: 18.4 months versus 9.6 months 3

This represents the first FDA-approved therapy specifically for first-line treatment of endocrine-resistant, PIK3CA-mutated HR-positive advanced breast cancer 3.

Patient Selection Criteria

Mandatory requirements for inavolisib therapy:

• PIK3CA mutation confirmed by FDA-approved testing (FoundationOne Liquid CDx assay) using plasma ctDNA first, followed by tissue testing if plasma is negative 1, 3
• HR-positive, HER2-negative locally advanced or metastatic breast cancer 1
• Endocrine-resistant disease: defined as recurrence during or within 12 months after completing adjuvant endocrine therapy 1, 3
• No uncontrolled diabetes: baseline HbA1c must be <6.5% 5

The reflex testing approach is critical because plasma testing misses approximately 44% of mutations confirmed in tissue 5, 6.

Treatment Positioning

Inavolisib is positioned as first-line therapy for metastatic disease in the endocrine-resistant population, given in combination with palbociclib (125 mg orally daily for 21 of 28 days) and fulvestrant (500 mg intramuscularly) 1, 3. This differs from alpelisib, which ASCO guidelines recommend only after CDK4/6 inhibitor failure 5.

The INAVO120 trial specifically enrolled patients who had not received prior CDK4/6 inhibitors in the metastatic setting, establishing inavolisib's role earlier in the treatment sequence 2, 4.

Safety Profile and Management

Common adverse events requiring proactive management:

• Hyperglycemia (67.9% any grade, 5.6% grade 3-4): Monitor fasting glucose and HbA1c weekly for the first 4 weeks, then as clinically indicated. Median time to grade 3 hyperglycemia is 15 days 1, 7
• Stomatitis (48.9% any grade, 5.6% grade 3-4): Prophylactic dexamethasone mouthwash should be initiated at treatment start. Median time to onset is 13 days 1, 7
• Diarrhea (65.3% any grade, 3.7% grade 3-4): Manage with standard antidiarrheal medications. This is a later toxicity with median onset at 139 days 5, 7
• Neutropenia (80.2% grade 3-4): Monitor complete blood counts before each cycle and on day 14 of the first two cycles 1

Critical management points:

• Only 6.8% of patients discontinued inavolisib due to adverse events, demonstrating manageable toxicity with appropriate monitoring 1, 4
• Dose interruptions occurred in 69% of patients, but dose reductions were needed in only 14% 1
• Prophylactic non-sedating antihistamines should be started at treatment initiation to prevent rash 6, 7

Post-CDK4/6 Inhibitor Setting

While INAVO120 enrolled CDK4/6 inhibitor-naïve patients, phase 1b data show inavolisib plus fulvestrant has activity in the post-CDK4/6 inhibitor setting:

• Objective response rate: 25.0% in patients with prior CDK4/6 inhibitor exposure 8
• Median PFS: 7.1 months in the post-CDK4/6 inhibitor population 8

However, the FDA approval and strongest evidence support first-line use in endocrine-resistant disease 1, 3.

Comparison to Alpelisib

Inavolisib offers several advantages over alpelisib, the other PI3Kα inhibitor approved for this population:

• Superior efficacy: Inavolisib shows overall survival benefit (HR 0.67), while alpelisib did not meet prespecified OS significance in SOLAR-1 5, 2
• Earlier treatment line: Inavolisib is used first-line with CDK4/6 inhibitor, while alpelisib is recommended after CDK4/6 inhibitor failure 5
• Lower discontinuation rate: 6.8% versus higher rates with alpelisib 1
• Improved tolerability: Grade 3-4 hyperglycemia 5.6% versus 36.6% with alpelisib; no grade 3-4 rash versus 9.9% with alpelisib 1, 4

ASCO guidelines note there are no data for sequencing PI3K inhibitors, so alpelisib should not be used after inavolisib progression 5.

Quality of Life Considerations

Despite the toxicity profile, quality of life data from INAVO120 showed no overall deterioration in Global Health Status/QoL scores between inavolisib and placebo arms, with improvement in pain scores 5, 6. This supports the clinical benefit despite requiring close monitoring and supportive care.

Common Pitfalls to Avoid

• Do not use inavolisib without confirmed PIK3CA mutation: The benefit is specific to PIK3CA-mutated disease 3, 4
• Do not skip tissue testing if plasma is negative: 44% of mutations are missed by plasma testing alone 5, 6
• Do not initiate without weekly glucose monitoring plan: Hyperglycemia occurs early (median 15 days) and requires proactive management 5, 1
• Do not use in patients with uncontrolled diabetes: HbA1c must be <6.5% at baseline 5
• Do not delay supportive care: Prophylactic antihistamines and dexamethasone mouthwash should start with cycle 1 6, 7