Clinical trialPhase 3Breast cancer

Inavolisib-Based Therapy in PIK3CA -Mutated Advanced Breast Cancer

N Engl J Med · 2024325 patients (161 in the inavolisib group and 164 in the placebo group)

Turner NC, Im SA, Saura C, Juric D, Loibl S, Kalinsky K, et al. N Engl J Med. 2024. 391:1584-1596

Study type: Clinical trial
Study name: INAVO120
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled phase 3 trial
Sample size: 325 patients (161 in the inavolisib group and 164 in the placebo group)
Source: N Engl J Med · 2024
Trial registration: NCT04191499

In plain words

In this study, women and men with advanced hormone-sensitive breast cancer whose tumour had a change (mutation) in the PIK3CA gene were given the new drug inavolisib together with the drugs palbociclib and fulvestrant. This combination greatly lengthened the time until the disease got worse (on average 15 months versus 7.3 months with treatment without inavolisib). Side effects such as high blood sugar, mouth sores and inflammation, and diarrhoea were more common with this drug, but few patients stopped treatment because of side effects. Decisions about using this treatment should be made with your doctor.

Key results

15.0 months vs 7.3 months (inavolisib group vs placebo group)

Median progression-free survival

95% CI 11.3–20.5 vs 5.6–9.3

0.43

Hazard ratio for disease progression or death

95% CI 0.32–0.59; P<0.001

58.4% vs 25.0%

Objective response

Inavolisib group vs placebo group

21.3 months vs 21.5 months

Median follow-up

Inavolisib group vs placebo group

Drugs in this study:Fulvestrant (Faslodex)Palbociclib (Ibrance)

Dose and schedule cards

Inavolisib + palbociclib + fulvestrant (INAVO120)

Advanced HR-positive/HER2-negative disease with a PIK3CA mutation (in a plasma sample), endocrine-resistant: recurrence during adjuvant hormone therapy or within 12 months of completing itEach drug’s schedule in the tableOn the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Advanced HR-positive/HER2-negative disease with a PIK3CA mutation (in a plasma sample), endocrine-resistant: recurrence during adjuvant hormone therapy or within 12 months of completing it

Drug	Dose	Route	Schedule
Inavolisib	9 mg once daily	Oral	Continuous
Palbociclib	125 mg once daily	Oral	Days 1–21, every 28 days
Fulvestrant	500 mg	IM	Days 1, 15 and 29, then monthly

Cycle schedule: Palbociclib 21 days on and 7 days off; inavolisib daily and continuously; fulvestrant on days 1, 15 and 29, then monthly
Duration: Until progression or unacceptable toxicity

Blood glucose: measure and optimise fasting glucose and HbA1c before starting, and monitor during treatment; fasting glucose above 160 to 250 mg/dL: withhold until 160 or lower. Dose reduction: 6 and then 3 mg; lower starting dose in moderate and severe renal impairment.

On the page “Breast cancer” · Advanced hormone receptor-positive / HER2-negative disease

Inavolisib + palbociclib + fulvestrant (INAVO120)

HR-positive/HER2-negative advanced disease with a PIK3CA mutation, endocrine-resistant (recurrence during or after completing adjuvant endocrine therapy)Each drug’s schedule in the tableOn the page “Palbociclib (Ibrance)” · Standard doses (FDA label)

HR-positive/HER2-negative advanced disease with a PIK3CA mutation, endocrine-resistant (recurrence during or after completing adjuvant endocrine therapy)

Drug	Dose	Route	Schedule
Inavolisib	9 mg	Oral	Once daily, continuously
Palbociclib	125 mg	Oral, with or without food, tablet swallowed whole	Once daily, days 1 to 21, every 28 days
Fulvestrant	500 mg	Intramuscular injection	Cycle 1: days 1 and 15; then day 1 every 28 days

Cycle schedule: Palbociclib 21 days on and 7 days off; inavolisib daily and continuously; fulvestrant on days 1 and 15 of cycle 1, then every 28 days
Duration: Until disease progression or unacceptable toxicity

Schedule as described for the trial in the palbociclib label. Before starting inavolisib, check fasting glucose and HbA1c and optimise blood glucose; a missed inavolisib dose can be taken within 9 hours, after that it is skipped.

On the page “Palbociclib (Ibrance)” · Standard doses (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Inavolisib group

Inavolisib 9 mg orally once daily + palbociclib 125 mg orally once daily, days 1 to 21 of each 28-day cycle + fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of each 28-day cycle; until progression or unacceptable toxicity.

2Placebo group

Placebo once daily + palbociclib 125 mg (days 1 to 21 every 28 days) + fulvestrant 500 mg (days 1 and 15 of cycle 1, then day 1 every 28 days).

Source of the regimen details: Abstract of the paper and the FDA label for Ibrance (DailyMed, section 14, INAVO120)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer whose disease had recurred during adjuvant endocrine therapy or within 12 months of completing it. The study treatment was used as first-line therapy.

Endpoints

Primary endpoint: investigator-assessed progression-free survival (PFS). Objective response and adverse events are also reported in the abstract.

Safety and side effects

Grade 3 or 4 neutropenia: 80.2% versus 78.4%; grade 3 or 4 hyperglycaemia: 5.6% versus 0%; grade 3 or 4 stomatitis or mucosal inflammation: 5.6% versus 0%; grade 3 or 4 diarrhoea: 3.7% versus 0% (inavolisib group versus placebo group). No grade 3 or 4 rash was observed. Discontinuation of any study drug due to adverse events occurred in 6.8% of patients in the inavolisib group and 0.6% in the placebo group.

Clinical significance and place in guidelines

According to the abstract, adding inavolisib to palbociclib–fulvestrant in the first-line treatment of HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer that recurred during or within 12 months after adjuvant endocrine therapy significantly improved progression-free survival. Its use requires testing for PIK3CA mutation status and monitoring for adverse events such as hyperglycaemia, stomatitis and diarrhoea. The status of drug approvals and guideline recommendations should be checked separately, as they are not stated in the abstract.

Limitations

The abstract does not report overall survival data. The primary endpoint was investigator-assessed. The combination was associated with more toxicity (particularly hyperglycaemia, stomatitis and diarrhoea). The study population was limited to patients with recurrence during or within 12 months after adjuvant endocrine therapy. The study was funded by the manufacturer.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.