Itovebi Combo Boosts Progression-Free Survival in PIK3CA-Mutated HR-Positive, HER2-Negative Metastatic Breast Cancer

Credit: Sara_P | stock.adobe.com

Data from the Phase III INAVO120 trial (NCT04191499) published in The New England Journal of Medicine show Roche’s Itovebi (inavolisib) combined with Ibrance (palbociclib) and Faslodex (fulvestrant) significantly improved progression-free survival (PFS) in patients with PIK3CA-mutated, endocrine-resistant, HR-positive, HER2-negative metastatic breast cancer (MBC).^1-3

The combination based around Itovebi, a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the PI3K complex, was approved by the FDA earlier this month for this indication.⁴ The FDA previously granted the New Drug Application for the combination with Priority Review status.⁵

“Publication of these Phase III results in The New England Journal of Medicine further highlights the transformative potential of the Itovebi-based regimen,” Levi Garraway, MD, PhD, Roche chief medical officer and head of Global Product Development, said in a press release. “This new treatment exemplifies our ambition to target specific disease pathways more effectively and improve outcomes in people with breast cancer, while also emphasising the importance of comprehensive testing for mutations like PIK3CA at the time of diagnosis.”¹

Investigators noted that 40% of all HR-positive MBCs have the PIK3CA mutation. The PI3K pathway plays a vital role in progression of the disease and has presented a challenge for targeted therapies.¹

The double-blind, randomized INAVO120 trial compared first-line treatment with Itovebi administered orally at a dose of 9 mg once daily plus Ibrance–Faslodex vs. placebo plus Ibrance–Faslodex in patients with PIK3CA-mutated, HR–positive, HER2–negative locally advanced or MBC whose disease relapsed during or within 12 months following completion of adjuvant endocrine therapy. The trial’s primary endpoint was investigator-assessed PFS, with secondary endpoints that include overall survival, objective response rate, and clinical benefit rate.

Investigators randomly assigned 161 patients to the Itovebi combination cohort and 164 patients to the placebo cohort, with a median follow-up of 21.3 months and 21.5 months, respectively. Results show a median PFS of 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the Itovebi combination cohort compared with 7.3 months (95% CI, 5.6 to 9.3) in the placebo cohort (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). Objective response was observed in 58.4% of patients in the Itovebi combination cohort compared with 25.0% of patients in the placebo cohort.

“The substantial clinical benefit observed in our trial can be attributed to the simultaneous blockade of the three critical signaling pathways that drive PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer (the PI3K, estrogen receptor, and CDK4/6 pathways), which delayed and prevented the emergence of treatment resistance directed mainly by cross-talk among these pathways,” the study authors wrote. “Moreover, the clinical benefit of the inavolisib regimen occurred early after the start of treatment and was durable, as shown by the separation of Kaplan–Meier curves for progression-free survival at the time of the first tumor assessment and throughout the follow-up period. The landmark survival analysis showed that the probability of death by 6 months was 10.1% in the placebo group and 2.7% in the inavolisib group, which emphasizes the importance of administering inavolisib plus palbociclib–fulvestrant to this patient population as a first-line therapy.”³

In terms of adverse events (AEs), grade 3 or 4 neutropenia occurred in 80.2% of patients in the Itovebi combination cohort compared with 78.4% in the placebo cohort; grade 3 or 4 hyperglycemia occurred in 5.6% of patients in the Itovebi combination cohort compared with 0% in the placebo cohort; grade 3 or 4 stomatitis or mucosal inflammation occurred in 5.6% of the Itovebi combination cohort vs. 0% with placebo; and grade 3 or 4 diarrhea occurred in 3.7% of the Itovebi combination cohort vs. 0% with placebo. AEs leading to discontinuation occurred in 6.8% of the patients in the Itovebi combination cohort vs. 0.6% in the placebo cohort.

Based on these findings, Itovebi is currently under evaluation in a pair of Phase III trials for PIK3CA-mutated locally advanced or MBC in various combinations.

“With a doubling of progression-free survival and consistent benefits in people whose disease had spread to multiple challenging-to-treat locations, including the liver and lungs, these INAVO120 data are significant for patients,” INAVO120 co-principal investigator Komal Jhaveri, MD, section head of the endocrine therapy research portfolio and clinical director of the early drug development service at Memorial Sloan Kettering Cancer Center, said in the release. “I’m confident this Itovebi-based regimen could become a new first-line standard of care for this patient population with one of the most commonly mutated genes in metastatic breast cancer, associated with a poor prognosis.”¹

References

1. New England Journal of Medicine publishes landmark phase III results for Roche’s Itovebi, showing more than doubling of progression-free survival in certain type of HR-positive advanced breast cancer. News release. Roche. October 31, 2024. Accessed October 31, 2024. https://www.roche.com/media/releases/med-cor-2024-10-31

2. 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). ClinicalTrials.gov. Updated October 9, 2024. Accessed October 31, 2024. https://clinicaltrials.gov/study/NCT04191499

3. Turner N., et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. Published October 30, 2024. N Engl J Med 2024;391:1584-1596. DOI: 10.1056/NEJMoa2404625. VOL. 391 NO. 17

4. FDA Approves Genentech’s Itovebi, a Targeted Treatment for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer With a PIK3CA Mutation. Genentech. October 10, 2024. Accessed October 31, 2024. https://www.gene.com/media/press-releases/15039/2024-10-10/fda-approves-genentechs-itovebi-a-target

5. FDA Grants Priority Review to Genentech’s Inavolisib for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer With a PIK3CA Mutation. Genentech. May 28, 2024. Accessed October 31, 2024. https://www.gene.com/media/press-releases/15026/2024-05-28/fda-grants-priority-review-to-genentechs