Novel PI3K Inhibitor as Part of Triplet Improves Outcomes in Hormone Receptor–Positive, HER2-Negative Breast Cancer

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The addition of inavolisib to first-line treatment with palbociclib plus fulvestrant more than doubled progression-free survival in patients with recurrent PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer, according to a late-breaking primary analysis of the phase III INAVO120 trial presented at the 2023 San Antonio Breast Cancer Symposium.1

In patients with a breast cancer recurrence within 12 months of adjuvant endocrine therapy, treatment with the investigational selective PI3K inhibitor inavolisib achieved more than a doubling of median progression-free survival, from 7.3 months with palbociclib plus fulvestrant to 15 months, a significant 57% improvement (P < .0001). The study also revealed a trend toward improved overall survival at the first interim analysis (median follow-up of 21.3 months) with inavolisib compared with placebo as add-on therapy.

“This triplet therapy may represent a new standard of care for patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer. What we have learned so far is that we have not been able to combine alpelisib [another PIK3 inhibitor] with a CDK4/6 inhibitor, due to challenges with the safety profile. This is the first time we’ve been able to use a triplet combination of inavolisib with a CDK4/6 inhibitor and endocrine therapy, guided by preclinical data showing synergistic activity,” stated lead author Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

What is reassuring is not only the favorable impact on efficacy, but we’re also seeing low discontinuation rates with such a triplet regimen.
— Komal Jhaveri, MD

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“What is reassuring is not only the favorable impact on efficacy, but we’re also seeing low discontinuation rates with such a triplet regimen,” she noted. The discontinuation rate was 6.8% with inavolisib treatment vs 0.6% with palbociclib plus fulvestrant alone,” she noted.

Inavolisib is an oral, highly potent, and selective inhibitor of the PI3Kα protein that also promotes the degradation of p110α, which is thought to improve the therapeutic window. Currently available α-isoform PI3K inhibitors are limited by safety and tolerability issues. Palbociclib is approved by the U.S. Food and Drug Administration in combination with letrozole for the treatment of postmenopausal women and men with hormone receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.

Study Details and Results

The phase III, randomized, double-blind, placebo-controlled INAVO120 trial compared inavolisib combined with palbociclib/fulvestrant or placebo combined with palbociclib/fulvestrant in PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer.

“The study was enriched with poor-prognosis patients,” Dr. Jhaveri noted. Eligibility criteria included measurable disease and disease progression during or within 12 months of completion of adjuvant endocrine therapy. No prior therapy for advanced breast cancer was allowed. A fasting glucose < 126 mg/dL and a hemoglobin A1c < 6% were required for enrollment.

A total of 325 patients were randomly assigned 1:1 to the triplet regimen of inavolisib (9 mg orally daily) with standard-of-care doses of palbociclib/fulvestrant or placebo with the same doublet until disease progression or unacceptable toxicity. At the time of the analysis, 42% of the patients in the inavolisib arm compared with 30% in the control arm were alive and remained on therapy.  Both arms had comparable baseline characteristics. Median patient age was 53, 35% were Asian, about 40% were premenopausal, 50% had three or more visceral metastases, and 50% had liver involvement.

The progression-free survival benefit with the triplet vs the doublet was maintained in all key subgroups. At the interim analysis, median overall survival was not reached in the inavolisib arm and was 31.1 months in the placebo arm (P = .0338 in favor of inavolisib). At the 6-month landmark analysis, 97.3% of the triplet arm and 89.9% of the patients in the placebo arm were still alive, and by the 18-month mark, these percentages dropped to 73.7% and 67.5%, respectively. The median duration of response was 18.4 months with the triplet and 9.6 months for the control arm.

Inavolisib plus palbociclib/fulvestrant had a manageable safety profile consistent with the safety profiles of the individual agents, with no new safety signals. The percentage of patients who developed neutropenia was similar in the inavolisib and placebo arms: 88.9% vs 90.7%, respectively.

The main toxicities that were increased with inavolisib included hyperglycemia, stomatitis, rash, and diarrhea. In the inavolisib arm, the rate of all-grade hyperglycemia was 58.6%, with grade 3 or 4 hyperglycemia in 5.6%, compared with 8.6% and 0%, respectively, in the control arm. The rate of grade 3 or 4 stomatitis was 5.6% in the inavolisib arm and 0% in the placebo arm. Almost half (48%) of the patients who received inavolisib had diarrhea, with 3.7% having grade 3 or 4 diarrhea, whereas 16% in the control arm had all-grade diarrhea and no grade 3 or 4 diarrhea. Also, 25% experienced rash in the inavolisib arm, with no cases of grade 3 or 4 rash, compared with rates of all-grade and grade 3 or 4 rash of 17.3% and 0%, respectively, in the control arm.

Low-grade ocular toxicity, a concern based on preclinical research, was reported in 22.2% of patients in the inavolisib group vs 13% in the control arm. “Because we had longitudinal eye exams, we picked up asymptomatic ocular toxicities or dry eyes. These toxicities were clinically not significant,” Dr. Jhaveri noted.

Primary prophylaxis for hyperglycemia, diarrhea, rash, or stomatitis was not offered in INAVO120. If the drug is approved, there are prophylactic measures that may prevent rash and stomatitis, and antidiarrheal medications are available. 

Expert Point of View

Virginia Kaklamani, MD

Virginia Kaklamani, MD

Press briefing moderator and Co-Director of the San Antonio Breast Cancer Symposium, Virginia Kaklamani, MD, of UT Health San Antonio, said: “Most of my colleagues and I were not eager to be looking at triple combinations. I think we were initially shocked [that] we had to look at combinations in the first place.”

She continued: “I was impressed with the results of this study. We have a pretty active doublet with a CDK4/6 inhibitor and endocrine therapy that many of us thought it would be hard to surpass, and we are surpassing [it] now.”

Dr. Kaklamani concluded: “Sometimes we’ve seen that when we take these drugs into our clinic, the toxicity profile changes. It’s great that we know how to plan ahead for these toxicities with steroidal mouthwash [for stomatitis], antihistamines [for rash], and metformin [for hyperglycemia] if we need it. It will help us to optimize the use of these drugs.”

DISCLOSURE: INAVO120 is supported by F. Hoffmann–La Roche. Dr. Jhaveri has served as a consultant or advisor to Novartis, Pfizer, Taiho Oncology, Genentech, AbbVie, Eisai, AstraZeneca, Blueprint Medicine, Daiichi Sankyo, Sun Pharma Advanced Research, Menarini/Stemline, Gilead Sciences, Scorpion Therapeutics, Lilly/Loxo Oncology, and Zymeworks; and has received research funding from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead Sciences, Puma Biotechnology, Merck Pharmaceuticals, Context Therapeutics, Scorpion Therapeutics, and Blueprint Medicines. Dr. Kaklamani has served as a consultant or speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, Seattle Genetics, Puma Biotechnology, Athenex, and Immunomedics.


1. Jhaveri K, Seock-Ah, I, Saura C, et al: Phase III study of inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: INAVO120 primary analysis. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-13. Presented December 8, 2023.