“Inavolisib plus palbociclib and fulvestrant significantly improved overall survival compared with placebo plus palbociclib/fulvestrant…. This is the first time overall survival has been significantly improved by a PI3K pathway–targeted drug,” said Nicholas Turner, MD, PhD, FRCP,FMedSci, who reported the results at a press briefing ahead of the 2025 ASCO Annual Meeting. Dr. Turner is Director of Clinical Research and Development at the Royal Marsden Hospital and Institute of Cancer in London.

“The time to chemotherapy was substantially improved with the inavolisib chemotherapy, with a delay of almost 2 years.”

— Nicholas Turner, MD, PhD, FRCP, FMedSci

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“The improvement in median overall survival of 7 months with the inavolisib combination (34.0 vs 27.0 months; hazard ratio [HR] = 0.67) was statistically significant (P = .0190), and the previously seen improvement in progression-free survival was maintained during longer follow-up,” he said. “We also looked at an endpoint that is really important for patients—the time to chemotherapy—and this was substantially improved with the inavolisib chemotherapy, with a delay of almost 2 years.”

What’s Different About Inavolisib?

Approximately 40% of advanced hormone receptor–positive breast cancers harbor mutations in the PIK3CA gene. In these cancers, the estrogen receptor as well as CDK4/6 and PI3K signaling pathways are key to cancer growth and survival; targeting these three pathways simultaneously with different drugs may enhance response to treatment and also delay resistance. However, previous PI3K inhibitors have been difficult to use in combination because of related toxicity. The unique properties of inavolisib enable it to be paired more easily with other drugs of benefit to this subset of patients, explained Dr. Turner.

“We’ve been trying to develop PI3K inhibitors for many years. We’ve learned that the more specific and selective a drug can be for the mutant protein, the more effective it is because it reduces side effects. Inavolisib targets PI3K alpha, and it selectively degrades the mutant kinase, and this likely makes it more selective for breast cancer that has the PIK3CA mutation. That maximizes its ability to target PI3K in the tumor while relatively sparing normal cells in the body. That’s probably why inavolisib is better able to be used in combination than other PI3K inhibitors,” he said.

Inavolisib was approved in 2024 by the U.S. Food and Drug Administration for use in combination with palbociclib and fulvestrant for PIK3CA-mutated, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer. This approval was based on the primary analysis of INAVO120, which showed a statistically significant and clinically meaningful investigator-assessed progression-free survival benefit in the inavolisib arm vs the placebo arm (HR = 0.43; P < .0001).² At that time, the interim overall survival analysis was immature. At the press briefing, Dr. Turner presented the final overall survival analysis as well as updated efficacy and safety data.

Key Results and Tolerability

Patients received inavolisib (9 mg orally daily on days 1–28 of a 28-day cycle) or placebo, plus palbociclib (125 mg daily on days 1–21 of each cycle) plus fulvestrant (500 mg intramuscularly on cycle 1 days 1 and 15 then every 4 weeks). Overall survival and objective response rate were formally tested, whereas progression-free survival was descriptive. The data cutoff for this analysis was at 34.2 months of median follow-up.

The addition of the PI3K inhibitor improved several outcomes, Dr. Turner reported, with these findings for the experimental vs control arms, respectively:

• Median overall survival: 34.0 vs 27.0 months (HR = 0.67; P = .0190)
• Overall survival probability: 87.0% vs 76.7% at 12 months and 56.5% vs 46.3% at 30 months, with benefit across key subgroups
• Objective response rate: 62.7% vs 28.0% (P < .0001)
• Median time to chemotherapy: 35.6 vs 12.6 months (HR = 0.43; 95% CI = 0.30–0.60)
• Median progression-free survival (updated): 17.2 vs 7.3 months (HR = 0.42; 95% CI = 0.32–0.55), with landmark analyses supporting a durable benefit
• At 24 months, 41.8% vs 16.7% of patients remained progression-free.

“With longer exposure to inavolisib, no new safety signals, nor changes in the safety profile, were noted, supporting relatively good tolerability, which was reflected in low treatment discontinuation due to adverse events,” Dr. Turner said. However, he acknowledged, inavolisib is not a drug without side effects. “Inavolisib does cause hyperglycemia, and it can cause diarrhea, though it causes less rash than other PI3K inhibitors.” These adverse events were generally manageable in the study, he added.

Grade 3 or 4 adverse events were seen in 90.7% of the inavolisib arm and 84.7% of the placebo arm; there were no new grade 5 adverse events. Any-grade hyperglycemia was noted in 63.4% and 13.5%, respectively. Adverse events leading to treatment discontinuation were observed in 6.8% and 0.6% of patients, respectively. 

Looking Ahead

Dr. Turner credited the outcomes in this study—culminating in an overall survival benefit—on the ability to create a well-tolerated targeted triplet regimen. “It’s the evolving improved drug design of PI3 kinase inhibitors along with the ability to combine inavolisib with palbociclib and fulvestrant that really draws out the efficacy,” he added.

Asked whether he could foresee a time when inavolisib may be combined with other drugs, Dr. Turner emphasized that the triplet therapy is designed for a very specific endocrine-resistant population for whom fulvestrant is the standard of care. However, he noted, studies of this agent are underway in patients with endocrine-sensitive cancer for whom other endocrine agents may be effective. 

DISCLOSURE: Dr. Turner has served as a consultant or advisor to AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Inivata, Guardant Health, and Exact Sciences; and has received research funding from AstraZeneca, Pfizer, Roche/Genentech, Merck Sharp and Dohme, Guardant Health, Invitae, Inivata, Personalis, and Natera.

REFERENCES

1. Turner NC, et al: 2025 ASCO Annual Meeting. Abstract 1003. Presented at a press briefing May 21, 2025.

2. Turner NC, Im SA, Saura C, et al: Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med 391:1584-1596, 2024.

EXPERT POINT OF VIEW

Two breast cancer oncologists from the Division of Hematology/Oncology at the UCLA David Geffen School of Medicine, UCLA Health Jonsson Comprehensive Cancer Center, offered their thoughts on the INAVO120 findings. Aditya Bardia, MD, MPH, Professor, and Marla Lipsyc-Sharf, MD, Instructor, shared these comments with The ASCO Post: “It is wonderful to see improvement in overall survival with the triplet regimen in this practice-changing study, which highlights the importance of mutation testing for genotype-directed therapy selection.”

Aditya Bardia, MD, MPH

Marla Lipsyc-Sharf, MD

Moving forward from the current findings, the trial also raises several important questions for the field, they said:

• What is the optimal CDK4/6 inhibitor backbone? Would ribociclib or abemaciclib have similar vs superior efficacy to palbociclib with this triplet regimen? Does prior receipt of a CDK4/6 inhibitor influence efficacy?
• What is the optimal endocrine therapy backbone? What is the role of an oral selective estrogen receptor degrader in place of fulvestrant, particularly in the setting of dual ESR1 and PIK3CA mutations?
• What is the optimal sequencing approach for PI3K inhibitors? How does an upfront combinatorial approach with a triplet compare with a sequential doublet approach?

“These questions could be addressed in future studies, as we continually strive to improve outcomes for patients with metastatic breast cancer. Overall, study investigators are to be congratulated on conducting a study backed by strong preclinical data that led to improvement in overall survival, the gold standard in oncology,” Drs. Bardia and Lipsyc-Sharf said.

Also commenting on the study’s findings was press briefing moderator and breast cancer expert

Julie R. Gralow, MD, FACP, FASCO

, Chief Medical Officer and Executive Vice President of ASCO. “I’m particularly impressed by the almost 2-year delay in going on chemotherapy, from 12.6 months to 35.6 months,” Dr. Gralow offered. “Delaying the need for chemotherapy in the metastatic setting by almost 2 years is certainly an outcome that matters to patients.”

She agreed with Drs. Bardia and Lipsyc-Sharf that the benefits seen with the triplet—notably, the increase in overall survival but also the delay in the need for chemotherapy—highlight the importance of testing patients for targetable mutations at the time of first recurrence. 

DISCLOSURE: Dr. Bardia has served as a consultant to Pfizer, Novartis, Genentech, Merck, Menarini, Gilead Sciences, Sanofi, AstraZeneca/Daiichi Sankyo, Alyssum Therapeutics, and Eli Lilly. Dr. Lipsyc-Sharf and Dr. Gralow reported no conflicts of interest.