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Roche recently announced that the positive results of its oral small molecule therapy Itovebi (inavolisib) in the Phase 3 clinical trial INAVO120 were published in The New England Journal of Medicine (NEJM). The trial results support Itovebi's approval in the U.S. this month.FDA Approval, in combination with the CDK4/6 inhibitor Ibrance (palbociclib) and fulvestrant, for the treatment of tumors carryingPIK3CAMutations, endocrine therapy resistance, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in adult patients. The analysis shows,Itovebi combination therapy significantly reduced the risk of disease progression or death by 57%.Data from INAVO120 is also being used to support regulatory submissions to other global health authorities, including the European Medicines Agency (EMA).

HR-positive breast cancer is the most common type of all breast cancers, accounting for approximately 70%.HR-Positive Breast Cancer Refers to Breast Cancers That Express Estrogen Receptor (ER) and/or Progesterone Receptor (PR), Which Can Promote Tumor Growth.Patients diagnosed with HR-positive metastatic breast cancer often face the risk of disease progression and treatment side effects, thus requiring additional treatment options.Approximately 40% of HR-positive metastatic breast cancer patients have tumorsPIK3CAMutation, which is considered a potential mechanism of resistance to standard endocrine therapy combined with CDK4/6 inhibitors.

INAVO120 is a randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate Itovebi in combination with Ibrance and fulvestrant compared to placebo plus Ibrance and fulvestrant in the treatment ofPIK3CAEfficacy and safety in patients with mutant, HR-positive, HER2-negative locally advanced or metastatic breast cancer, who experienced disease progression during treatment or within 12 months after completing adjuvant endocrine therapy, and have not received systemic therapy for treating metastatic tumors.The study enrolled 325 patients, with the primary endpoint being investigator-assessed progression-free survival (PFS), defined as the time from randomization to disease progression or death from any cause.Secondary endpoints include overall survival (OS), objective response rate, and clinical benefit rate.

The analysis shows,The median PFS for patients receiving Itovebi combination therapy reached 15 months (95% CI: 11.3-20.5), compared to 7.3 months (95% CI: 5.6-9.3) in the control group.Itovebi reduced the risk of disease progression or death by 57% (HR=0.43, 95% CI: 0.32-0.59, p<0.001). Notably,Patients benefited from PFS consistently across all predefined subgroups, including those whose disease had spread to three or more locations.

▲Itovebi Combination Therapy Improves Median PFS in Patients (Image Source: Reference [2])

In addition,58.4% of patients in the Itovebi combination therapy group achieved objective remission, compared to only 25.0% in the control group.The overall survival data was not yet mature at the time of analysis, but a positive trend for Itovebi has been observed (stratified HR=0.64, 95% CI: 0.43-0.97, p=0.03). The trial will continue to analyze the follow-up results of patient OS.

▲AcceptItovebi Combination Therapy Shows Positive Trend in OS Benefits for Patients (Image Source: Reference [2])

In terms of safety, the incidence rates of grade 3 or 4 neutropenia in the Itovebi combination therapy group and the control group were 80.2% and 78.4%, respectively; the incidence rates of grade 3 or 4 hyperglycemia were 5.6% and 0%, respectively; the incidence rates of grade 3 or 4 stomatitis or mucosal inflammation were 5.6% and 0%, respectively; the incidence rates of grade 3 or 4 diarrhea were 3.7% and 0%, respectively. No grade 3 or 4 rash was observed. In the Itovebi combination therapy group and the control group, 6.8% and 0.6% of patients discontinued any trial medication due to adverse events, respectively.

▲AcceptItovebi Combination Therapy Achieves High Objective Response Rate in Patients (Image Source: Reference [2])

Roche is currently evaluating in three Phase 3 clinical trials (INAVO120, INAVO121, INAVO122).ItovebiUnder different drug combination methods, carryingPIK3CAEfficacy in patients with locally advanced or metastatic breast cancer with mutations:

• INAVO121：Efficacy and Safety of Itovebi in Combination with Fulvestrant versus Alpelisib Plus Fulvestrant for the Treatment of HR-Positive/HER2-Negative Breast Cancer Patients Previously Treated with CDK4/6 Inhibitors and Endocrine Combination Therapy

• INAVO122：The Role and Safety of Itovebi in Combination with Phesgo Therapy (Pertuzumab and Trastuzumab Subcutaneous Injection) as a Maintenance Therapy for HER2-Positive Breast Cancer Patients, Compared with Endocrine Therapy Chosen by Physicians in Combination with Phesgo.

Itovebi is an oral therapy with high in vitro PI3Kα inhibition potency and selectivity, capable of specifically triggering the degradation of PI3Kα protein mutants.Through this unique dual mechanism of action,ItovebiMay be HR-positive/HER2-negative,PIK3CAPatients with mutant advanced breast cancer are provided with well-tolerated, durable disease control and potentially improved outcomes. It once received Breakthrough Therapy Designation from the U.S. FDA.

Currently in the clinical stage, PI3K inhibitors include the PI3K/mTOR inhibitor developed by Celcuity.gedatolisib. The therapy received Breakthrough Therapy Designation from the U.S. FDA in July 2022 for the treatment of HR-positive/HER2-negative metastatic breast cancer patients, and currently, the related Phase 3 clinical trial is underway. Relay Therapeutics announced its investigational therapy in September this year.RLY-2608Positive interim data from the first human trial. Analysis shows that previously heavily treated patients carryingPIK3CAPatients with HR-positive, HER2-negative locally advanced or metastatic breast cancer who received RLY-2608 (600 mg) in combination with fulvestrant demonstrated clinically meaningful improvement in PFS. The press release noted,RLY-2608 is the first allosteric inhibitor targeting PI3Kα, with mutant and isoform selectivity.

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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. Retrieved October 31, 2024 from https://www.globenewswire.com/news-release/2024/10/31/2972258/0/en/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-adva.html

[2] Turner NC, Im SA, Saura C, Juric D, Loibl S, Kalinsky K, Schmid P, Loi S, Sunpaweravong P, Musolino A, Li H, Zhang Q, Nowecki Z, Leung R, Thanopoulou E, Shankar N, Lei G, Stout TJ, Hutchinson KE, Schutzman JL, Song C, Jhaveri KL. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med. 2024 Oct 31;391(17):1584-1596. doi: 10.1056/NEJMoa2404625. PMID: 39476340.

[3] A Study to Evaluate the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer. Retrieved October 31, 2024 from https://clinicaltrials.gov/study/NCT05894239

[4] Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1) (VIKTORIA-1). Retrieved October 31, 2024 from https://clinicaltrials.gov/study/NCT05501886?intr=gedatolisib&aggFilters=phase:3&rank=1

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