Molecular Features of Response to Palbociclib + Fulvestrant ± Inavolisib in Hormone Receptor–positive, HER2-negative, PIK3CA-mutated Advanced Breast Cancer as Assessed from Baseline Circulating Tumor DNA in the Pivotal Phase 3 INAVO120 Trial
Inavolisib plus palbociclib and fulvestrant is approved for the treatment of PIK3CA-mutated, hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–), endocrine-resistant advanced breast cancer, having demonstrated significantly improved efficacy compared to placebo plus palbociclib and fulvestrant in the INAVO120 trial. In this study, researchers analyzed circulating tumor deoxyribonucleic acid (ctDNA) data from patients enrolled in the INAVO120 trial to determine molecular features of response. Among 277 patients with baseline ctDNA data, 267 had detectable tumor fraction (TF). Median TF was 3.8 percent. Inavolisib provided treatment benefit compared to placebo in both above and below median TF groups, with no interaction observed between TF and treatment benefit from inavolisib (p=0.935). Higher TF was associated with shorter progression-free survival (PFS) in both inavolisib and placebo arms. After PIKCA mutations, the most commonly mutated genes were TP53 (49.4%), CDH1 (17.6%), and ESR1 (14.5%), and 10.9 percent of patients harbored deleterious PTEN alterations. The treatment benefit of inavolisib versus placebo was similar in patients with kinase and helical PIK3CA mutations (both hazard ratio [HR]: 0.5, 95% confidence interval [CI]: 0.3–0.8), as well as among patients with single (HR: 0.5, 95% CI: 0.3–0.7) or multiple PIK3CA mutations (HR: 0.6, 95% CI: 0.3–1.1), with an interaction p-value of 0.677. Inavolisib PFS benefit was comparable between patients with ESR1 short variant mutation (HR: 0.5, 95% CI: 0.4–0.7) and no ESR1 mutation (HR: 0.2, 95% CI: 0.1–0.7; interaction p=0.705). Similarly, inavolisib demonstrated treatment benefit over placebo among patients with and without deleterious PTEN alterations (HR: 0.6 and 0.5, respectively; 95% CI: 0.2–1.4 and 0.3–0.6, respectively; interaction p=0.706). Although TP53 mutation was identified as a negative prognostic factor in both inavolisib and placebo arms, inavolisib maintained PFS benefit over placebo in this patient population (HR: 0.5, 95% CI: 0.4–0.8).
First Preclinical Evaluation of Inavolisib-based Combinatorial Strategies in PIK3CA-mutant Breast Cancer Brain Metastasis Models
In breast cancer brain metastases (BCBM), PIK3CA mutations activate PI3K, thereby promoting tumor cell survival and therapeutic resistance. Inavolisib is a PI3K-alpha inhibitor currently approved for the treatment of PIK3CA-mutated, HR+, HER2– advanced breast cancer. In this study, researchers evaluated the efficacy of inavolisib combination therapy in intracranial murine models and patient-derived xenografts (PDX) of BCBM harboring PIK3CA mutations in HER2+ and triple-negative breast cancer (TNBC) subtypes. For the TNBC models, inavolisib was combined with anti-programmed cell death protein 1 (PD-1) antibody or albumin-bound paclitaxel. For the HER2+ models, inavolisib was combined with trastuzumab plus pertuzumab, trastuzumab deruxtecan (T-DXd), or tucatinib. Treatment with inavolisib plus anti-PD-1 antibody resulted in a significant decrease in tumor volume and longer survival in TNBC models, whereas inavolisib monotherapy showed limited efficacy. In HER2+ models, combination therapy with inavolisib plus T-DXd and inavolisib plus trastuzumab plus pertuzumab significantly improved survival and delayed neurologic decline compared to single agent therapy and standard of care comparator (tucatinib plus trastuzumab plus capecitabine). Brain tumor burden decreased with inavolisib plus T-DXd in a dose-dependent manner. At Week 3, imaging showed that combination therapy resulted in lower brain bioluminescence compared to vehicle or monotherapy, and signals near or below the detection limit were commonly observed in the inavolisib plus high-dose T-DXd group. Decreased proliferation, increased apoptosis, and enhanced immune infiltration were observed with combination therapy. Additionally, researchers found that tumors treated with combination therapy showed a shift toward a less aggressive, luminal-like gene expression profile. These preclinical findings suggest that combination therapies including a PI3K inhibitor, such as inavolisib, might be a viable strategy for treating BCBM.
Comparative Analysis of Blood- and Tissue-based PIK3CA Mutation Detection Methods in the Pivotal Phase 3 INAVO120 trial of Palbociclib + Fulvestrant ± Inavolisib in Hormone Receptor–positive, HER2-negative Advanced Breast Cancer
Presence of a PIK3CA mutation is necessary for treatment with an approved PI3Ka inhibitor, such as inavolisib, but cross-assay concordance studies for PIK3CA mutation detection are limited. As such, researchers utilized data from the INAVO120 trial to compare the ability of various molecular tests to detect PIK3CA mutations. A total of 1,422 participants had data from FoundationOne®Liquid CDx (F1LCDx®; Foundation Medicine, Inc.) profiling on ctDNA, from central screening for eligibility (n=1,383, including 5 patients screened by the preceding assay to F1LCDx) or postenrollment ctDNA testing of local blood/tumor tissue (n=39). Retrospective assessment of DNA from archival or fresh tumor tissue was conducted with FoundationOne®CDx (F1CDx®; n=323) sequencing and/or the Cobas® PIK3CA Mutation Test, a polymerase chain reaction [PCR] test (n=84). Among those who underwent central screening, 242 participants with PIK3CA mutation who were enrolled and underwent treatment were included for analysis, as were the 39 participants who screened with a PIK3CA-positive local test, for a total efficacy-evaluable population of 281 (F1LCDx: n=277; F1CDx: n=218 [reference]; Cobas PCR: n=42 [reference]). Thirty-seven local test–identified patients also underwent testing with F1LCDx, 27 of whom had PIK3CA mutation identified by both assays; discordance was largely due to low tumor fraction (TF), as median TF was zero percent among discordant patients and six percent among nondiscordant patients. Among 29 patients who underwent local testing and F1CDx, PI3KCA mutation was detected by both assays in all patients. Evaluating data from 315 patients with both F1LCDx and F1CDx (enrolled and treated: n=214, screened but not enrolled/treated: n=101), researchers found that the positive percent agreement (PPA) between F1LCDx and F1CDx was high, at 92.2 percent. Negative percent agreement (NPA) was 72.7 percent, and overall percent agreement (OPA) was 88.6 percent. Assessing data from 84 patients (enrolled and treated: n=42, screened but not enrolled/treated: n=42) with Cobas PCR and F1LCDx testing, researchers calculated a PPA, NPA, and OPA of 90.2, 100, and 94.0 percent, respectively. PFS benefit with inavolisib over placebo was largely similar to that of the intention-to-treat population (HR: 0.43), regardless of assay type. In the F1LCDx test–positive subgroup, median PFS was 7.3 months with placebo versus 16.6 months with inavolisib (HR: 0.47, 95% CI: 0.34–0.65). In the F1CDx test–positive subgroup, median PFS was 7.3 months with placebo versus 17.2 months with inavolisib (HR: 0.47, 95% CI: 0.32–0.68). In the Cobas PCR test–positive subgroup, median PFS was 12.6 months with placebo and 25.7 months with inavolisib (HR: 0.47, 95% CI: 0.18–1.23). Among patients with PIK3CA positivity on a local test, median PFS was 9.3 months with placebo and 19.4 months with inavolisib, with a HR of 0.70 (95% CI: 0.31–1.54); the increased HR is due to the small sample size.
Relationship of Early ctDNA Dynamics with Response to Inavolisib Alone or in Combination with Endocrine Therapy +/- CDK4/6 Inhibitor in PIK3CA-mutated HR+, HER2– Metastatic Breast Cancer from the First-in-human PhI/Ib Trial
Researchers assessed the relationship between treatment response and changes in ctDNA after 15 days of inavolisib treatment among patients enrolled in the first-in-human Phase I/Ib trial. Patients had PIK3CA-mutated, HR+, HER2– locally advanced or metastatic breast cancer. Patients received either inavolisib monotherapy or combination therapy. Plasma samples were collected prior to treatment at baseline and at Cycle 1 Day 15 (C1D15). Total number of alterations (totalAlts) and maximum or sum of PIK3CA variant allele frequency (max VAF/sumVAF) among a subset of responder and nonresponder samples were key ctDNA metrics. Univariate logistic regression analysis showed that the percent change in PIK3CA maxVAF (p=0.007), percent change in sumVAF (p=0.006), and C1D15 totalAlts (p=0.034) were significantly associated with confirmed best overall response (cBOR). For responders, median percent change between baseline and C1D15 PIK3CA sumVAF was –58.41 percent, compared to zero percent for nonresponders. Additionally, median percent change between baseline and C1D15 in totalAlts was –27.0 percent for responders compared to zero percent for nonresponders. Since maxVAF and sumVAF were highly correlated (rho=0.996), further analyses focused on sumVAF. Multivariate analysis showed no significant association between C1D15 totalAlts and PIK3CA sumVAF (rho=0.186, p=0.063). Furthermore, totalAlts was not significantly associated with cBOR (p=0.058). Percent change in PIK3CA sumVAF maintained significance with cBOR in the multivariate model (p=0.027). Researchers then evaluated the ability of percent change in PIK3CA sumVAF to stratify patients by PFS, and zero percent was determined to be the optimal cutoff point (HR: 10.4, 95% CI: 4.6–23.6); 90 patients had a percent change of zero percent or less (median: –61.18%), and 10 patients had a percent change above zero percent (median: 43.74%). Stratification by percent change in quartiles and above and below median percent change were not effective in stratifying patients based on PFS.
INAVO123: Phase III Study of First-line Inavolisib/Placebo + a Cyclin-dependent Kinase 4/6 Inhibitor + Letrozole in Participants with PIK3CA-mutated, Hormone receptor–positive, HER2-negative, Endocrine-sensitive Advanced Breast Cancer
Although combination treatment with endocrine therapy (ET) plus cyclin-dependant kinase 4/6 (CDK4/6) inhibitor is the standard of care for PIK3CA-mutant, HR+, HER2–, endocrine-sensitive advanced breast cancer, resistance and subsequent progression are common. The INAVO120 trial showed that first-line treatment with inavolisib, a PI3K-alpha inhibitor that promotes mutant p110-alpha degradation, plus palbociclib and fulvestrant significantly improved PFS compared to placebo plus palbociclib and fulvestrant in this patient population, and recent data have shown a meaningful overall survival (OS) benefit as well. The Phase III INAVO123 trial aims to evaluate the efficacy and safety of inavolisib or placebo plus CDK4/6 inhibitor plus letrozole in patients with PIK3CA-mutant, HR+, HER2–, endocrine-sensitive advanced breast cancer. Key inclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, fasting blood glucose less than 126mg/dL, hemoglobin A1c (HbA1c) less than 6.5 percent. Key exclusion criteria include patients who progressed while on or within 12 months of adjuvant therapy, receipt of prior systemic therapy for locally advanced or metastatic breast cancer, pregnancy or breastfeeding or intention to become pregnant during the study or within the period wherein contraception is necessary, presence of known and untreated or active central nervous system metastases, presence of symptomatic active lung disease, history of or active inflammatory bowel disease, and history of leptomeningeal disease or carcinomatous meningitis. Patients will be randomized 1:1 to receive either inavolisib- or placebo-based regimens, which will consist of inavolisib 9mg daily or placebo plus CDK4/6 inhibitor daily (21 days on, 7 days off) plus letrozole 2.5mg oral daily in 28-day cycles. Additionally, pre-/perimenopausal women and men will receive a luteinizing hormone-releasing hormone agonist. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, death, or study termination. The primary endpoint is PFS, and secondary endpoints include OS, investigator-assessed objective response rate, investigator-assessed duration of response, investigator-assessed clinical benefit rate, patient-reported outcomes, and safety.
GPER Signaling as a Biomarker for Endocrine Therapy Sensitivity in PIK3CA-mutant, HR+, Advanced Breast Cancer
The INVAO120 trial demonstrated the efficacy of inavolisib plus palbociclib and fulvestrant in PIK3CA-mutant, HR+ advanced breast cancer with resistance to endocrine therapy. Currently, the effectiveness of combination therapy with inavolisib and alternative CDK4/6 inhibitors is unknown. G protein-coupled estrogen receptor (GPER) has been implicated as a driver of endocrine resistance; thus, researchers hypothesized that GPER signaling modulated CDK4/6 inhibitor sensitivity in PIK3CA-mutant breast cancer, and evaluated its potential as a biomarker to guide personalized decision-making. Utilizing PIK3CA-mutant breast cancer cell lines (MCF-7 and T-47D), researchers developed tamoxifen-resistant (TAM-R) and palbociclib-resistant (Palb-R) models, representing first- and second-line endocrine resistance, respectively. In both TAM-R and Palb-R models, GPER and ABCG2 expression were upregulated compared to parental controls. Inavolisib plus abemaciclib or ribociclib showed improved antiproliferative effects compared to palbociclib-based regimens in TAM-R models. In Palb-R models, inavolisib plus abemaciclib or ribociclib combination therapy outperformed inavolisib monotherapy. GPER/ABCG2 knockdown led to improved efficacy of CDK4/6 inhibitors when combined with inavolisib in TAM-R models; in Palb-R models, knockdown of GPER/ABCG2 partially reversed palbociclib resistance, and also improved the sensitivity of abemaciclib/ribociclib plus inavolisib therapy. These findings indicate the GPER could be a useful biomarker to inform personalized decision-making in PIK3CA-mutant, HR+ advanced breast cancer.