Combination effect of inavolisib and FGFR inhibitors in FGFR2-expressing cell lines

FGFR2 controls HER3 to induce p85β binding and signaling in FGFR2 high-expressing cell lines

Proposed mechanistic model of FGFR2-mediated inavolisib sensitivity

Representativeness of study participants

Evaluation of the anti-tumor activity of FGFR2 inhibitor in combination with inavolisib in MFM223x2.2 xenograft model

Notable large-scale immuno-oncology consortia formed in the recent era.

Effects of FGFR1/2/3/4 knockdown on inavolisib sensitivity

1013 Background: In the phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286) SG + pembro showed significant and clinically meaningful progression-free survival (PFS) improvement vs chemo + pembro in pts with previously untreated PD-L1+ mTNBC. SG + pembro exhibited a manageable safety profile consistent with prior studies for each agent. We present preplanned exploratory efficacy analyses in ASCENT-04 by biomarker subgroups. Methods: 443 pts received (1:1 ratio) SG + pembro in 21-day cycles or chemo (gemcitabine + carboplatin; taxane) + pembro. From centrally tested fresh or archival tumor samples, Trop-2 expression was determined by immunohistochemistry (IHC), tumor BRCA (tBRCA) status by whole exome sequencing, and HER2 expression by in situ hybridization (ISH) + IHC. Pts were grouped by Trop-2 expression quartiles, tBRCA status (wild-type [WT] or mutant [mut] in BRCA1/BRCA2 /both), and HER2 status (IHC 0 vs Low [IHC 1+ or IHC 2+/ISH–]). Biomarker subgroups were analyzed descriptively for association with PFS by blinded independent central review (BICR); other outcomes by biomarker status are forthcoming. Results: Median Trop-2 H-score was 280, ranges: quartile 1 (Q1) 0-224, Q2 225-279, Q3 280-298, Q4 299-300. SG + pembro demonstrated longer PFS by BICR in Q3/Q4 vs Q1/Q2, and benefit was observed for SG + pembro vs chemo + pembro in all quartiles (Table). Hazard ratios (HR; 95% confidence interval [CI]) were: Q1, 0.81 (0.48-1.36); Q2, 0.73 (0.44-1.22); Q3, 0.46 (0.27-0.80); Q4, 0.57 (0.33-0.99). Proportion of pts with tBRCA mutations (~20%) was similar between treatment groups. Longer PFS was observed with SG + pembro with HR (95% CI) of 0.67 (0.49-0.91) in the tBRCA WT and 0.88 (0.45-1.74) in the tBRCA mut subgroups. PFS was longer with SG + pembro vs chemo + pembro in the HER2 IHC 0 and HER2 low subgroups, HR (95% CI) 0.69 (0.46-1.04) and 0.67 (0.48-0.92), respectively. Conclusions: SG + pembro demonstrated longer PFS vs chemo + pembro across all Trop-2, tBRCA, and HER2 subgroups. These analyses strengthen support for the significant, clinically meaningful benefit of SG + pembro as first-line treatment for mTNBC across subgroups. Clinical trial information: NCT05382286 . Efficacy, BICR N Median PFS (95% CI), mo Biomarker Subgroup SG + pembro Chemo + pembro SG + pembro Chemo + pembro HR (95% CI) Trop-2(n = 400) Q1 48 47 9.3(7.4-19.4) 9.0(6.0-10.9) 0.81(0.48-1.36) Q2 50 50 9.6(7.3-16.7) 7.4(6.9-9.7) 0.73(0.44-1.22) Q3 55 50 13.5(9.3-NR) 8.4(5.6-10.8) 0.46(0.27-0.80) Q4 51 49 16.6(8.1-NR) 9.2(5.5-11.3) 0.57(0.33-0.99) tBRCA(n = 332) WT 130 131 9.6(7.6-16.7) 7.4(6.9-9.2) 0.67(0.49-0.91) Mut 39 32 16.6(7.5-NR) 12.9(7.1-NR) 0.88(0.45-1.74) HER2(n = 435) IHC 0 84 82 16.6(9.1-21.2) 9.0(7.2-10.8) 0.69(0.46-1.04) Low 133 136 11.2(9.1-16.6) 7.7(7.0-9.4) 0.67(0.48-0.92)

Effects of inavolisib and FGFR2 inhibition on downstream signaling in FGFR2-high and FGFR2-low expressing cell lines

Study NCT03006172 Arm A participants whose liquid biopsies harbored an FGFR2 mutation

PURPOSE:We aimed to investigate the prognostic and predictive value of tumor infiltrating lymphocytes (TILs) for adjuvant immunotherapy in high-risk early TNBC. PATIENTS AND METHODS:The phase III A-BRAVE trial randomized 466 patients with high-risk early TNBC to adjuvant avelumab or observation after standard therapy. Inclusion criteria allowed two strata: Stratum A (primary surgery followed by adjuvant chemotherapy, defined at high risk based on pathological stage) and Stratum B (neoadjuvant chemotherapy followed by surgery without pathological complete response). TILs were centrally assessed on treatment-naive tumor samples (BSL-TILs) and on residual disease after neoadjuvant chemotherapy (RD-TILs, Stratum B). Residual cancer burden (RCB) was assessed in Stratum B. Survival endpoints were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS:BSL-TILs were available for 387 patients, RD-TILs for 330 patients (290 with both BSL-TILs and RD-TILs). Higher BSL-TILs were independently associated with improved outcomes across all endpoints. In Stratum B, higher RD-TILs showed a significant independent association with improved outcomes, outperforming BSL-TILs. RCB was also independently prognostic. Avelumab improved outcomes only for patients with BSL-TILs ≥30%, particularly in Stratum B (3-yr DDFS rates 92.0% vs 58.7%, HR 0.20 in high BSL-TILs and 70.4% vs 70.1%, HR 0.92 in low BSL-TILs, interaction p=0.019). Similar results for DFS and OS. RCB was not predictive for avelumab benefit. CONCLUSIONS:TILs may predict benefit from adjuvant immunotherapy in early TNBC. These findings warrant validation and support TILs-guided immunotherapy strategies in future trials. TRIAL REGISTRATION:NCT02926196.

The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER+ breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ). Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

Foundation Medicine (FMI) FoundationACT (FACT) panel of NGS features selected by model as associated with response

Pembrolizumab plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in the phase 3 randomized KEYNOTE-355 study in participants with previously untreated, advanced triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) ≥ 10. Among participants with clinical benefit from pembrolizumab plus chemotherapy, discontinuation of chemotherapy before pembrolizumab for any reason was associated with similar median PFS and OS to that in the overall population. Additionally, we further characterized immune-mediated adverse events (AEs) in KEYNOTE-355. Most immune-mediated AEs were manageable with treatment interruption and supportive care. In participants treated with pembrolizumab plus chemotherapy with immune-mediated AEs, there appeared to be numerical improvement in efficacy. This analysis provides additional information on the use of pembrolizumab plus chemotherapy as standard-of-care therapy in patients with previously untreated, advanced TNBC with PD-L1 CPS ≥ 10. This trial is registered at ClinicalTrials.gov (NCT02819518; registration date, June 28, 2016).

Relationship between FGFR2 expression and inavolisib sensitivity and pAKT S473 baseline expression

Drug combination effect of inavolisib and the FGFR2i as measured by a two-way 10 x 8 serial dilution matrix in a 5-day viability assay

507 Background: KEYNOTE-522 (NCT03036488) showed statistically significant and clinically meaningful improvements in pCR, EFS, and OS with the addition of pembrolizumab (pembro) to chemotherapy (chemo) in participants (pts) with high-risk early-stage TNBC. Here, we present updated results from the final analysis. Methods: Eligible pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or placebo (pbo), both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS (time from randomization to disease progression that precluded definitive surgery, local/distant recurrence, second primary cancer, or death from any cause); OS is the key secondary endpoint. Results: 1174 pts were randomized to pembro (n = 784) or pbo (n = 390). At the data cutoff date (October 14, 2025), median follow-up (range) was 93.8 mo (84.7-102.8). The 7-yr EFS rate (95% CI) was 78.3% (75.3-81.1) in the pembro group vs 69.8% (65.0-74.2) in the pbo group; the HR was 0.68 (95% CI, 0.54-0.86). The 7-yr OS rate (95% CI) was 85.1% (82.5-87.5) in the pembro group vs 77.2% (72.7-81.1) in the pbo group; the HR was 0.64 (95% CI, 0.49-0.85). The benefit of pembro on EFS and OS was generally consistent across most prespecified subgroups, including those defined by PD-L1 expression, nodal status, and disease stage. Rates of grade ≥3 treatment-related AEs were 77.1% in the pembro group and 73.3% in the pbo group (death incidence, 0.5% vs 0.3%, respectively); rates of any grade immune-mediated AEs were 35.0% vs 13.1%, respectively. Conclusions: After a median follow-up of 7.8 years, neoadjuvant pembro + chemo followed by adjuvant pembro continues to show a clinically meaningful survival benefit compared with neoadjuvant chemo alone in pts with high-risk early-stage TNBC. Clinical trial information: NCT03036488 .

MANIFEST Consortium List of Authors

TPS1131 Background: Endocrine therapy(ET) resistance is a major challenge in treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC); estrogen receptor (ESR1) mutations are an important mechanism of resistance. The standard of care (SOC) first-line treatment for ER+, HER2– MBC is ET plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Despite the benefit of ET and CDK4/6i, disease progression and acquired resistance to the combination remain a challenge. Novel, more effective ETs that can overcome resistance are needed to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a novel oral, complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD) that acts by blocking both transcriptional activation function domains, AF1 and AF2, regardless of ESR1 mutation status. As monotherapy, palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in heavily-pretreated patients during phase 1/2 studies, regardless of ESR1 mutation status (NCT04505826; Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Adult patients are eligible with a diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1 or 2 prior lines of ET with the last ET duration of ≥6 months; must have received and have disease progression on CDK4/6i with ET for MBC. Prior chemotherapy for MBC is not allowed. The study included a dose selection phase, where participants were randomized to 90 mg qd or 120 mg qd palazestrant or SOC; enrollment in this phase is complete. After the dose selection of palazestrant, the study will continue with the selected dose compared to SOC ET at a 1:1 randomization. Overall, 510 patients will be randomized to palazestrant or SOC ET during the study. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations (dual primary endpoint). Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, exposure and patient-reported outcomes in patients with and without ESR1 mutations. Study recruitment began in November 2023. Clinical trial information: NCT06016738 .