Episode Notes
Rationale behind combination
Target different points along same pathway
PI3K Pathway
Or RTK/RAS/CTNNB1 pathway altered in 80-90% of low-grade endometrioid tumors
Interacts with androgen/estrogen signaling pathway
PI3K inhibitors (i.e. alpelisib) only work with concomitant hormonal inhibition
GOG 3069: phase 2 study of alpelisib + fulvestrant for PIK3CA-mutated ER-positive endometrioid endometrial cancer
mTOR Inhibitors
Downstream from PI3K
Endometrial cancer: everolimus + letrozole
But only agent that can be used as monotherapy (still less effective though)
Albumin-bound sirolimus: preferred systemic option for locally-advanced unresectable or metastatic malignant PEComa
TSC2 mutation strongly predicts benefit
AKT Inhibitors
Capivasertib: only FDA-approved
Approved in combination with fulvestrant for HR-positive, HER2-negative advanced/metastatic breast cancer with a PIK3A/AKT1/PTEN alteration
Approved in combination with abiraterone and prednisone for PTEN-deficient metastatic prostate cancer
CDK4/6 Inhibitors
Combined with anti-estrogen
Cyclin D - CDK4/6 - Rb axis drives the cell cycle
Cyclin D1
Direct transcriptional target of estrogen receptor
Green et al.
Phase 2 study of fulvestrant + abemaciclib in HR-positive advanced or recurrent endometrial cancer
ORR 44% vs 3-14% seen with SERD monotherapy
91% of responses occurred in copy-number-low, NSMP tumors
Zero benefit in p53 mutated tumors
GOG 3025, Slomovitz et al.
Phase 2 study of letrozole + ribociclib in LGSOC
ORR 31%, clinical benefit rate 84%, median duration of response 21.2 months
Resistance Mechanisms
ESR1 mutation
Makes estrogen pathway constitutively active (on without estrogen binding)
Can use SERD to degrade the receptor
Fulvestrant better than exemestane in ESR1-mutant breast disease
Imlunestrant
Newer oral SERD
FDA-approved in ESR1-mutateed breast cancer
Being investigated in endometrioid endometrial cancer in phase ½ EMBER trial
ORR 18% when combined with abemaciclib
Elacestrant
FDA-approved in ESR1-mutated breast cancer
Under investigation w/ or w/o abemaciclib in endometrial cancer
Toxicities
Generally favorable compared to cytotoxics
CDK4/6
Neutropenia: G3+
22% abemaciclib + fulvestrant
47% ribociclib + letrozole
44% palbociclib + letrozole
mTOR
Everolimus + letrozole
Most common AEs: anemia, mucositis, hyperglycemia, fatigue, pneumonitis
Image: from Ray-Coquard et al 2023
Figure 1 Combining endocrine and targeted therapies to overcome resistance. Resistance to endocrine therapies is common in hormone-driven cancers. Current strategies to overcome this resistance are focused on inhibiting upstream signaling pathways and CDK4/6. Approved therapies, and those currently in clinical development (italicized), are depicted with mechanisms of action that include targeting estrogens, estrogen receptor (ER), growth signaling pathways, and CDK4/6.
Bibliography
1. Gaillard S, Sill M, Klein J, et al. GOG3069: Phase 2 study of alpelisib and fulvestrant for PIK3CA-mutated estrogen receptor (ER)-positive endometrioid endometrial cancers. Journal of Clinical Oncology. 2024;42(16_suppl):TPS5639-TPS5639. doi:10.1200/JCO.2024.42.16_SUPPL.TPS5639
2. Gershenson DM, Bodurka DC, Coleman RL, Lu KH, Malpica A, Sun CC. JOURNAL OF CLINICAL ONCOLOGY Hormonal Maintenance Therapy for Women With Low-Grade Serous Cancer of the Ovary or Peritoneum. J Clin Oncol. 2017;35:1103-1111. doi:10.1200/JCO.2016.71.0632
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