Abstract 96MO
Background
ALP + fulvestrant is approved for PIK3CA-mutated, HR+/HER2– advanced BC in the US and EU. HG is an on-target adverse event (AE) of ALP and the most common all grade (G) and G3/4 AE in the phase III SOLAR-1 trial. Antihyperglycemic agents (AHAs) and ALP dose modifications (mods) and discontinuations (discs) were used to manage this AE (Table). We present a pooled risk factor model using safety sets of the phase I X2101 (NCT01219699) and SOLAR-1 (NCT02437318) trials and its application to SOLAR-1 data.
Methods
Pts (505) were randomly divided into training (405 pts) and testing sets (100 pts). Baseline factors for HG were identified, multiple models tested, and a random forest model was used to categorize pts as high or low risk for G3/4 HG based on 5 baseline factors (fasting plasma glucose [FPG], BMI, HbA1c, monocyte counts, and age). Performance metrics will be presented.
Results
The training set identified G3/4 HG in 126/131 high (96.2%) vs 3/274 low risk (1.09%) pts, and was validated in the testing set with 20/33 high (60.6%) vs 12/67 low risk (17.9%) pts. A 2-month (mo) analysis of G3/4 HG risk confirmed decreased probability at lower risk scores (area under the curve: training set = 0.991, testing set = 0.767). In all pts in the ALP arm of SOLAR-1, the model found a higher incidence of all-G and G3/4 HG, use of multiple AHAs, and more dose mods and discs in the high vs low risk pts (Table). There was no difference in median PFS in high (11.0 mo) vs low risk (10.9 mo) pts in the ALP arm with PIK3CA mutations. Table: 96MO
| HG incidence and management, n (%) | All Pts N = 284 | High Risk N = 106 | Low Risk N = 178 |
| All-G HG | 187 (65.8) | 101 (95.3) | 86 (48.3) |
| G3/4 HG | 108 (38.0) | 96 (90.6) | 12 (6.7) |
| Patients who received AHAs | 163 (57.4) | 94 (88.7) | 70 (39.3) |
| 1 AHA | 67 (41.1) | 24 (25.5) | 43 (61.4) |
| 2 AHA | 49 (30.1) | 31 (33.0) | 18 (25.7) |
| ≥3 AHA | 47 (28.8) | 39 (41.5) | 9 (12.9) |
| Dose mods for any reason (reductions and/or interruption of ALP) | 213 (75.0) | 92 (86.8) | 122 (68.5) |
| Permanent discs for any reason | 244 (85.9) | 90 (84.9) | 154 (86.5) |
| Discs due to HG | 19 (6.7) | 15 (14.2) | 4 (2.2) |
Conclusions
Risk modeling identified 5 baseline factors (FPG, BMI, HbA1c, monocyte counts, and age) associated with a higher probability of ALP-induced G3/4 HG. High risk pts had higher rates of AHAs and ALP mods. This model could be used clinically to identify pts at high risk for ALP-induced HG. Regardless of risk, pts with PIK3CA mutations derived a similar PFS benefit from ALP.
Clinical trial identification
NCT02437318, NCT01219699.
Editorial acknowledgement
This abstract was developed with editorial assistance provided by Daniele Cary, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
J. Rodon: Honoraria (self), Advisory/Consultancy: Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, Nov; Research grant/Funding (institution): Bayer, Novartis, Blueprint Pharmaceuticals, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline, Ipsen; Travel/Accommodation/Expenses: ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Co; Non-remunerated activity/ies: European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline. D. Demanse: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. H.S. Rugo: Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution), Travel/Accommodation/Expenses: OBI Pharma; Research grant/Funding (institution): Eisai; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Celsion; Research grant/Funding (institution): Merck; Travel/Accommodation/Expenses: Roche/Genentech; Travel/Accommodation/Expenses: Bayer. F. André: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche. I. Mayer: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Honoraria (self), Advisory/Consultancy: Puma; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Immunomedics; Honoraria (self), Advisory/Consultancy: Macrogenics; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Cylacel. H. Burris: Honoraria (institution), Research grant/Funding (institution): AstraZeneca, Incyte, Novartis, Bayer, Pfizer; Honoraria (institution): FORMA Therapeutics, Celgene, Daiichi Sankyo, HCA Healthcare/Sarah Cannon, GRAIL; Research grant/Funding (institution): Roche/Genentech, Bristol-Myers Squibb, MedImmune, Macrogenics, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna, CytomX, GlaxoSmithKline, Verastern, Tesaro, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFEC. A. Farooki: Leadership role: Novartis. H. Hu, I. Lorenzo, C. Quadt: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. D. Juric: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Genentech; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy: EMD Serono. All other authors have declared no conflicts of interest.