Abstract CT109: A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with <i>PIK3CA</i>-mutant, hormone receptor-positive/HER2-negative breast cancer
Bibliographic record
Abstract
Abstract Background: PIK3CA encodes the PI3K p110α subunit, and dysregulating mutations are widely seen in breast cancer (BC) and other solid tumors. GDC-0077 (G) is a potent p110α-selective inhibitor that degrades mutant p110α and demonstrates antitumor activity in PIK3CA-mutant BC xenograft models, either as a single agent, or combined with anti-estrogen therapy. From an ongoing, open-label, phase I/Ib dose-escalation study of G alone and combined with endocrine + targeted therapies (NCT03006172), we present data of G + fulvestrant (F) in postmenopausal patients (pts) with PIK3CA-mutant, hormone receptor-positive/HER2-negative BC, including a food-effect assessment on the pharmacokinetics (PK) of G. Methods: Safety (NCI-CTCAE v4), PK, and preliminary antitumor activity (clinical benefit rate [CBR]: RECIST v1.1 stable disease for ≥24 weeks, partial response [PR], or complete response) of 9 mg oral once-daily G + 500 mg intramuscular F on Day 1 (and Day 15 of Cycle 1) of 28-day cycles were assessed until intolerable toxicity/disease progression. The effect of a standard high-fat meal on the PK of G was evaluated after a single dose and at steady state. Relevant signaling and pharmacodynamic (PD) biomarkers were assessed using circulating tumor (ct) DNA samples. Results: At clinical cutoff (Jul 19, 2019), 20 pts were enrolled in the food-effect portion of the G + F arm. Fifteen (75%) had received ≥2 prior lines of therapy for metastatic BC. Median G treatment duration was 5.9 months (range 1.7-17.8); cumulative dose intensity, 98%. Adverse events (AEs) led to dose reduction in 3 pts (15%). The most common treatment-related (TR) AEs (≥4 pts, 20%) were hyperglycemia (11, 55%), diarrhea (10, 50%), stomatitis (grouped term; 9, 45%), nausea (8, 40%), decreased appetite (7, 35%), dysgeusia, fatigue, and muscle spasms (4 each, 20%). Grade ≥3 TRAEs were hyperglycemia, nausea, lymphopenia, hyperamylasemia, and hyperlipasemia (1 each, 5%). The PK of G in combination with F was similar to single-agent PK. Comparable G exposures (Cmax and AUC0-24) were observed following administration in fasted or fed states. Seventeen pts (85%) discontinued treatment, all due to radiographic/clinical disease progression. Overall, 5/14 pts with measurable disease had a PR (36%; 2 received prior F; 4, prior CDK4/6i), of whom 2 pts (14%) had a confirmed PR. CBR was 60% (12/20 pts). Most pts showed decreased ctDNA PIK3CA-mutant allele frequency during treatment. Conclusion: G + F demonstrated a manageable safety profile, similar PK to G alone, preliminary antitumor activity, and PD modulation of PIK3CA-mutant allele frequency in ctDNA. The presence of food did not significantly impact the rate or extent of G absorption following single or multiple doses. Additional pts are being enrolled in the G + F arm to further inform the safety and efficacy of this combination. Citation Format: Kevin Kalinsky, Dejan Juric, Philippe L. Bedard, Mafalda Oliveira, Andres Cervantes, Erika Hamilton, Ian E. Krop, Nick Turner, Peter Schmid, Andrea Varga, Antoine Italiano, Zachary Veitch, Cristina Saura, Valentina Gambardella, Sravanthi Cheeti, Naoki Kotani, Guiyuan Lei, Katherine E. Hutchinson, Stephanie Royer-Joo, Anjali Vaze, Jennifer L. Schutzman, Komal Jhaveri. A phase I/Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT109.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".