157TiP Krascendo-170 Lung: A phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+ advanced non-small cell lung cancer (NSCLC)
Bibliographic record
Abstract
The KRAS G12C mutation, present in ∼12% of NSCLC patients, drives oncogenic signalling and cancer formation and is associated with poor prognosis. The current first-line treatment for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) ± chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumour activity. We hypothesize that divarasib + CPI ± CT may improve outcomes for patients with KRAS G12C+ NSCLC. Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumour cell expression ≥1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumour cell expression level (Cohort B). Patients must be ≥18 years old with untreated unresectable/metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRAS G12C mutation, and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumour assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterise pharmacokinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1).Table: 157TiPCohortPD-L1 tumour cell expressionDose finding*Dose expansion†A≥1%Divarasib + PembrolizumabDivarasib + PembrolizumabBAnyDivarasib + Pembrolizumab + CT‡ + PemetrexedDivarasib + Pembrolizumab + CT‡ + Pemetrexed*Participants will receive one of two doses of divarasib. †Dose expansion will depend on pre-specified safety parameters during the dose-finding stage; ‡CT: 4 cycles of carboplatin (intravenously, every 3 weeks, AUC5) or cisplatin (intravenously, every 3 weeks, 75 mg/m2) per investigator’s choice. Drug administration schedule: Divarasib: orally once daily; Pemetrexed: 500 mg/m2 intravenously every 3 weeks; Pembrolizumab: 200 mg intravenously every 3 weeks. Open table in a new tab *Participants will receive one of two doses of divarasib. †Dose expansion will depend on pre-specified safety parameters during the dose-finding stage; ‡CT: 4 cycles of carboplatin (intravenously, every 3 weeks, AUC5) or cisplatin (intravenously, every 3 weeks, 75 mg/m2) per investigator’s choice. Drug administration schedule: Divarasib: orally once daily; Pemetrexed: 500 mg/m2 intravenously every 3 weeks; Pembrolizumab: 200 mg intravenously every 3 weeks. NCT05789082. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Neave Baldwin, BSc, of Ashfield MedComms, an Inizio company. F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".