MK-1084 for KRAS G12C-mutated (mut) metastatic non–small-cell lung cancer (mNSCLC): Results from KANDLELIT-001.
Bibliographic record
Abstract
8605 Background: MK-1084 is an oral, next-generation, selective KRAS G12C-GDP covalent inhibitor. The phase 1 KANDLELIT-001 study (NCT05067283) showed manageable safety and antitumor activity for MK-1084 monotherapy in KRAS G12C-mut solid tumors and MK-1084 + pembrolizumab (pembro) in KRAS G12C-mut mNSCLC. We report additional NSCLC and preliminary ctDNA data from this study. Methods: Pts had confirmed KRAS G12C-mut, RECIST-measurable disease and ECOG PS 0-1. Pts with any advanced solid tumor and ≥1 prior systemic therapy received MK-1084 monotherapy 25-800 mg/d in arms 1 and 3. Pts with previously untreated mNSCLC and PD-L1 TPS ≥1% received MK-1084 25-400 mg/d + pembro 200 mg Q3W in arm 2 dose escalation and expansion cohorts. Pts with previously untreated nonsquamous mNSCLC received MK-1084 50-200 mg/d + pembro 200 mg, carboplatin, and pemetrexed Q3W in arm 4. Dose-limiting toxicities (DLTs), AEs, and AEs leading to discontinuation were the primary endpoints; ORR, DCR, and PFS per RECIST v1.1 by investigator review were secondary. KRAS G12C variant allele fraction (VAF) and maximum somatic allele frequency (MSAF) in ctDNA were assessed in serial blood samples collected from 23 pts in arm 1 using the Guardant Health OMNI panel. Results: There were 99 pts in arms 1+3 (21 with NSCLC), 34 in arm 2 escalation cohorts, 26 in arm 2 expansion cohorts, and 24 in arm 4 as of the 12 Aug 2024 data cutoff. Median study follow-up was 14.8 mo, 16.2 mo, 2.5 mo, and 4.1 mo, respectively. DLTs occurred in 1 pt in arm 2 (gr 3 ALT and AST increase) and 1 pt in arm 4 (gr 3 diarrhea). Drug-related AEs occurred in 62% of pts in arms 1+3, 88% of pts in arm 2, and 96% of pts in arm 4, were gr ≥3 in 9%, 33%, and 58%, and led to discontinuation of any drug in 1%, 20%, and 17%. There was 1 drug-related death (myelosuppression and platelet count decrease in arm 2). Rates of drug-related ALT increase (any/gr ≥3) were 16%/3% in arm 1, 33%/10% in arm 2, and 33%/4% in arm 4. Rates of drug-related AST increase (any/gr ≥3) were 17%/3%, 30%/8%, and 25%/4%. Efficacy is shown in the Table. Median KRAS G12C VAF was 14.0% at baseline and 0.9% at week 6; median MSAF was 26.0% and 2.2%, respectively. Conclusions: In pts with KRAS G12C-mut mNSCLC, MK-1084 shows manageable safety and antitumor activity as monotherapy for previously treated disease and in combination with pembro ± chemo as first-line (1L) therapy. The >90% decrease from baseline in KRAS G12C VAF in ctDNA confirms MK-1084 target engagement. The phase 3 KANDLELIT-004 study is evaluating MK-1084 + pembro as 1L therapy for KRAS G12C-mut mNSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT05067283 . Arm ORR DCR PFS n a % (95% CI) n a % (95% CI) n Med (95% CI), mo 1+3 NSCLC(MK-1084 alone) 21 38 (18-62) 21 76 (53-92) 21 8 (4-NR) 2 escalation(MK-1084 + pembro) 34 74 (56-87) 34 91 (76-98) 34 25 (9-NR) 2 expansion(MK-1084 + pembro) 20 40 (19-64) 20 80 (56-94) 26 NR (NR-NR) 4(MK-1084 + pembro + chemo) 22 41 (21-64) 22 82 (60-95) 24 NR (5-NR) a Pts with ≥1 MK-1084 dose ≥5 wk before data cutoff.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".