Main Session

Sep 29

PQA 07 - Head and Neck Cancer, Lung Cancer/Thoracic Malignancies, and Nursing and Supportive Care

3555 - Exploratory Outcomes from a Phase II ctDNA-Guided Consolidation Trial in KRAS G12C-Mutant Locally Advanced NSCLC

03:45pm - 05:00pm ET

Poster Hall - Exhibit Hall A

Screen: 24

POSTER

Presenter(s)

Nikhil Mankuzhy, MD - Memorial Sloan Kettering Cancer Center, Middletown Township, NJ

N. P. Mankuzhy¹, J. Y. Shin¹, P. Iyengar¹, J. Eng², R. Rosenblum², A. Iqbal², A. J. Wu¹, D. Y. Gelblum¹, C. B. Simone II³, T. L. Chaunzwa¹, J. Isbell⁴, B. T. Li², D. R. Gomez¹, J. Chaft², and N. Shaverdian¹; ¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ²Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ³New York Proton Center, New York, NY, ⁴Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY

Purpose/Objective(s):

KRAS G12C inhibitors (KRASi) may enable personalized consolidation strategies after concurrent chemoradiation (cCRT) in unresectable locally advanced (LA) KRAS G12C-mutant NSCLC. We conducted a phase II trial using post-cCRT liquid biopsy to select for KRASi therapy (sotorasib). The trial closed early due to unexpected funding limitations. We analyzed the enrolled cohort to assess feasibility for ctDNA-directed management and clinical outcomes.

Materials/Methods:

This phase II trial (NCT06333678) enrolled patients with KRAS G12C-mutant LA-NSCLC receiving cCRT. Plasma ctDNA (Guardant Reveal Assay) was assessed post-cCRT (before durvalumab) and again at durvalumab cycle 3. ctDNA persistence was intended to trigger randomization to sotorasib vs. continued durvalumab. The trial closed before any patients were randomized. We analyzed those who initiated cCRT for post-cCRT response, and progression-free (PFS) and overall survival (OS) from cCRT start. Outcomes were compared by post-cCRT ctDNA tumor fraction (TF) using the log-rank test.

Results:

Ten patients were enrolled; 1 developed distant metastasis before initiating cCRT and 9 were included for analysis. Median age was 73 years (range 56-84), 5 (56%) were female, and all had a smoking history. All had non-squamous NSCLC: 4 (44%) stage IIIA, 4 (44%) stage IIIB, and 1 (11%) with mediastinal recurrence. PD-L1 was =1% in 6 (67%) patients.

All received cCRT to 60-66 Gy with concurrent platinum-doublet chemotherapy, and 8 (89%) initiated durvalumab. Table 1 shows post-cCRT ctDNA and response (stable disease [SD], partial response [PR]).

After median follow-up of 11.6 months, 5 patients progressed (3 distant, 2 locoregional and distant). Median PFS was 6.5 months (95% CI 3.7-NR). One-year PFS and OS were 44% (95% CI 21-92%) and 89% (95% CI 71-100%), respectively. Median PFS was 12 months (95% CI 4.2-NR) for patients with post-cCRT ctDNA TF <0.05% (n = 4) compared with 3.7 months (95% CI 3.2-NR) for those with TF >0.05% (n = 3, p = 0.4).

Of the 9 who initiated cCRT, only 3 patients (33%) underwent ctDNA assessment at both planned time points due to progression prior to cycle 3 (n = 3), sample collection error (n = 1), ctDNA clearance (n = 1), and study closure (n = 1).

All patients who progressed subsequently received a KRASi for a median of 3.4 months (range: 0.4-14.7) with 2 still on therapy.

Conclusion:

Progression prior to cycle 3 of durvalumab was the dominant barrier to longitudinal ctDNA assessment, highlighting feasibility challenges for ctDNA-persistence triggered consolidation strategies in high-risk subsets. Although underpowered, higher post-cCRT ctDNA had numerically shorter PFS. Earlier integration of KRASi in KRAS G12C mutated LA-NSCLC warrants further prospective evaluation.

Table 1 – Post-cCRT
ctDNA TF	Response
<0.05%	SD
<0.05%	SD
0.165%	SD
0.105%	PR
sample collection error	SD
<0.05%	SD
0%	PR
0.112%	PR
Progressed	NA