Background: Circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection is a promising approach for personalization of adjuvant therapy in non-small cell lung cancer (NSCLC). First generation ctDNA MRD assays that employ tumor-informed approaches to track single nucleotide variants (SNVs) have limits of detection (LOD95) of ~1E-4 and have high positive predictive values for recurrence. However, they have suboptimal clinical sensitivity, with false negative results at the completion of therapy in most patients who will ultimately recur. PhasED-Seq is a novel ctDNA MRD method that tracks multiple “phased” variants (PVs) within individual DNA fragments with a LOD95 ~100-fold better than first generation assays. Here we report PhasED-Seq ctDNA MRD results for the first prospective cohort of early stage NSCLC patients. Methods: Tumor tissues (n=46), PBMCs (n=46) and plasma samples (n=169) from 46 Stage I-III NSCLC patients treated with curative intent were prospectively collected at Memorial Sloan Kettering Cancer Center. All patients underwent resection and received neoadjuvant +/- adjuvant therapy (n=14), adjuvant therapy only (n=17), or neither (n=15). Samples were analyzed in Foresight Diagnostics' CLIA laboratory (Aurora, CO) using personalized PhasED-Seq. Briefly, PVs were identified via whole genome sequencing of tumors and matched blood germline DNA. Custom capture panels targeting PVs were synthesized and used to assess MRD status in pre-, on- and post-treatment plasma samples. Detection of ctDNA MRD was assessed at a post-treatment landmark, defined as the first post-therapy sample or when not available the last post-surgical sample taken during therapy. To enable comparisons, the same plasma samples were analyzed using an SNV-based ctDNA MRD approach. Results: PVs were identified in tumor tissue from all 46 patients. Across all plasma samples PhasED-Seq achieved a median LOD95 of 1.3E-6 and as low as 2.5E-7. Of 74 plasma samples with detectable ctDNA, 38 (51%) contained concentrations below 1E-4 and the lowest level of ctDNA MRD detected was 1.7E-7. For post-treatment landmark samples (n=45), the median time from end of therapy was 2 months. Cancer recurred in all patients (n=10) with detectable MRD at the landmark. Furthermore, PhasED-Seq better stratified freedom from recurrence (log-rank p=3E-8, Cox HR=10.8) than the SNV-based approach (log-rank p=0.08, Cox HR=2.5) and detected MRD at the landmark in more patients who ultimately recurred (56% vs 28%). PhasED-Seq also achieved longer lead times, including detecting MRD in 66% of samples collected 12 to 24 months prior to recurrence versus only 33% using SNV-based monitoring. Conclusion: PhasED-Seq achieves ctDNA detection below 1 part per million and appears to be significantly more sensitive than SNV-based MRD monitoring. These results suggest that PhasED-Seq is a promising approach for use in risk adapted trials in early stage NSCLC. Citation Format: James M. Isbell, Bob T. Li, Pedram Razavi, Jorge Reis-Filo, Si-Yang Liu, Pier Selenica, Prasad Adusumilli, Matthew Bott, David R. Jones, Valerie W. Rusch, Smita Sihag, Darren J. Buonocore, Justin Jee, Emily Lebow, Daniel Gomez, Andreas Rimner, Fernando C. Santini, Charles M. Rudin, Jordan E. Eichholz, Andres Martinez, Daphne Alerte, Gregory J. Hogan, Andre Schultz, Ronald P. Schuyler, Alanna Roff, Dustin Hite, Jacob J. Chabon, David M. Kurtz, Ash A. Alizadeh, Maximilian Diehn. Ultrasensitive ctDNA minimal residual disease monitoring in early NSCLC with PhasED-Seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3375.
ImportanceThe addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non–small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization.ObjectivesTo evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC.Design, Setting, and ParticipantsThis cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022.ExposuresPatients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (<10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway).Main Outcomes and MeasuresThe primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS).ResultsIn this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS.Conclusions and RelevanceIn this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.
9052 Background: Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted drug approved for NSCLC with human epidermal growth factor receptor 2 ( HER2, ERBB2) mutation in the second or later line settings. However, the optimal first-line treatment for these patients remains unclear. Access to rapid tissue sequencing is not always available, thus presenting challenges to first-line drug development. Circulating tumor DNA (ctDNA) analysis has the potential to overcome these obstacles to guide optimal first-line targeted therapy for patients with HER2-mutant NSCLC. Methods: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx Lung. Results: We identified 64 patients with metastatic HER2-mutant NSCLC who had received at least one line of systematic therapy. The median age was 63 years (range: 23–90), and there were more women (n = 38, 60%), and never-smokers (n = 38, 60%). The activating HER2 mutations included exon 20 insertions (73%), exon 8 (11%), 19 (11%), and 20 SNVs (5%). Plasma ctDNA was tested before initial therapy in 40 patients with a median overall survival (OS) of 28 months (95% CI 21-34), in whom 31 patients (78%) had at least one detectable ctDNA alteration by MSK-ACCESS and ctDx Lung. 55% (17/31) received chemoimmunotherapy with pembrolizumab as the first-line treatment. The median time to treatment discontinuation (TTD) was 6 months (95%CI 5.5-6.9). Additionally, 19% of patients (6/31) received a HER2-targeted antibody-drug conjugates (ADC) as first-line treatment with a median TTD of 6 months (95% CI 2-10), including 5 with T-DM1 and one who received first-line T-DXd treatment with a TTD of 9 months. Patients with baseline ctDNA alterations had significantly shorter OS (hazard ratio (HR), 5.25; 95% CI, 1–24; p = 0.019). Conclusions: Baseline plasma ctDNA has the potential to guide first-line targeted therapy for patients with HER2-mutant NSCLC. As an independent negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies to avoid underestimating the effects of therapy.
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