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Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer
Abstract
102 Background: Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread adoption of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we examine the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy. Methods: 497 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 17 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 377 pts treated with first-line CPP (or > 1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 120 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP. Results: Among 377 CPP-treated pts, STK11/LKB1 genomic alterations (N = 102) were associated with significantly shorter PFS (mPFS 4.8m vs 7.2m, HR 1.5, 95% CI 1.1 to 2.0; P = 0.0063) and shorter OS (mOS 10.6m vs 16.7m, HR 1.58, 95% CI 1.09 to 2.27; P = 0.0083) compared with STK11/LKB1-wt tumors (N = 275). ORR also differed significantly between the two groups (32.6% vs 44.7%, P = 0.049). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N = 333). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not improve PFS (mPFS 4.8m vs 4.3m, HR 1.13, 95% CI 0.83 to 1.54, P = 0.75) or OS (mOS 10.6m vs 10.3m, HR 1.03, 95% CI 0.71 to 1.49, P = 0.79) compared to CP alone. Conclusions: In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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In the citing paper
“This study defines a subgroup of patients with STK11 alterations who do not benefit from immunotherapy”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“and shorter overall survival (10.6 vs. 16.7 months, HR 1.58, 95% CI 1.09–2.27; P = 0.0083) compared with patients without STK11 alteration (N = 275).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“the addition of pembrolizumab to platinum-doublet chemotherapy did not significantly improve PFS (4.8 vs. 4.3 months, HR 1.13, 95% CI 0.83–1.54, P = 0.75)”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“a recent study (36) showed that among 377 non-squamous NSCLC patients treated with platinum-doublet chemotherapy (carboplatin or cisplatin and pemetrexed) plus pembrolizumab (anti-PD1), the therapy response was significantly associated with the genetic status of STK11.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“or overall survival (10.6 vs. 10.3 months, HR 1.03, 95% CI 0.71–1.49, P = 0.79) compared to the chemotherapy alone (36).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“Also, the objective response rate (RR) was significantly different between the two groups (32.6 vs. 44.7%, P = 0.049).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“patients with genomic alterations of STK11 (N = 102) were associated with significantly shorter PFS (4.8 vs. 7.2 months, HR 1.5, 95% CI 1.1–2.0; P = 0.0063)”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [36]
In the citing paper
“ATM co-alterations increase the sensitivity of KRAS and BRAF-mutant NSCLC cell lines to MEK inhibitor-induced apoptosis”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [168]
In the citing paper
“genetic deletion of Atm is associated with increased sensitivity to poly(ADP-ribose) polymerase (PARP) and ATR inhibitors as well as to radiation therapy in mouse models of Kras-mutant LUAD168, 169.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [168]
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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
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“Recently, their groupdemonstratedthat STK11/LKB1 and/or KEAP1 alterationsdrive primary resistance to immune checkpoint inhibitors with a lack of bene fi t from the addition of pembrolizumab to chemotherapy and an inferior OS in patients with non-squamous NSCLC (29).”
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“79) compared to the chemotherapy alone (36).”
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“In addition to the poor efficacy of immunotherapy in NSCLC patients with driver mutations (positive EGFR and ALK), genes such as STK11 that are tumor suppressor genes are frequently mutated in NSCLC and may reduce cluster of differentiation (CD) 8 T cell density or function, thus affecting the tumor-related immune res…”
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“Similarly, in a retrospective, multicenter, international study, poor clinical outcomes were reported in patients with STK11m versus STK11wt non-squamous metastatic NSCLC treated with pembrolizumab plus platinum-based chemotherapy [22].”
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“0083) compared with STK11/LKB1-wild type tumors [55].”
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“The predictive role for KRAS/STK11 co-mutations detected in tissue in patients receiving ICIs was recently depicted by Skoulidis et al. (56).”
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“For instance, tumors harboring STK11 mutations tend to exhibit intrinsic resistance to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies [158–161].”
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Current and future biomarkers for outcomes with immunotherapy in non-small cell lung cancer
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“Furthermore, co-mutations in either LKB1/STK11 or KEAP1 were associated with worse clinical outcomes with chemoimmunotherapy using pemetrexed-carboplatin (or cisplatin) plus the anti-PD-1 antibody pembrolizumab in non-squamous NSCLC (55).”
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“Further analysis revealed that there was no enhanced clinical benefit in patients with mutations in KEAP1 receiving immunotherapy and chemotherapy than those receiving chemotherapy alone [23].”
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“The co-occurrence of these mutations is associated with poor prognosis, related to a particularly aggressive cancer phenotype resistant to chemo-immunotherapy, for which no targeted therapies are available [15–17].”
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“In a non-squamous NSCLC cohort, STK11/KRAS co-mutation patients showed lower PFS and OS after treatment with pembrolizumab plus doublet chemotherapy.([62]) On the contrary, STK11/TP53-wild NSCLC patients present longer OS according to a genomic analysis.”
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“7%) have been demonstrated in retrospective analysis of more than 300 chemo-immunotherapy treated patients [61].”
BackgroundSelf-citationRare Hereditary Gynecological Cancer Syndromes
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“Besides the driver genes that are frequently mutated in NSCLC, inhibitory mutations, such as STK11 and KEAP1, often co ‐ occur with the KRAS mutation, and help to define a subgroup of patients who have a poor response and survival to chemoimmunotherapy [68].”
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Immunotherapy for extensive stage small cell lung cancer
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“Unlike chemoimmunotherapy in NSCLC, the OS benefit was more modest and there does not yet appear to be a significant tail on the curve that would suggest that the OS benefit of durvalumab plus EP will greatly improve with longer follow-up (8,12-14).”
BackgroundInfluentialPrecision immune regulation in KRAS-mutated cancers: the final piece of the puzzle?
Fu, S., Ma, J., Cai, C., Tan, J., Deng, X., Shen, H., Zeng, S., Chen, Y., & Han, Y. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03444-1 · Cited by 11
Provencio, M., Pérez-Parente, D., Olson, S., Hasan, H., Campos, B., Rodríguez‐Abreu, D., Piqueras, M., Pal, N., Wilkinson, S., Vilas, E., et al. (2024) · Clinical & Translational Oncology · doi:10.1007/s12094-023-03362-8 · Cited by 12
“Additional studies have also reported that patients harboring KEAP1 mutations showed shorter survival regardless of treatment type [23, 24].”
Negrao, M. V., Papadimitrakopoulou, V. A., Price, A. C., Tam, A. L., Furqan, M., Laroia, S., Massarelli, E., Pacheco, J. M., Heymach, J. V., Tsao, A. S., et al. (2022) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2022.100423 · Cited by 10
Self-citationThe efficacy of immune checkpoint inhibitors in thoracic malignancies
Remón, J., Facchinetti, F., & Besse, B. (2021) · European Respiratory Review · doi:10.1183/16000617.0387-2020 · Cited by 9
Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation
An, J., Yan, M., Yu, N., Chennamadhavuni, A., Furqan, M., Mott, S. L., Loeffler, B. T., Kruser, T. J., Sita, T. L., Feldman, L. E., et al. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-21-177 · Cited by 9
“Although data in the literature showed association of STK11 with poor outcomes in advanced stage NSCLC (9,11,15), its impact on stage III NSCLC has not been established.”
BackgroundHyperprogressive disease with immunotherapy: new directions
Lau, S. C. M., & Leighl, N. B. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.08.88 · Cited by 8
“Due to the widespread use of extended molecular profiling, astute investigators have observed that a subgroup of STK11 and KEAP1 mutant lung cancers derive little benefit from PD-1 inhibition (13,14).”
BackgroundVernieri, C., Ganzinelli, M., Rulli, E., Farina, G., Bettini, A., Bareggi, C., Rosso, L., Signorelli, D., Galli, G., Russo, G. L., et al. (2020) · ESMO Open · doi:10.1136/esmoopen-2020-000748 · Cited by 8
Immunotherapy Combinations for the Treatment of Patients with Solid Tumors
Bluthgen, M. V., Basté, N., & Recondo, G. (2020) · Future Oncology · doi:10.2217/fon-2020-0303 · Cited by 8
Popper, H., Gruber-Moesenbacher, U., Pall, G., Müllauer, L., Hochmair, M. J., Krenbek, D., Brčić, L., Schmitz, K., Lamprecht, B., Eckmayr, J., et al. (2020) · memo - Magazine of European Medical Oncology · doi:10.1007/s12254-019-00565-0 · Cited by 8
If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer
Köhler, J., & Janne, P. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063025 · Cited by 7
“These tumors are linked to poor outcomes with immunotherapy and platinum-based chemotherapy [75,141,142].”
BackgroundHeath, E. I., Dyson, G. E., Ribeiro, J. R., Xiu, J., Poorman, K. A., Mamdani, H. M., Hallak, M. N. A., Shields, A. F., Elayoubi, J. A., Winer, I. S., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-24-0321 · Cited by 7
“Together with a case report of an individual with STK11 / KRAS co-mutated advanced lung cancer with near complete response to pembrolizumab and platinum-doublet therapy (45), these data suggest that STK11 mutation should not be used as a strict exclusion criterion for immune checkpoint blockade in NSCLC.”
BackgroundInfluentialKEYNOTE-407: changing the way we treat stage IV squamous non-small cell lung cancer
Pacheco, J. M. (2020) · Translational Lung Cancer Research · doi:10.21037/tlcr.2020.01.12 · Cited by 7
“The presence of KRAS and specific co-mutations has been associated with efficacy or lack thereof in patients treated with immune checkpoint inhibitors (19,20).”
BackgroundAnother Brick in the Wall: Sintilimab Plus Chemotherapy in Advanced Lung Cancer
Lam, V. K. L., & Forde, P. M. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.08.013 · Cited by 7
Naqash, A. R., Floudas, C. S., Aber, E. R., Maoz, A., Nassar, A. H., Adib, E., Choucair, K., Xiu, J., Baca, Y., Ricciuti, B., et al. (2024) · JCO Precision Oncology · doi:10.1200/po.23.00371 · Cited by 7
“54 To identify comutations capable of rescuing this phenotype in STK11 mut NSCLC, we analyzed the STING pathway as a surrogate for immune activation and sensitivity to ICI-based therapy, especially since the downstream type I IFN signaling from this pathway acts as a bridge between innate immunity and adaptive immunit…”
InfluentialSelf-citationTeixidó, C., & Reguart, N. (2020) · Future Oncology · doi:10.2217/fon-2020-0171 · Cited by 6
Dual Checkpoint Inhibition: An Approach for STK11 and KRAS Co-Mutated Lung Adenocarcinoma?
Stein, M. K., Prouet, P., & Martin, M. G. (2019) · JCO Precision Oncology · doi:10.1200/po.19.00211 · Cited by 6
Chemoimmunotherapy for stage IV non-small-cell lung cancer
Uprety, D. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30498-x · Cited by 6
Karthikeyan, S. K., Gimbrone, N. T., Percy, T. R., & Cress, W. D. (2020) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2020.100286 · Cited by 6
Pathak, R., & Salgia, R. (2021) · Clinical Lung Cancer · doi:10.1016/j.cllc.2021.07.007 · Cited by 4
Hotspots and trends in liver kinase B1 research: A bibliometric analysis
Song, Y., Zhao, F., Ma, W., & Li, G. (2021) · PLoS ONE · doi:10.1371/journal.pone.0259240 · Cited by 4
Lung cancer as a predominant feature in a patient with Peutz–Jeghers syndrome: Case report
Fostira, F., Fountzilas, E., Papadopoulou, K., et al. (2022) · Thoracic Cancer · doi:10.1111/1759-7714.14447 · Cited by 4
“Interestingly, the presence of STK11 pathogenic variants has been associated with worse clinical outcomes, in terms of survival and response rates, in patients with NSCLC who received treatment with immunotherapy combined with doublet chemotherapy.(10) Hereditary lung cancer is rare, with germline STK11 pathogenic var…”
BackgroundIraqi, M., Bolel, P., Sarkar, R., Bhattacharya, B., Ahmad, M. A., Edri, A., Roisman, L. C., Elkabets, M., Shalata, W., Peled, N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214054 · Cited by 3
Approach to stage IV non-small-cell lung cancer: how to select among first-line therapy options?
Pacheco, J. M. (2019) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0000000000000659 · Cited by 3
Basse, C., Swalduz, A., Levra, M. G., Girard, N., Remón, J., & Moro‐Sibilot, D. (2020) · Bulletin du Cancer · doi:10.1016/j.bulcan.2020.04.018 · Cited by 3
Cancer-specific associations of driver genes with immunotherapy outcomePreprint
Jun, T. W., Qing, T., Dong, G., Signaevsky, M., Hopkins, J. F., Frampton, G. M., Albacker, L. A., Cordon‐Cardo, C., Samstein, R. M., Pusztai, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.16.155895 · Cited by 3
Gaeta, B., Eichholz, J., Walch, H. S., Ilıca, A. T., Boe, L. A., Kratochvil, L. B., Yu, Y., Gomez, D. R., Imber, B. S., Li, B. T., et al. (2025) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2025.01.033 · Cited by 2
Self-citation„Kelch-like ECH-associated protein 1“ (KEAP1)
Scheffler, M. (2024) · Trillium Krebsmedizin · doi:10.47184/tk.2024.04.8 · Cited by 1
Self-citationЛактионов, К. К., Kazakov, A. M., Саранцева, К. А., Scherbo, D. S., & Koval, A. P. (2022) · Siberian Journal of Oncology · doi:10.21294/1814-4861-2022-21-1-115-121 · Cited by 1
“STK11 также показал себя как отрицательный прогностический маркер и в группах пациентов, получавших комбинированную химиоиммунотерапию [24].”
Qiao, M., Zhou, F., Liu, X., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2283207/v1 · Cited by 1
Immuntherapie des metastasierten nichtkleinzelligen Lungenkarzinoms
Sackmann, S., Ogundele, S., & Ukena, D. (2019) · Der Pneumologe · doi:10.1007/s10405-019-00276-7
Griesinger, F. (2019) · International Journal of Pulmonary & Respiratory Sciences · doi:10.19080/ijoprs.2019.04.555634
Transcription Strikes Back: Clinical Utility of Lung Adenocarcinoma Subtypes
Skoulidis, F. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3914
“This was a relevant analysis because inactivation of STK11/ LKB1 by mutational or nonmutational mechanisms mediates establishment of a non-T-cell–inflamed tumor immunemicroenvironment in ns-NSCLC and drives poor clinical outcomes with PD-1 axis inhibitor monotherapy, chemo-immunotherapy, as well as platinum-based chem…”
Self-citationDrug Resistance in Lung Cancer
Colarusso, C., Terlizzi, M., Pinto, A., & Sorrentino, R. (2022) · Interdisciplinary cancer research · doi:10.1007/16833_2022_62
Ferrara, R., Naigeon, M., Auclin, É., Duchemann, B., Cassard, L., Jouniaux, J.-M., Boselli, L., Grivel, J., Desnoyer, A., Mezquita, L., et al. (2023) · doi:10.1158/1078-0432.c.6530142
Self-citationGao, L., Jiang, J., Zhu, L., Xie, Z., Chen, Y., Lv, Z., Chen, Y., Zhou, W., Chen, J., Zhong, Y., et al. (2025) · BMC Medicine · doi:10.1186/s12916-025-04561-6
“Mutations in STK11 and KEAP1 have been associated with poor clinical outcomes among KRAS -mut NSCLC patients receiving chemotherapy and immunotherapy [31, 57–59].”
Daher, S., Shalata, W., Shirron, N., Shentzer, T., Goshen‐Lago, T., Biras, L., Moskovitz, M. T., Shamai, S., Urban, D., Gantz-Sorotsky, H., et al. (2026) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2026.100981
“29 On the other hand, the incidence of KRAS mutations in our cohort was similar to that in the general population.”
Influential
Metadata
- Authors
- Skoulidis, F., Arbour, K. C., Hellmann, M. D., Patil, P. D., Marmarelis, M. E., Awad, M. M., Murray, J. C., Hellyer, J., Gainor, J. F., Dimou, A., Bestvina, C. M., Shu, C. A., Riess, J. W., Blakely, C. M., Pecot, C. V., Mezquita, L., Tabbò, F., Scheffler, M., Papadimitrakopoulou, V., & Heymach, J.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cleveland Clinic (US)
- Brigham and Women's Hospital (US)
- Massachusetts General Hospital (US)
- Johns Hopkins University (US)
- Stanford Cancer Institute (US)
- University of Colorado Cancer Center (US)
- University of Chicago (US)
- Columbia University Irving Medical Center (US)
- UC Davis Comprehensive Cancer Center (US)
- University of California, San Francisco (US)
- University of North Carolina at Chapel Hill (US)
- Institut Gustave Roussy (FR)
- University of Turin (IT)
- University of Cologne (DE)
- ORCID
- Skoulidis, Ferdinandos
- Arbour, Kathryn Cecilia
- Hellmann, Matthew David
- Patil, Pradnya Dinkar
- Marmarelis, Melina Elpi
- Awad, Mark M.
- Murray, Joseph Christopher
- Hellyer, Jessica
- Gainor, Justin F.
- Dimou, Anastasios
- Bestvina, Christine M.
- Shu, Catherine A.
- Riess, Jonathan W.
- Blakely, Collin Michael
- Pecot, Chad Victor
- Mezquita, Laura
- Tabbò, Fabrizio
- Scheffler, Matthias
- Papadimitrakopoulou, Vassiliki
- Heymach, John
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- 102-102
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2947248753
- Cited by
- 102
- References
- 0
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 23 · 2020: 33 · 2019: 10
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- STK11/LKB1, pembrolizumab, non-squamous non-small cell lung cancer, metastatic lung cancer, platinum-based chemotherapy, carboplatin, pemetrexed, chemoimmunotherapy, PD-1/PD-L1 blockade, treatment resistance, progression-free survival, overall survival, objective response rate, EGFR/ALK wild-type
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