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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This study defines a subgroup of patients with STK11 alterations who do not benefit from immunotherapy.
“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]
Patients with genomic alterations of STK11 had 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.
“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]
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) compared to chemotherapy alone.
“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]
Among 377 non-squamous NSCLC patients treated with platinum-doublet chemotherapy plus pembrolizumab, therapy response was significantly associated with the genetic status of STK11.
“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]
Addition of pembrolizumab to platinum-doublet chemotherapy did not significantly improve overall survival (10.6 vs 10.3 months, HR 1.03, 95% CI 0.71-1.49, P=0.79) compared to chemotherapy alone.
“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]
Objective response rate was significantly different between STK11-altered and unaltered groups (32.6 vs 44.7%, P=0.049).
“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]
Patients with genomic alterations of STK11 (N=102) had significantly shorter PFS (4.8 vs 7.2 months, HR 1.5, 95% CI 1.1-2.0; P=0.0063) compared with patients without STK11 alteration (N=275).
“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]
ATM co-alterations make KRAS- and BRAF-mutant NSCLC lines more sensitive to apoptosis caused by MEK inhibition.
“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 Kras-mutant LUAD mouse models, deleting Atm raises sensitivity to PARP inhibitors, ATR inhibitors, and radiation.
“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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“7 months).([19]) STK11 and KEAP1 comutations occur in approximately 13% of all lung cancers with a higher median tumor mutational burden (9.”
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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
Watanabe, T., Soeda, S., Endo, Y., Okabe, C., Sato, T., Kamo, N., Ueda, M., Kojima, M., Furukawa, S., Nishigori, H., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031563 · Cited by 14 · see citing works
Daher, S., Lawrence, Y. R., Dudnik, E., Hanovich, E., Urban, D., Peled, N., Navon, R., Leibowitz‐Amit, R., Hammerman, A., Battat, E., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.625668 · Cited by 13 · see citing works
Xu, Z., Zou, Z., Hao, X., Xing, P., & Li, J. (2023) · Cancer Innovation · doi:10.1002/cai2.49 · Cited by 11 · see citing works
“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].”
BackgroundBorzi, C., Galli, G., Ganzinelli, M., Signorelli, D., Vernieri, C., Garassino, M. C., Sozzi, G., & Moro, M. (2020) · Pharmaceuticals · doi:10.3390/ph13110385 · Cited by 12 · see citing works
Immunotherapy for extensive stage small cell lung cancer
Pacheco, J. M. (2020) · Journal of Thoracic Disease · doi:10.21037/jtd.2020.01.37 · Cited by 11 · see citing works
“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 · see citing works
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 10 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 6 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Pathak, R., & Salgia, R. (2021) · Clinical Lung Cancer · doi:10.1016/j.cllc.2021.07.007 · Cited by 4 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Self-citation„Kelch-like ECH-associated protein 1“ (KEAP1)
Scheffler, M. (2024) · Trillium Krebsmedizin · doi:10.47184/tk.2024.04.8 · Cited by 1 · see citing works
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 · see citing works
“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 · see citing works
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
- 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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