STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma

Ferdinandos Skoulidis; Michael E. Goldberg; Danielle M. Greenawalt; Matthew D. Hellmann; Mark M. Awad; Justin F. Gainor; Alexa B. Schrock; Ryan J. Hartmaier; Sally E. Trabucco; Laurie Gay; Siraj M. Ali; Julia A. Elvin; Gaurav Singal; Jeffrey S. Ross; David Fabrizio; Peter M. Szabo; Han Chang; Ariella Sasson; Sujaya Srinivasan; Stefan Kirov; Joseph Szustakowski; Patrik Vitazka; Robin Edwards; Jose A. Bufill; Neelesh Sharma; Sai Hong I. Ou; Nir Peled; David R. Spigel; Hira Rizvi; Elizabeth Jimenez Aguilar; Brett W. Carter; Jeremy Erasmus; Darragh F. Halpenny; Andrew J. Plodkowski; Niamh M. Long; Mizuki Nishino; Warren L. Denning; Ana Galan-Cobo; Haifa Hamdi; Taghreed Hirz; Pan Tong; Jing Wang; Jaime Rodriguez-Canales; Pamela A. Villalobos; Edwin R. Parra; Neda Kalhor; Lynette M. Sholl; Jennifer L. Sauter; Achim A. Jungbluth; Mari Mino-Kenudson; Roxana Azimi; Yasir Y. Elamin; Jianjun Zhang; Giulia C. Leonardi; Fei Jiang; Kwok Kin Wong; J. Jack Lee; Vassiliki A. Papadimitrakopoulou; Ignacio I. Wistuba; Vincent A. Miller; Garrett M. Frampton; Jedd D. Wolchok; Alice T. Shaw; Pasi A. Jänne; Philip J. Stephens; Charles M. Rudin; William J. Geese; Lee A. Albacker; John V. Heymach

doi:10.1158/2159-8290.CD-18-0099

STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma

Ferdinandos Skoulidis, Michael E. Goldberg, Danielle M. Greenawalt, Matthew D. Hellmann, Mark M. Awad, Justin F. Gainor, Alexa B. Schrock, Ryan J. Hartmaier, Sally E. Trabucco, Laurie Gay, Siraj M. Ali, Julia A. Elvin, Gaurav Singal, Jeffrey S. Ross, David Fabrizio, Peter M. Szabo, Han Chang, Ariella Sasson, Sujaya Srinivasan, Stefan KirovJoseph Szustakowski, Patrik Vitazka, Robin Edwards, Jose A. Bufill, Neelesh Sharma, Sai Hong I. Ou, Nir Peled, David R. Spigel, Hira Rizvi, Elizabeth Jimenez Aguilar, Brett W. Carter, Jeremy Erasmus, Darragh F. Halpenny, Andrew J. Plodkowski, Niamh M. Long, Mizuki Nishino, Warren L. Denning, Ana Galan-Cobo, Haifa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez-Canales, Pamela A. Villalobos, Edwin R. Parra, Neda Kalhor, Lynette M. Sholl, Jennifer L. Sauter, Achim A. Jungbluth, Mari Mino-Kenudson, Roxana Azimi, Yasir Y. Elamin, Jianjun Zhang, Giulia C. Leonardi, Fei Jiang, Kwok Kin Wong, J. Jack Lee, Vassiliki A. Papadimitrakopoulou, Ignacio I. Wistuba, Vincent A. Miller, Garrett M. Frampton, Jedd D. Wolchok, Alice T. Shaw, Pasi A. Jänne, Philip J. Stephens, Charles M. Rudin, William J. Geese, Lee A. Albacker, John V. Heymach

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Abstract

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define dis tinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRAS^MUT;STK11/LKB1^WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMB^{Intermediate/High} LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. SIGNIfICANCE: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets.

Original language	English (US)
Pages (from-to)	822-835
Number of pages	14
Journal	Cancer discovery
Volume	8
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-18-0099
State	Published - Jul 2018

ASJC Scopus subject areas

Oncology

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Biostatistics Resource Group
Clinical and Translational Research Center
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource
Clinical Trials Office

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10.1158/2159-8290.CD-18-0099

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Skoulidis, F., Goldberg, M. E., Greenawalt, D. M., Hellmann, M. D., Awad, M. M., Gainor, J. F., Schrock, A. B., Hartmaier, R. J., Trabucco, S. E., Gay, L., Ali, S. M., Elvin, J. A., Singal, G., Ross, J. S., Fabrizio, D., Szabo, P. M., Chang, H., Sasson, A., Srinivasan, S., ... Heymach, J. V. (2018). STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer discovery, 8(7), 822-835. https://doi.org/10.1158/2159-8290.CD-18-0099

Skoulidis, F, Goldberg, ME, Greenawalt, DM, Hellmann, MD, Awad, MM, Gainor, JF, Schrock, AB, Hartmaier, RJ, Trabucco, SE, Gay, L, Ali, SM, Elvin, JA, Singal, G, Ross, JS, Fabrizio, D, Szabo, PM, Chang, H, Sasson, A, Srinivasan, S, Kirov, S, Szustakowski, J, Vitazka, P, Edwards, R, Bufill, JA, Sharma, N, Ou, SHI, Peled, N, Spigel, DR, Rizvi, H, Aguilar, EJ, Carter, BW , Erasmus, J, Halpenny, DF, Plodkowski, AJ, Long, NM, Nishino, M, Denning, WL, Galan-Cobo, A, Hamdi, H, Hirz, T, Tong, P, Wang, J, Rodriguez-Canales, J, Villalobos, PA, Parra, ER , Kalhor, N, Sholl, LM, Sauter, JL, Jungbluth, AA, Mino-Kenudson, M, Azimi, R, Elamin, YY , Zhang, J, Leonardi, GC, Jiang, F, Wong, KK, Lee, JJ, Papadimitrakopoulou, VA, Wistuba, II, Miller, VA, Frampton, GM, Wolchok, JD, Shaw, AT, Jänne, PA, Stephens, PJ, Rudin, CM, Geese, WJ, Albacker, LA & Heymach, JV 2018, 'STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma', Cancer discovery, vol. 8, no. 7, pp. 822-835. https://doi.org/10.1158/2159-8290.CD-18-0099

@article{feba39e5db594a2081cd56eba82a3127,

title = "STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma",

abstract = "KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define dis tinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. SIGNIfICANCE: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets.",

author = "Ferdinandos Skoulidis and Goldberg, {Michael E.} and Greenawalt, {Danielle M.} and Hellmann, {Matthew D.} and Awad, {Mark M.} and Gainor, {Justin F.} and Schrock, {Alexa B.} and Hartmaier, {Ryan J.} and Trabucco, {Sally E.} and Laurie Gay and Ali, {Siraj M.} and Elvin, {Julia A.} and Gaurav Singal and Ross, {Jeffrey S.} and David Fabrizio and Szabo, {Peter M.} and Han Chang and Ariella Sasson and Sujaya Srinivasan and Stefan Kirov and Joseph Szustakowski and Patrik Vitazka and Robin Edwards and Bufill, {Jose A.} and Neelesh Sharma and Ou, {Sai Hong I.} and Nir Peled and Spigel, {David R.} and Hira Rizvi and Aguilar, {Elizabeth Jimenez} and Carter, {Brett W.} and Jeremy Erasmus and Halpenny, {Darragh F.} and Plodkowski, {Andrew J.} and Long, {Niamh M.} and Mizuki Nishino and Denning, {Warren L.} and Ana Galan-Cobo and Haifa Hamdi and Taghreed Hirz and Pan Tong and Jing Wang and Jaime Rodriguez-Canales and Villalobos, {Pamela A.} and Parra, {Edwin R.} and Neda Kalhor and Sholl, {Lynette M.} and Sauter, {Jennifer L.} and Jungbluth, {Achim A.} and Mari Mino-Kenudson and Roxana Azimi and Elamin, {Yasir Y.} and Jianjun Zhang and Leonardi, {Giulia C.} and Fei Jiang and Wong, {Kwok Kin} and Lee, {J. Jack} and Papadimitrakopoulou, {Vassiliki A.} and Wistuba, {Ignacio I.} and Miller, {Vincent A.} and Frampton, {Garrett M.} and Wolchok, {Jedd D.} and Shaw, {Alice T.} and J{\"a}nne, {Pasi A.} and Stephens, {Philip J.} and Rudin, {Charles M.} and Geese, {William J.} and Albacker, {Lee A.} and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2018",

month = jul,

doi = "10.1158/2159-8290.CD-18-0099",

language = "English (US)",

volume = "8",

pages = "822--835",

journal = "Cancer discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

TY - JOUR

T1 - STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma

AU - Skoulidis, Ferdinandos

AU - Goldberg, Michael E.

AU - Greenawalt, Danielle M.

AU - Hellmann, Matthew D.

AU - Awad, Mark M.

AU - Gainor, Justin F.

AU - Schrock, Alexa B.

AU - Hartmaier, Ryan J.

AU - Trabucco, Sally E.

AU - Gay, Laurie

AU - Ali, Siraj M.

AU - Elvin, Julia A.

AU - Singal, Gaurav

AU - Ross, Jeffrey S.

AU - Fabrizio, David

AU - Szabo, Peter M.

AU - Chang, Han

AU - Sasson, Ariella

AU - Srinivasan, Sujaya

AU - Kirov, Stefan

AU - Szustakowski, Joseph

AU - Vitazka, Patrik

AU - Edwards, Robin

AU - Bufill, Jose A.

AU - Sharma, Neelesh

AU - Ou, Sai Hong I.

AU - Peled, Nir

AU - Spigel, David R.

AU - Rizvi, Hira

AU - Aguilar, Elizabeth Jimenez

AU - Carter, Brett W.

AU - Erasmus, Jeremy

AU - Halpenny, Darragh F.

AU - Plodkowski, Andrew J.

AU - Long, Niamh M.

AU - Nishino, Mizuki

AU - Denning, Warren L.

AU - Galan-Cobo, Ana

AU - Hamdi, Haifa

AU - Hirz, Taghreed

AU - Tong, Pan

AU - Wang, Jing

AU - Rodriguez-Canales, Jaime

AU - Villalobos, Pamela A.

AU - Parra, Edwin R.

AU - Kalhor, Neda

AU - Sholl, Lynette M.

AU - Sauter, Jennifer L.

AU - Jungbluth, Achim A.

AU - Mino-Kenudson, Mari

AU - Azimi, Roxana

AU - Elamin, Yasir Y.

AU - Zhang, Jianjun

AU - Leonardi, Giulia C.

AU - Jiang, Fei

AU - Wong, Kwok Kin

AU - Lee, J. Jack

AU - Papadimitrakopoulou, Vassiliki A.

AU - Wistuba, Ignacio I.

AU - Miller, Vincent A.

AU - Frampton, Garrett M.

AU - Wolchok, Jedd D.

AU - Shaw, Alice T.

AU - Jänne, Pasi A.

AU - Stephens, Philip J.

AU - Rudin, Charles M.

AU - Geese, William J.

AU - Albacker, Lee A.

AU - Heymach, John V.

PY - 2018/7

Y1 - 2018/7

N2 - KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define dis tinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. SIGNIfICANCE: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets.

AB - KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define dis tinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. SIGNIfICANCE: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets.

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STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma

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MD Anderson CCSG core facilities

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