Reference Detail

Ref Type Journal Article
PMID (29773717)
Authors 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 SI, Peled N, Spigel DR, Rizvi H, Jimenez Aguilar E, 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
Title STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.
Journal Cancer discovery
Vol
Issue
Date 2018 May 17
URL
Abstract Text KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations define distinct 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 SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 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 survival (P=0.0015) compared to KRASMUT;STK11/LKB1WT LUAC. Among 924 LUAC, 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 NSCLC. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS mutant lung adenocarcinoma predicted - sensitive unspecified PD-1 antibody Clinical Study - Cohort Actionable In a clinical study, lung adenocarcinoma patients harboring a KRAS mutation demonstrated an intermediate objective response rate (28.6% vs 35.7% vs 7.4%), PFS (2.7mo vs 3.0 vs 1.8), and OS (16.1mo vs 16.0 vs 6.4) compared to patients with co-occurring KRAS and TP53 mutations, and patients with co-occurring KRAS and STK11 mutations when treated with a PD-1 inhibitor (Nivolumab, n=146; Pembrolizumab, n=19) (PMID: 29773717). 29773717
KRAS mutant TP53 mutant lung non-small cell carcinoma predicted - sensitive Nivolumab Phase III Actionable In a Phase III trial, non-small cell lung carcinoma patients co-harboring a KRAS mutation and TP53 mutation demonstrated an objective response rate (ORR) of 57.1% (4/7) when treated with Opdivo (nivolumab) compared to an ORR of 0% (0/6) in patients co-harboring a KRAS mutation and STK11 mutation and an ORR of 18.2% (2/11) in patients with mutant KRAS only (PMID: 29773717; NCT01673867). 29773717
KRAS mutant TP53 mutant lung adenocarcinoma predicted - sensitive unspecified PD-1 antibody Clinical Study - Cohort Actionable In a clinical study, lung adenocarcinoma patients co-harboring a KRAS mutation and TP53 mutation demonstrated a greater objective response rate (35.7% vs 7.4% vs 28.6%), longer PFS (3.0mo vs 1.8 vs 2.7) and OS (16mo vs 6.4 vs 16.1) compared to patients with KRAS and STK11 mutations and patients with KRAS mutations only when treated with a PD-1 inhibitor (Nivolumab, n=146; Pembrolizumab, n=19) (PMID: 29773717). 29773717
KRAS mut STK11 mut lung adenocarcinoma predicted - resistant unspecified PD-1 antibody Clinical Study - Cohort Actionable In a clinical study, lung adenocarcinoma patients co-harboring a KRAS mutation and STK11 mutation demonstrated a lower objective response rate (7.4% vs 35.7% vs 28.6%) and shorter PFS (1.8mo vs 3.0 vs 2.7), and OS (6.4mo vs 16 vs 16.1) compared to patients with KRAS and TP53 mutations and patients with KRAS mutations only when treated with a PD-1 inhibitor (Nivolumab, n=146; Pembrolizumab, n=19) (PMID: 29773717). 29773717
KRAS mutant lung non-small cell carcinoma predicted - sensitive Nivolumab Phase III Actionable In a Phase III trial, non-small cell lung carcinoma patients harboring a KRAS mutation demonstrated an objective response rate (ORR) of 18.2% (2/11) when treated with Opdivo (nivolumab) compared to an ORR of 57.1% (4/7) in patients co-harboring a KRAS mutation and TP53 mutation and an ORR of 0% (0/6) in patients co-harboring a KRAS mutation and STK11 mutation (PMID: 29773717; NCT01673867). 29773717
KRAS mut STK11 mut lung non-small cell carcinoma predicted - resistant Nivolumab Phase III Actionable In a Phase III trial, non-small cell lung carcinoma patients co-harboring a KRAS mutation and STK11 mutation demonstrated an objective response rate (ORR) of 0% (0/6) when treated with Opdivo (nivolumab) compared to an ORR of 57.1% (4/7) in patients co-harboring a KRAS mutation and TP53 mutation and an ORR of 18.2% (2/11) in patients with mutant KRAS only (PMID: 29773717; NCT01673867). 29773717