STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma
Phase 2 or 3 results paper on KRAS in Non-small-cell lung cancer, in Cancer Discovery (2018), one of the most cited Europe PMC records with KRAS in its title.
Overview
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations 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 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. Cancer Discov; 8(7); 822-35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794 This article is highlighted in the In This Issue feature, p. 781.
Indexed on Europe PMC as PubMed record 29773717 (DOI 10.1158/2159-8290.cd-18-0099). Its title names KRAS and its text names Non-small-cell lung cancer; PubMed types it as a clinical trial report (Clinical Trial, Phase III, Research Support, Non-U.S. Gov't, research-article, Randomized Controlled Trial, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural). It was matched automatically to the idea "Turn a brake back on: drugs that reactivate the PP2A phosphatase" and no figure has been checked by an editor.
One of the most cited trial reports Europe PMC returns for KRAS in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
- Matched by KRAS in the title and Non-small-cell lung cancer in the title or abstract of the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.
- Chosen as a phase 2 or 3 report by the record's publication type or its own wording, not by reading the paper.
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