Outcomes of Patients With Stage III Non-Small Cell Lung Cancer (NSCLC) That Harbor a STK11 Mutation

Josiah An; Melissa Yan; Nanmeng Yu; Adithya Chennamadhavuni; Muhammad Furqan; Sarah L. Mott; Bradley T. Loeffler; Timothy Kruser; Timothy L. Sita; Lawrence Feldman; Ryan Nguyen; Mary Pasquinelli; Nasser H. Hanna; Taher Abu Hejleh

Disclosures

Transl Lung Cancer Res. 2021;10(8):3608-3615. 

In This Article

Abstract and Introduction

Abstract

Background: STK11 mutation (STK11m ) in patients (pts) with stage IV non-small cell lung cancer (NSCLC) is associated with inferior survival and poor response to immune checkpoint inhibitors (ICI). The significance of STK11m in stage III NSCLC pts treated with concurrent chemoradiation (CCRT) with or without consolidation ICI is unknown.

Methods: Stage III NSCLC patients who received CCRT and had known STK11 mutational status were included in this retrospective study. The data on the STK11m pts were collected from 4 cancer institutions. A cohort of pts with wild type STK11 (STK11w ) from the University of Iowa served as a comparison group. Patient demographics and clinical characteristics were collected. Cox regression models were used to explore the effect of STK11 mutation on survival.

Results: 75 pts with stage III NSCLC who had known STK11 mutational status were identified. 16/75 (21%) had STK11m . 5/16 with STK11 m did not receive CCRT so they were excluded from the analysis. The clinical and demographic characteristics for the 11 STK11m and 59 STK11w pts were not statistically different (STK11m vs. STK11w ): mean age: 57 vs. 64 yrs, non-squamous histology: 8/11 (73%) vs. 37/59 (63%), KRAS mutation: 3/11 (27%) vs. 11/59 (19%), TP53 mutation: 6/11 (55%) vs. 15/59 (25%), PD-L1 ≥50%: 1/8 (13%) vs. 10/32 (31%), and consolidation ICI 6/11 (55%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3–17) vs. 6 (range, 1–25) in the 17 pts with STK11w who received ICI (durvalumab). After adjusting for performance status and cancer stage, multivariable analysis showed that progression free survival (PFS) for the STK11m pts was significantly worse than STK11 w pts (HR =2.25; 95% CI, 1.03–4.88, P=0.04), whereas overall survival (OS) showed no significant difference for STK11m vs. STK11w patients (HR 1.47, 95% CI, 0.49–4.38, P=0.49).

Conclusions: In stage III NSCLC patients who received CCRT, STK11m was associated with worse PFS compared to STK11w . Larger studies are needed to further explore the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.

Introduction

Unresectable stage III non-small cell lung cancer (NSCLC) in patients with good performance status is treated with concurrent platinum based chemotherapy with definitive dose radiation (CCRT) followed by the PD-L1 inhibitor, durvalumab.[1] The addition of durvalumab to CCRT improved survival from 55.6% to 66.3% at 24 months.[1] Although this improvement in survival is practice changing, a large number of stage III NSCLC patients still have a poor prognosis. In 2020, it is estimated there will be 229,000 new cases of lung cancer[2] of which stage III cancer is expected in approximately 30% of all NSCLC cases.

Serine/threonine kinase 11 (STK11), also known as liver kinase B1 (LKB1), is a gene found on chromosome 19p13. Germline mutation of STK11 is associated with Peutz-Jeghers Syndrome (PJS).[3] Patients with PJS can develop intestinal hamartomatous polyps and are more likely to develop malignancies such as gastrointestinal, testis, ovary, and breast cancers.[3] In lung cancer, somatic mutations of STK11 are seen in up to 42% of NSCLC; however, most studies have shown a mutation frequency of approximately 20%.[4]STK11 functions as a tumor suppressor gene and is involved in the activation of AMP-activated protein kinase (AMPK), which modulates cell glucose and lipid metabolism.[5] More importantly, in-vivo studies indicate that STK11 is involved in the differentiation and metastases of lung cancer.[6]STK11 inactivation leads to increase in pro-inflammatory cytokines such as CXCL7 and causes a shift in the microenvironment with neutrophil accumulation and decrease in T cell lymphocytes.[7,8]

The effect of STK11m on outcomes of stage III NSCLC treated with curative intent is unknown. It is unclear whether STK11m affects prognosis of stage III NSCLC or predicts response to ICI consolidation after CCRT. In advanced stage NSCLC, STK11m has been associated with poor response to chemotherapy and ICI, and inferior survival outcomes.[9–15] In this study, we sought to explore STK11m as a prognostic genetic alteration in stage III NSCLC patients managed with definitive chemoradiation +/− consolidative ICI. We present the following article in accordance with the REMARK reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-177).

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