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.

Skoulidis, Ferdinandos; Arbour, Kathryn C.; Hellmann, Matthew D.; Patil, Pradnya D.; Marmarelis, Melina E.; Awad, Mark M.; Murray, Joseph C.; Hellyer, Jessica A.; Gainor, Justin F.; Dimou, Anastasios; Bestvina, Christine M.; Shu, Catherine A.; Riess, Jonathan W.; Blakely, Collin M.; Pecot, Chad V.; Mezquita, Laura; Tabbò, Fabrizio; Scheffler, Matthias; Papadimitrakopoulou, Vassiliki A.; Heymach, John V.

doi:10.1200/jco.2019.37.15_suppl.102

Cited by 91 publications

(81 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The current data, in a large observational genomic study among patients receiving routine clinical care, support the association of STK11m with poor treatment outcomes previously observed in smaller clinical trial cohorts [18][19][20][21][22][23][24]. Shorter OS and reduced response rates have been observed in patients with STK11m versus STK11wt non-squamous metastatic NSCLC treated with durvalumab (with or without tremelimumab) across multiple phase 1/2 trials [18].…”

Section: Plos Onesupporting

confidence: 78%

“…PD-L1 expression on tumor cells has been used to guide treatment selection, and more recently tumor mutational burden (TMB) has shown potential as a predictive biomarker for IO benefit [12][13][14][15]. Mutations in individual genes and co-mutation patterns have also been linked to patient response to standard chemotherapy and/or IO in advanced NSCLC [16][17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

et al. 2020

View full text Add to dashboard Cite

Background Mutations in STK11 (STK11m) and frequently co-occurring KRAS mutations (KRASm/ STK11m) are associated with poor survival in metastatic NSCLC (mNSCLC) immuno-oncology trials. There are limited data regarding the prognostic significance of these mutations in a real-world setting. Methods This retrospective cohort study analyzed de-identified electronic medical records from the Flatiron Clinico-Genomic database to identify patients with mNSCLC who had initiated firstline immunotherapy (IO; alone or in combination) or chemotherapy under routine care between January 1, 2013 and June 30, 2017. The primary objectives were to assess the prevalence of STK11m and KRASm/STK11m and to determine associations of these mutations with overall and progression-free survival (OS, PFS). Results Of 2407 patients with mNSCLC, STK11m and KRASm/STK11m were present in 13.6% and 6.5% of patients, respectively. Worse OS outcomes were observed in patients with STK11m versus STK11wt mNSCLC receiving IO (first-line, HR [95% CI], 1.4 [0.9-2.3; p = 0.1]; second-line [subset of first-line cohort], HR, 1.6 [1.3-2.0; p = 0.0002]) or chemotherapy (first-line, HR, 1.4 [1.2-1.6; p < 0.0001]); PFS outcomes showed similar trends. KRASm/ STK11m double mutations were associated with worse OS and PFS outcomes versus KRASwt/STK11wt with IO and chemotherapy, similar to the single mutation (STK11m vs STK11wt) findings. Conclusions This large observational genomic study among patients receiving routine care highlights the negative prognostic impact of STK11m in patients with mNSCLC treated with IO or

show abstract

Section: Plos Onesupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

et al. 2020

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4][5][6] Despite the improved overall survival (OS) rates observed with anti PD-L1 ICIs in lung cancer, there are a significant number of patients who do not reap a clinical benefit from this therapeutic strategy. Several factors such as innate resistance mechanisms including the absence of PD-L1 expression, 7 low tumor mutational burden (TMB), 8 STK11/LKB1 mutations, 9 among others can deter the expected response to these agents. 7 On the other hand, synergistic associations can potentiate the effect of these agents.…”

Section: Introductionmentioning

confidence: 99%

Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non‐small cell lung cancer (AB‐CLICaP)

et al. 2020

View full text Add to dashboard Cite

Background The intestinal microbiota is an important factor in modulating immune‐mediated tumor cell destruction. Alterations in the microbiome composition have been linked to reduced efficacy of immune checkpoint inhibitor (ICI) therapies. Therefore, antibiotic treatment (ATB), which modifies the diversity of the gut bacteria populations, could lead to a reduced efficacy of ICI treatments. Methods This was a retrospective cohort study. Patients with advanced non‐small cell lung cancer (NSCLC) treated with anti‐programmed cell death ligand‐1 (PD‐L1) alone, or in combination in three different countries in Latin America were included. After identification, patients were placed into three groups: Non‐ATB exposed (no‐ATB), exposed within 30 days of the first dose of ICI (pre‐ICI ATB) and patients receiving ATB concomitantly with ICI (ICI‐ATB). Progression‐free survival (PFS), overall survival (OS) and response rates to treatment with ICI were assessed. Results A total of 140 patients were included, of which 32 patients (23%) received ATB treatment. The most common ATB types were fluoroquinolones and B‐lactams. No differences in survival according to antibiotic type were identified. Median OS in patients not exposed to ATB was 40.6 months (95% CI: 32–67.7), compared with 20.3 months (95% CI: 12.1‐non‐reached [NR]) for patients with pre‐ICI ATB treatment and 24.7 months (95% CI: 13‐NR) for patients treated with ATB concomitantly with ICI. There were no significant differences in terms of PFS, or response rates across all treatment groups. Conclusions Antibiotic treatment was associated with reduced OS in Hispanic patients with NSCLC treated with ICIs.

show abstract

“…In contrast to previous assumptions suggesting a mutual exclusive driver mutation function of MAP2K1 in predominantly localized NSCLC, parallel sequencing using NGS detected a variety of co-occurring mutations. Among them, KEAP1 mutations could be found in 28% of patients tested, suggesting that therapeutic approaches using chemotherapy, immunotherapy, or both combined might be ineffective in this sub-cohort [35][36][37]. In contrast, concurrent aberrations like activating EGFR mutations, MET exon 14 skipping mutation, BRAF V600E or ROS1 rearrangements are targetable.…”

Section: Discussionmentioning

confidence: 95%

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. Methods: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. Results: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. Conclusion: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

show abstract

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.

Cited by 91 publications

References 0 publications

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

STK11 (LKB1) mutations in metastatic NSCLC: Prognostic value in the real world

Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non‐small cell lung cancer (AB‐CLICaP)

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

Contact Info

Product

Resources

About