STK11 mutation

The addition of ICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.

P2, N=96, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Nov 2026 --> Nov 2024

P2, N=42, Active, not recruiting, Amgen | Trial completion date: Nov 2024 --> Jan 2026 | Trial primary completion date: Nov 2024 --> Jan 2026

SWI/SNF-d pulmonary neoplasms, whether with multiple or single subunit losses, exhibit similar clinicopathological characteristics. Radiotherapy and immunotherapy are effective treatments for these patients, and the combination of radiotherapy with immunotherapy may offer synergistic effects.

The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.

This case underscores the transient efficacy of targeted therapy in SMARCA4-deficient NSCLC with concurrent EGFR mutations. It highlights the need for continuous therapeutic adjustments and emphasizes the importance of further research into effective strategies for treating this complex and challenging subset of NSCLC, as current modalities have limitations in sustained efficacy.

Here, we identified targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment...Treatment with SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. Together, these data suggest that targeting SOS1 could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.

A high index of suspicion is required to make the diagnosis of STK11 adnexal tumor due to its non-distinct pathology and IHC staining. Due to the rarity of this neoplasm, analysis of current and future cases of the STK11 adnexal tumor is necessary to understand its pathogenesis, genetic mutational analysis, clinical course, and best treatment options.

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Oct 2032 --> Mar 2031

Whole exome sequencing revealed loss of function mutations in TP53, STK11, PBRM1, SMAD3, FN1, NTRK1, and FANCD2, as well as gain of function mutations in MTOR, BCL11A and COL1A1, along with amplification of CCND3 and MDM2. This mutational landscape halfway between thymic carcinoma (TP53, PBRM1) and hepatoid variant carcinoma of other sites (STK11) suggests that, at some point during carcinogenesis, a switch occurred from an epithelial thymic phenotype to a hepatoid-like one.

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Aug 2033 --> Oct 2032

Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

Updated analyses from POSEIDON after median FU of >5 y showed durable long-term OS benefit with the approved regimen of T+D+CT (vs CT alone). These results support its use as a 1L treatment option for pts with mNSCLC, including harder-to-treat subgroups such as those with PD-L1 TC <1%.

Patients with KRAS G12C were more likely to be smokers. Advanced KRAS G12C NSCLC patients who received immunotherapy had a better ORR than those who did not, suggesting that patients with G12C mutations are more likely to benefit from immunotherapy.

Ten additional participants have experienced Grade 4 treatment-related adverse events, nine of which are non-hematologic toxicities. There is one participant with a Grade 3 treatment-related Hepatobil disorders-Other due to autoimmune hepatitis.

Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

These findings identified novel variants and key genes contributing to disease development and progression. Further analysis of less studied genes, including RBMX, MRC1, ATM, CTNNB1, and CDKN2A, in TNBC may reveal new potential genes for targeted therapeutic strategies and contribute to clinical advancements in the treatment of TNBC.

In conclusion, it is challenging to diagnose EWDGA using biopsy specimens. Recognizing and addressing this rare entity will increase diagnostic accuracy to ensure the early diagnosis of cancer.

Accordingly, this case died of pneumonia with septic shock during treatment. Our findings suggest that the presence of rhomboid crystals in bone marrow smears may alert pathologists to look for the possibility of crystal-storing histiocytosis and the prognosis of patients with multiple myeloma may depend on the genetic features of tumor cells rather than the association with crystal-storing histiocytosis.

Our results indicated that dinaciclib and alvocidib exhibited similar activity and sensitivity in the neuroendocrine cluster. Also, a lineage factor named KLF5 recognized by inferred transcriptional factors activity could be suppressed by verteporfin.

Specifically, in BM-S2, these sialylation modifications are predominantly localized to the lysosomes, underscoring the critical role of N-glycosylation in the tumor progression of BM-LUAD. Overall, our study not only provides a comprehensive multi-omic data resource but also offers valuable biological insights into BM-LUAD, highlighting potential mechanisms and therapeutic targets for further investigation.

Additionally, immunotherapy efficacy in patients with SMARCA4 mutations depended on the co-mutant genes. Thus, SMARCA4 could be an important factor to be considered for LUAD diagnosis and treatment.

Furthermore, these metabolites enhanced the cytotoxicity of activated T cells on H460 cells in vitro and can activate the stimulator of the interferon genes (STING) pathway independently of AXIN1. Relying on AXIN1, metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in STK11 mutant NSCLC, indicating a potential immunotherapeutic strategy for STK11 mutant NSCLC.

ALK positivity was associated with specific aggressive pathological features and inferior RFS in stage I LUAD. ALK-positive patients seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

P3, N=280, Recruiting, AstraZeneca | Trial completion date: Mar 2031 --> Aug 2033

Although deep learning models trained on larger cohorts show improved robustness and generalizability in predicting oncogenic mutations, they cannot replace comprehensive molecular profiling. However, they may support patient pre-selection for clinical trials and deepen the insight in genotype-phenotype relationships.

KRAS mutation subtypes exhibit distinct clinical and molecular characteristics and varying responses to immunotherapy. G12C and G12V mutations correlate with better immunotherapy outcomes, while G12D mutations are associated with poorer responses.

After median follow-up of >5 years, T+D+CT showed durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

P2; Active, not recruiting --> Completed

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. $$table_{7740CBC2-774F-48DA-932A-077113E7FED5}$$

Conclusions : SMARCA4 -deficient NSCLCs has a distinct tumor immune microenvironment characterized by increased myeloid cell and macrophage infiltration, potentially contributing to resistance to immune checkpoint inhibitors. Additional work is underway to profile and spatially analyze the tumor immune microenvironment and to characterize its relation to STK11 co-mutation status.

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. Cumulative incidence of venous and arterial TEs % 0 6 weeks 6 months 1 year 2 years 3 years Overall 2.8 6 11.7 15.8 21.5 26.2 ALK 5.3 10.7 12 14.8 14.8 17 BRAF 2.1 5.8 12.9 16.3 19.5 27.9 EGFR 2 5.8 10.2 14 17.9 23 HER2 0 3.5 7.2 9.2 19.5 23 KRAS 2.7 5.1 11.3 15.3 22.5 27.1 MET 14 6.8 11.3 21.2 21.2 23.9 27.7 RET 13.3 23.3 33.3 36.6 44.5 50.1 ROS1 12 20 34.2 34.2 45.1 53.3

This study highlights serial ctDNA profiling's benefits for managing advanced NSCLC, providing real-time genetic data. It offers predictive insights as potential imaging substitutes, enables dynamic treatment adjustments, and identifies resistance to therapies.

We assessed gene signatures indicative of B cell infiltration/TLS presence (Messina et al., 2012; Goc et al., 2014; Cabrita et al., 2020; Meylan, et al., 2022), correlating these with clinical outcomes, including overall survival (OS) and time on treatment (TOT) for ICIs such as pembrolizumab, nivolumab, and ipilimumab. This large TLS atlas based on real-world data demonstrate that TLS gene is a robust biomarker for predicting responses to immunotherapy in solid tumors.

P2, N=96, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

Furthermore, 7 IRGs, namely CALCA, BMP6, S100P, THPO, CGA, PCSK1 and MUC5AC, were found significantly overexpressed in STK11-mutated NSCLC in both LUSC and LUAD histology. Low STK11 expression at protein level and presence of STK11 mutation were associated with poor prognosis in NSCLC, and mutated STK11 might probably alter the expression IRGs profiling.

These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.

SCD1 inhibition augmented the effect of ferroptosis inducer, erastin... Our study is the first to highlight the importance of the ferroptosis regulators, SCD1-SLC7A11,in regulating unique metabolic and ferroptosis evasion pathways in KSK patient tumor and preclinical models. The study data furthers the understanding of ferroptosis in NSCLCand the potential to translate SCD1 inhibitors and ferroptosis inducers in KRAS NSCLC clinical trials.

We identified molecular alterations and immune-related features that distinguish wtRET from mutRET MTC. While RET mutation drives MTC in the absence of other alterations, we showed that wtRET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with oncology immune-oncology agents for selected patients with wtRET MTC.

Patients with STK11-mutant NSCLC had low PD-L1 expression and ORR to ICIs, and their PFS and OS were worse than patients with STK11wt after comprehensive treatment. In the future, more reasonable systematic treatments should be explored for this subgroup of patients with STK11-mutant NSCLC.

The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.