KRAS G12C + PD-L1 expression

Here we present a case series of metastatic LCNEC in which favorable clinical courses with persistent response periods towards immunochemotherapy with nivolumab/ipilimumab/carboplatin and paclitaxel were achieved. The case series presented here underlines the feasibility and efficacy of combined ICI targeting PD-1 and CTLA-4 in combination with a platinum doublet in metastatic LCNEC. Despite the limited number of cases, we suggest the TMB to be a frequent and potentially characteristic marker in LCNEC that is well known to predict responsiveness towards immunochemotherapy.

This suggests that additional factors beyond the immune environment may also influence immunotherapy responses in LUAS, highlighting the need for further investigation. Table 1: Genomic/Immune landscape of LUAS, AC, SCC along with LUAS primary and metastatic sites Adenosquamous (LUAS, n =374) Squamous (SCC, n = 9635) Adenocarcinoma (AC, n = 25665) p-value (SCC vs LUAS) p-value (AC vs LUAS) Overall Actional Alteration Prevalence EGFR, ALK, ROS1, RET fusions /rearrangements, METex14, BRAF V600E, KRAS G12C, NTRK fusions, HER2 110 (29.4%) 343 (3.67%) 9267 (36.22%) 1%) 228 (65.5%) 5293 (59.8%) 12789 (53.7%) 0.033 50%) 110 (31.6%) 2119 (26.3%) 6218 (31.2%) 0.0293 0.1843 PD-L1 low (1-49%) 112/348 (33.9%) 3009/8045 (37.8%) 6177/20023 (30.8%) 0.048 0.512 No PDL1 (0%) 126/348 (36.2%) 2917/8045 (35.9%) 7628/20023 (38.1%) 0.984 0.3621 TMB High ( > 10 Mut/MB) 112 (30.6%) 3488 (38.47%) 8159 (32.94%) 0.002 0.344 Tumor microenvironment LUAS Median cell fraction (%) SCC Median cell fraction (%) AC Median cell fraction (%) p-value (SCC vs LUAS) p-value (AC vs LUAS) Monocytes 0.02 0.06 0.10 0.138 0.017 T cells CD4 0.04 0.07 0.11 0.274 0.130 Neutrophils 5.57 5.23 4.85 0.165 0.020 NK cells 2.68 2.49 2.94 0.005 <0.001 T cells CD8 0.39 0.11 0.27 <0.001 0.164 Macrophages M2 6.08 4.65 6.19 <0.001 0.172 Macrophages M1 4.57 2.64 5.12 <0.001 0.005 B cells 4.08 4.19 3.87 0.092 0.160 Dendritic cells 0.61 1.07 0.54 <0.001 0.049 Tregs 2.92 1.75 2.76 <0.001 0.365 Immune-related genes LUAS Median Gene expression median ((Log2 (TPM+1)) SCC Median Gene expression median ((Log2 (TPM+1)) AC Median Gene expression median ((Log2 (TPM+1)) p-value (SCC vs LUAS) p-value (AC vs LUAS) PDCD1LG2 1.447 1.319 1.284 0.009 <0.001 PDCD1 0.817 0.711 0.790 0.003 0.251 CTLA4 1.914 1.629 1.638 <0.001 0.001 CD86 3.534 3.218 3.482 <0.001 0.337 ID01 2.850 2.300 2.241 <0.001 <0.01 CD274 3.210 3.122 3.031 0.717 0.132 CD80 2.888 2.569 2.798 <0.001 0.453 HAVCR2 4.511 3.999 4.499 <0.001 0.739 LAG3 1.037 1.043 0.865 0.466 0.001 IFNG 0.841 0.697 0.691 0.026 0.025

Conclusions : In our cohort, KRAS -mutant patients appear to have a different metastatic pattern depending on their KRAS mutation subtype. In addition, KRAS G12C and KRAS G12V -mutant patients seem to have better prognosis and response to chemoimmunotherapy than KRAS G12D -mutant patients.

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

PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.

First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.

ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with significantly lower frequencies of FGFR2 and IDH1 when compared with iCCA. In contrast, targetable GA in ERBB2 and KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA and cbdCCA respectively. GA in IO drug response associated biomarker frequencies (MSI, TMB level and PD-L1 expression) are similar in all 3 ehCCA subgroups.

ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with significantly lower frequencies of FGFR2 and IDH1 when compared with iCCA. In contrast, targetable GA in ERBB2 and KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA and cbdCCA respectively. GA in IO drug response associated biomarker frequencies (MSI, TMB level and PD-L1 expression) are similar in all 3 ehCCA subgroups.

TBD

We identified increased infiltration of cytotoxic T lymphocytes and APCs in PDA patients with KRAS G12C mutations relative to other mutations and non-cancerous pancreata. Furthermore, while all PDAs had elevated PD-L1 expression on APCs, KRAS G12C tumors had minimal expression on epithelial cells suggesting a mutation specific impact and a potential role of immune checkpoint inhibitors in combination with G12C inhibitors.

phCCA appears to be a distinctive form of ehCCA featuring significantly higher frequencies of potentially targetable ERBB2 and lower frequencies of targetable FGFR2 and IDH1 mutations, when compared to ihCCA. Predictive IO markers were similarly low in both ihCCA and ehCCA. >

While KRAS G12C mutations are very rare in the major GU malignancies, a small proportion of such patients may benefit from emerging specific anti-KRAS G12C targeted therapies. Additionally, given the low prevalence of KRAS G12C mutations among major GU malignancies, investigation may be best approached in basket-type clinical trials using novel anti-KRAS G12C targeted therapies.

Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of KRAS mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.

Notably, AMG510 provided complementary immune modulatory benefits that support the mechanism of Nivolumab. The findings suggest that combining KRAS G12C inhibitor with anti-PD-1 antibody holds a promising therapeutic potential for NSCLC patients.

Sotorasib and adagrasib are targeted drugs that have been proven effective and approved for KRAS G12C mutation, but they have not yet entered the Chinese market. Conclusions Bringing immunotherapy to first-line use in NSCLC patients with KRAS mutation might prolong their survival, and combination therapy is a preferable option compared to monotherapy. Positive PD-L1 expression and common KRAS mutations may serve as potential prognostic biomarkers for KRAS-mutated NSCLC patients who receive immunotherapy.