KRAS G12C + PD-L1 expression

This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.

Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line...Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.

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

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.

No abstract available

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

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. >

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.

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.