KRAS G12C Research Articles

The histopathological spectrum and molecular changes associated with KRAS G12C mutation in non-small cell lung carcinoma

KRAS G12C is the most common KRAS mutation in non-small cell lung carcinoma (NSCLC), for which targeted therapy has recently been developed. From the 732 cases of NSCLC that underwent next-generation sequencing at the Department of Anatomical Pathology, Liverpool Hospital, between July 2021 and May 2023, we retrieved 83 (11%) consecutive cases of KRAS G12C mutated NSCLC, and analysed their clinical, pathological, and molecular features. Of the 83 cases of KRAS G12C mutated NSCLC, there were 46 (55%) men and 37 (45%) women, with mean age of 72 years. Of the 49 cases with known clinical information, 94% were current or ex-smokers, and 49% were stage IV at diagnosis with median survival of 12 months. Sixty-three percent were histology cases and the remainder were cytology cases. Eighty-two percent were non-mucinous adenocarcinomas, with conventional histology including lepidic, acinar, solid, single cells and micropapillary patterns, and 62% were poorly differentiated. There were five (6%) cases of mucinous adenocarcinoma, one case of pleomorphic carcinoma and one case of high-grade fetal adenocarcinoma. TTF1 was positive in the majority (89%) of cases. Nineteen (23%) cases had TP53 co-mutation, and these cases had trends towards higher PD-L1 expression, poor differentiation, and presentation as stage IV disease, but the differences were not statistically significant. KRAS G12C mutated NSCLCs almost exclusively occurred in smokers and were mostly non-mucinous adenocarcinomas with conventional histological patterns which ranged from well to poorly differentiated. Around a quarter had TP53 co-mutation, the histological impacts and immune profile of which need to be assessed in a larger study.

Evaluation of the genomic and immune profiles of patients with lung adenosquamous carcinoma (LUAS) and association of response to treatment.

8567 Background: LUAS is a rare subset of non-small cell lung cancer (NSCLC) comprising up to 4% of cases, characterized by at least 10% of both adenocarcinoma and squamous components. Limited studies exist on LUAS regarding the genomic/immune landscape and response to immunotherapy (IO). Methods: NSCLC samples (n = 35404) underwent NextGen Sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) at Caris Life Sciences. PD-L1 expression was assessed using IHC (22c3; positive: TPS >1%). High tumor mutational burden (TMB-H) was defined as ≥10 mut/MB. Cell infiltration in the tumor microenvironment was estimated by quanTIseq. Gene expression profiles were analyzed for transcriptomic signatures (IFN-γ) predictive of IO response. Real-world overall survival (rwOS) was obtained from insurance claims data, calculated from time of biopsy to last contact. Time on treatment (TOT) was calculated from the first pembrolizumab (pembro) treatment to the last. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with p-values adjusted ( p < .05). Results: Among NSCLC samples, 1.0% (n=374) were LUAS, 26.5% (n = 9365) were squamous (SCC) and 72.5% (n = 25665) were adenocarcinoma (AC). LUAS exhibited actionable alterations in 29% (n = 110/374) of cases, with MET exon 14 skipping alteration ( METex14) significantly higher in LUAS compared to SCC or AC (9.02% vs 1.21% vs 2.61%, p < 0.01). BRAF V600E (0.54% vs 0.13%, p = 0.041) and ALK-Fusion (1.13% vs 0.12%, p = 0.0145) were higher in LUAS compared to SCC, while PIK3CA mutation was higher in LUAS compared to AC (10.8% vs 4.1%, p <0.01). Notably, LUAS exhibited higher prevalence of KRAS, targetable EGFRand STK11 mutations compared to SCC but lower compared to AC ( KRAS G12C: 8.63% vs 1.37% vs 13.24%, p <0.01; EGFR: 13.1% vs 1.12% vs 17.53%, p<0.01; STK11: 6.97% vs 1.83% vs 17.22%, p<0.01). LUAS exhibited significantly higher PD-L1+ (65.5% vs 59.8% vs 53.7%, p <0.01), along with elevated expression of immune checkpoint genes and the IFN-γ signature compared to AC and SCC. Moreover, LUAS exhibited significantly higher neutrophils, CD8 T cells, M2 macrophages and Tregs compared to SCC. LUAS showed improved rwOS compared to SCC (HR 0.792, p<0.01), with no difference noted in the rwOS between LUAS and AC (HR = 0.98, p = 0.81). While PD-L1+ was not associated with TOT on pembro in LUAS, high TMB showed improved TOT on pembro in LUAS. Conclusions: This study provides a comprehensive genomic landscape of LUAS, highlighting actionable alterations in ~ 29% of cases. LUAS exhibits distinct molecular and clinical features compared to AC and SCC, with enrichment in actionable METex14, emphasizing the need for NGS testing. Although PD-L1 status may not significantly impact TOT in LUAS, it remains relevant in other NSCLC subtypes on IO and high TMB emerges as a potential biomarker for favorable TOT on pembro in LUAS, warranting further investigation.

Survey of actionable driver mutations KRAS and EGFR in non–small cell lung cancer to evaluate coexisting splicing gene and pathway mutations: A CBioportal database analysis.

8561 Background: Molecularly targeted therapies have advanced treatment for certain cancers, such as lung cancer with specific EGFR or KRAS mutations. However, oftentimes the tumor becomes eventually treatment resistant. This may be partly because cancers driven by EGFR/KRAS mutations may also harbor additional co-occurring genetic alterations. In non-small cell lung cancer (NSCLC), aberrations in RNA splicing pathways have shown substantial implications for tumor behavior and therapeutic responsiveness. Our study focuses on elucidating the interplay between RNA splicing defects and prominent NSCLC mutations. Methods: In this retrospective, cross-sectional study, we analyzed data from 20,719 NSCLC patients enrolled in participating institutions between 2017 and 2022. The data were sourced from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (version 13.0). EGFR L858R, EGFR E746_750del, KRAS G12C, KRAS G12D and other KRAS G12 mutations cases were identified and individually analyzed to abstract co-occurring RNA splicing genomic alterations. Results: Among 20,719 patients with NSCLC, we identified 1309 patients with EGFR L 858R mutation, 1121 patients with EGFR E746_750del mutation, 2446 with KRAS 12C, 852 with KRAS G12D, 1107 with KRAS G12V, 452 with KRAS G12A, 173 with KRAS G12F, and 109 with KRAS G12S. RBM 10 was the most common co-occurring RNA splicing gene for EGFR L 858R (178, 13.6%), followed by CDK12 (31, 2.3%) and SPEN (27, 2 %). Similarly, the most prevalent co-occurring RNA splicing genes with EGFR E746_750del were RBM 10 (38, 3.4%) and SPEN (23, 2 %). RBM 10 was the most prevalent co-existing RNA splicing gene for KRAS G12C (211, 8.6 %), KRAS G12D (63, 7.4 %), KRAS G12V (80, 7.2%), KRAS G12A (59, 13.1%), KRAS G12F (12, 7.0%), KRAS G12S (11, 10.1%) and KRAS G12R (6, 8%). Conclusions: Our study uncovers a crucial link between EGFR and KRAS mutations in NSCLC and RNA splicing gene dysregulation, particularly involving RBM10. Further research in this field is warranted as targeting RNA splicing, alone or alongside existing targeted inhibitors, could substantially enhance treatment efficacy for EGFR+ or KRAS+ NSCLC patients. [Table: see text]

Effect of targeting FAK by ifebemtinib and immunogenic cell death of Kras G12C/G12D inhibition on the efficacy of PD1 blockade.

e15102 Background: Focal adhesion kinase (FAK) is one major component of focal adhesion complex and is important in regulating cancer cell survival. Previously, we found that a clinical-stage FAK inhibitor, ifebemtinib (aka IN10018) can overcome drug resistance of Kras G12C inhibitors by down regulating the FAK-YAP signaling. Combination of Kras G12Ci and FAKi has demonstrated encouraging efficacy in NSCLC. Here, we reported that targeting Kras G12D by selective Kras G12Di can also be enhanced by ifebemtinib. Further, Kras G12C inhibition plus PD1 blockade has demonstrated clinical benefits in PD-L1 high expression patient population, but ≈30% of patients experienced early disease progression; this might be attributed to loss-of-function of LKB1 and others. Immunogenic cell death (ICD) of Kras inhibition is enhanced by ifebemtinib, ICD reportedly enhances anti-PD1 activity. Thus, Kras inhibition and PD1 blockade plus ifebemtinib may be an ideal combination for patients with Kras G12D. Methods: Cell killing and apoptosis assays were performed to test the combination of Kras G12D inhibition and ifebemtinib. FACs analysis evaluated exposure levels vs. ICD biomarkers. The mice inoculated with CRC GP2D and PDAC PC-07-0013 were used for evaluating the combinational effects of Kras G12Di and ifebemtinib. The tumor bearing mice with Kras G12D mutant/LKB1 loss, NSCLC KPL, and CRC CT26 with knock-in Kras G12C were used for testing the effects of Kras inhibition, ifebemtinib, and PD1 blockade. Results: Ifebemtinib enhances the drug effects of Kras G12D inhibition in vitro and in vivo. The dual regimen of ifebemtinib and Kras inhibition outperformed either monotherapy with significant ICD induction in vitro (calreticulin/GRP94 exposure). The triple regimen of Kras inhibition, FAK inhibition and PD1 blockade exhibited stronger anti-cancer effects compared to the other related therapies, especially in a Kras G12D mutant, LKB1 loss animal model which is intrinsically resistant to PD1 blockade/Kras G12D inhibition. Conclusions: We discovered that targeting FAK by ifebemtinib enhances the anti-cancer effects of Kras G12D inhibition. It promotes ICD by targeting Kras G12D or G12C, further primes the dual regimen of Kras inhibition and ifebemtinib towards a response to anti PD1 therapy. The preclinical results warrant a further evaluation in the clinic.

Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202).

TPS8653 Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 <1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .

Survival and mutational differences based on ESR1 and ESR2 expression in non-small cell lung cancer (NSCLC).

8526 Background: Estrogen receptor (ER) can activate MAPK signaling but the contribution of the two classical receptors—ER-alpha ( ESR1) and ER-beta ( ESR2) is unclear. Past trials targeting ER and EGFR in NSCLC lacked efficacy. We evaluated the association of ESR1& 2 expression with the genomic landscape and overall survival (OS) in NSCLC. Methods: NSCLC tumors (N = 21603) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Mutation prevalence (-Mt) was calculated for pathogenic SNVs/indels. ESR1& 2 expression was split into quartiles (transcripts per million, top (-H) and bottom (-L) quartiles were compared). A transcriptomic signature associated with MAPK activation (MPAS, arbitrary units: AU) was applied. The X2 test was applied, p-value was adjusted for multiple comparisons ( p < .05). Real-world OS was obtained from insurance claims and Kaplan-Meier estimates were calculated. Results: There was a greater proportion of females in ESR1-H (53%) versus (v) -L (45%, p < .05) but not in ESR2-H v -L (50% v 50%). There was a greater proportion of adenocarcinoma (AD) in ESR1-H (65%) v -L (44%) and a greater proportion of squamous (SCC) tumors in ESR2-H (27%) v -L (15%) ( p < .001 all). The prevalence of EGFR-Mt and KRAS-Mt was greater in ESR1-H v -L and smaller in ESR2-H v -L. (Table) Of all KRAS-Mt, there was a greater percent of KRAS G12C-Mt in ESR1-H (44%) v -L (39%, p = .001). In EGFR-Mt, ESR1-H/ ESR2-H had a higher MPAS (1.4 AU) than ESR1-H/ ESR2-L (.52), ESR1-L/ ESR2-H (.59) or ESR1-L/ ESR2-L (-1.6, p < .05). In KRAS-Mt, ESR1-H/ ESR2-H (1.7 AU) and ESR1-L/ ESR2-H (1.8) had a higher MPAS than ESR1-H/ ESR2-L (.7) or ESR1-L/ ESR2-L (-.7, p < .001). ESR1-H had longer median OS v -L (22 months (m) v 16 m, p < .001) as did ESR2-H v -L (23 m v 15 m p< .001). ESR1-H/ ESR2-H had the longest OS (25 m) followed by ESR1-H/ ESR2-L (18 m), ESR1-L/ ESR2-H (16 m) and ESR1-L/ ESR2-L (14 m, p < .001). In EGFR-Mt, a significant difference in survival since treatment (SST) with osimertinib was seen for ESR1-L/ ESR2-H (40 m, N = 13), ESR1-H/ ESR2-L (36 m, N = 62), ESR1-H/ ESR2-H (34 m, N = 161) and ESR1-L/ ESR2-L (30 m, N = 138, p = .03). In KRAS G12C-Mt, a significant difference in SST was seen with sotorasib; ESR1-H/ ESR2-H had the longest SST (median not reached, N = 17), followed by ESR1-H/ ESR2-L (17 m, N = 17), ESR1-L/ ESR2-L (13 m, N = 34) and ESR1-L/ ESR2-H (1 m, N = 1, p = .002). Conclusions: ESR1-H had a higher percentage of females, AD, and EGFR/ KRAS-mt v ESR1-L while ESR2-H had no sex difference, more SCC, and fewer EGFR/ KRAS-mt v ESR2-L. ESR1-H/ ESR2-H tumors had the highest MPAS and longest OS and there were SST differences with EGFR and KRAS G12C inhibition. ESR1& 2 may play key roles in activating the MAPK pathway and future trials could consider targeted therapy combined with ER inhibition based on ESR1&2 expression. [Table: see text]

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( > 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .

Young lung adenocarcinoma: Molecular analysis pointing to early acquisition of aggressive mutations.

e20089 Background: Lung adenocarcinoma in young adults (≤50) has an aggressive course even in the presence of targetable mutations. Prior US studies were conducted predominantly in the Northeast where smoking prevalence is low compared to Kentucky. To assess the mutation spectrum in this high-risk population we performed a descriptive analysis of mutations in patients 50 years old and younger (YA), compared the survival of YA patients with and without NGS, and compared the survival of YA to patients older than 50 seen at an NCI designated Comprehensive Cancer Center situated in the tobacco belt. Methods: Using the Kentucky Cancer Registry (KCR) we identified 139 YA patients with lung adenocarcinoma seen at our institution between 01/2015 to 11/2023, 54 had NGS testing. 933 patients over age 50 were identified for comparison. Adenocarcinoma specimens were analyzed using next-generation sequencing of DNA (DNA-592-gene panel or whole exome) or RNA (whole transcriptome or +1,500-gene panel) at Caris Life Sciences or Foundation Medicine. Hazard ratios (HR) for survival were calculated using the Cox proportional hazards model. The cutoff for statistical significance was a p-value < 0.05 as calculated by the Chi-square test. Results: Of the 54 YA patients with NGS, 28 (52%) were female, 48 were white (88%), 3 Black (6%), and 3 Asian (6%). Only 18% were never smokers (median 28 pack years), and 44% had a family history of lung cancer. Targetable mutations were noted in 27 (50%). EGFR was mutated in 9 patients (17%), 2 with exon 19 deletion, 2 with exon 20 insertion, and 5 with exon 21 L858R. ALK rearrangement was seen in 3 patients (5%), while 3 (5%) had ERBB2 mutations. There was a mutation of KRAS in 17 patients (31%), and 16 of the 17 were transversion mutations. (13/17 G12C, 1/17 G12R, 1/17 G12V and 1/17 G13C). TP53 was mutated in 44 patients (81%), and 16 patients (30%) had mutations in homologous recombination repair (HHR) genes. The tumor mutation burden was high in 28 (52%) of patients. PD-L1 expression was > 50% in 22/54, 1-49% in 18/54, and 0% in 10/54 (4/54 NA). Survival was not significantly different between YA patients with and without NGS nor between YA and older patients. Conclusions: We identified a high prevalence of KRAS G12C, previously associated with increasing age and environmental insults, and EGFR exon 21 L858R in a YA population. Alterations in HHR genes and TP53 were present at high rates. Acquisition of aggressive forms of KRAS and EGFR mutation, as well as the high prevalence of TP53 and HHR defects, may contribute to early disease development. This highlights the importance of early tobacco cessation efforts and the need to assess germline mutations. Lung cancer remains a therapeutic challenge even in young patients with actionable mutations, as outcomes remain poor, equivalent to older patients.

Real-world KRAS testing and treatment utilization among patients with metastatic non-small cell lung cancer.

e20593 Background: About 30% of patients with non-small cell lung cancer (NSCLC) have been reported to harbor gene mutations of Kirsten rat sarcoma oncogene homologue (KRAS). KRAS testing is recommended at metastatic NSCLC (mNSCLC) diagnosis and targeted treatment has shown better outcomes among KRAS-positive patients. This study aimed to understand KRAS testing rates among mNSCLC patients and utilization of targeted treatment among KRAS G12C positive patients treated in the community oncology setting. Methods: A random sample of 836 mNSCLC patients from the Integra Connect PrecisionQ de-identified database was included in this retrospective observational analysis, with additional information supplemented by chart curation. The database contains ~80% community oncology and ~20% academic practices with over 3 million cancer patients across 500 sites of care. Eligible patients were those aged ≥18 years, diagnosed with mNSCLC, and who initiated treatment in the second line (2L) setting between 01-May-2021 and 01-Jan-2024. KRAS testing rates and utilization of targeted treatment use were assessed and presented for this study. Results: The median (IQR) age of 836 mNSCLC patients was 68 (62,75) years; 52.9% were female; 73.8% identified as White, 11.7% as African American, 1.9% as Asian, and 12.6% as Other. Testing for KRAS was reported in 749 (89.6%) of the mNSCLC patients any time during the evaluation period, with most of them (738/749) tested before 2L treatment initiation; 186/749 (24.8%) of those patients were positive, and 74 were KRAS G12C positive. Of the KRAS G12C positive patients, 53/74 (71.6%) reported a targeted KRAS treatment in the 2L or greater setting. Conclusions: In this real-world setting, the testing rates for KRAS are almost 90%, with about 70% of the mutated patients receiving a targeted treatment. However, there is still a proportion of patients who did not receive KRAS testing or targeted treatment in this real-world setting. Appropriate and timely testing and utilization of the targeted treatment is necessary for better patient outcomes. [Table: see text]

Phase 1/2 trial of the XPO1 inhibitor selinexor in combination with docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer (NSCLC).

8597 Background: KRAS mutant NSCLC remains a therapeutic challenge. Although KRAS G12C inhibitors are now approved for cases harboring that specific mutation, their efficacy is modest and the G12C variant accounts for only 40% of KRAS mutations in NSCLC. To date, there are no approved targeted therapies for non-G12C KRAS mutant NSCLC. Selective inhibitors of nuclear export (SINE) modulate cancer cell biology by retaining certain proteins—such as tumor suppressors—within the nucleus, where they remain physiologically active. The XPO1 inhibitor selinexor demonstrated efficacyinpreclinicalNSCLC models harboring various KRAS mutations. Methods: In this 3 + 3 dose-escalation phase 1/2 trial, patients with previously treated advanced KRAS mutant NSCLC received selinexor (dosed orally weekly) plus docetaxel 75 mg/m2 IV every three weeks (NCT03095612). Prior treatment with KRAS G12C inhibitors was permitted. Results: Among 40 enrolled patients, median age was 66 years, 22 (55%) were female, and 34 (85%) were white. KRAS mutation types included G12C (28%), G12V (23%), G12D (20%), G12A (13%), G12R (5%), G13C (5%), and one case each of G12S, G13D, Q61L, and K117N. Patients had received a median of 2 prior lines of therapy (range 1-4). The maximum tolerated dose of selinexor was 60 mg PO weekly combined with docetaxel. The most common adverse events (AE) were nausea (73%, Gr ≥3 8%), fatigue (70%, Gr ≥3 5%), neutropenia (65%, Gr ≥3 60%), diarrhea (58%, Gr ≥3 10%), anorexia (50%, Gr ≥3 0%), and vomiting (45%, Gr ≥3 5%). Of 32 patients evaluable for efficacy, 7 (22%) had partial response (PR) and 18 (56%) had stable disease (SD) as best response. Median progression-free survival (PFS) was 4.1 months (95% CI, 2.9-5 months); median overall survival (OS) was 7.1 months (95% CI, 4.5-13.7 months). Clinical outcomes did not differ significantly among KRAS mutation types. However, TP53co-mutations (48%) were associated with significantly worse outcomes: disease control rate (PR + SD) 27% vs 92% ( P=0.006); median PFS 1.8 vs 7.4 months ( P<0.001); median OS 5.8 vs 17 months ( P=0.006). Additional biomarker studies are ongoing. Conclusions: Selinexor plus docetaxel is tolerated with multi-agent supportive care. The combination shows moderate efficacy across KRAS mutation types, with promising activity in TP53 wild type cases. Clinical trial information: NCT03095612 .

Mapping incidence and survival of non-small-cell lung cancers stratified by mutation type in southern Appalachia: A single center retrospective study.

e20568 Background: Non-small cell lung cancer (NSCLC) is often a mutation-driven disease with variability in incidence and survival depending on location as seen in population-based cohort studies. Our study aims to delineate these differences based on molecular testing for these mutations in our study cohort at East Tennessee State University - Quillen College of Medicine, which is based on patients from east Tennessee, western North Carolina, and southwestern Virginia. Methods: We obtained pathology results of 294 patient samples with advanced/metastatic NSCLC from our cancer center/health system database over a 5 year period. PDL-1 was tested in all patients. Fluorescent in-situ hybridization (FISH) testing for common pathogenic driver mutations such as EGFR, ALK, ROS1, RET, MET and PTEN were performed as is standard of care. Molecular sequencing was performed and included over 40 genetic mutations and 2 biomarkers, several of which today are considered targetable for advanced NSCLC, per standard of care. Incidence of different mutations was measured in our patient population. Overall survival was calculated with date of diagnosis available based on pathology report and date of patient expiration obtained from electronic medical records. Data analysis was performed to ascertain which mutations carried an increased risk of death. Results: The TP53 mutation was very common, seen in 85% of squamous cell carcinoma (SCC) histology and 55% of adenocarcinoma. Similarly, incidence of PTEN deletion by FISH was noted to be 52% in SCC and 31% in adenocarcinoma. EGFR mutations were rare, seen in only 3% of tested patients. We had an incidence of KRAS G12C mutations at 11% overall, but it was present in up to 18% of adenocarcinomas. BRAF was seen in 4.8% of all cases, 8% of adenocarcinomas and 2% of SCC. Since there were more than 2 predictors, Cox proportional-hazards regression model was fit. Due to either having all negative values or very few positive values, the variables CCND1, CDKN2B, ERBB2, ERBB4, FGFR, FGFR2, MET, MSI, NRAS, PDGFRA, RET, RS01, SCR were excluded from analysis. A total of 156 samples were used in final analysis. After model building, it was found that BRAF and KRAS G12C mutation were significant predictors of survival by hazard ratios for death. Conclusions: In our unique patient population, there was a greater incidence of deleterious TP53 mutations and PTEN deletions compared to the general North American advanced/metastatic NSCLC population. Although BRAF and KRAS G12C mutations were not at a greater incidence in comparison to the rest of North America, they were notably significant predictors of survival, conferring nearly 3.4 and 2.7 times increased risk of death in our study. [Table: see text]

Contrasting comprehensive genomic profiles of adenocarcinomas of the appendix in younger versus older patients.

3626 Background: Adenocarcinoma of the appendix (AAC) is a rare form of intestinal malignancy that can pursue an aggressive clinical course. Little is known about the clinical and biologic features of this disease when it presents in young patients under 40. Methods: 1,840 cases of clinically advanced AAC were selected and analyzed by hybrid capture based comprehensive genomic profiles (CGP) to evaluate all classes of genomic alterations (GA). MSI high status and tumor mutation burden (TMB) were determined from sequencing results and PD-L1 was measured by immunohistochemistry (Dako 22C3). Results: 135 (7.3%) of the AAC were identified in patients of 39 years of age or younger (“younger”). The mean age of the younger patients was 32.9 years and for the 40 and over (“older”) patients it was 60.4 years. The slight female gender preponderance was higher in the older patients than the younger patients (Table). The GA per sample were similar. The younger patients had a significantly higher frequency of KRAS GA (71.1% vs 60.4%; p=.017) and TP53 GA (56.3% vs 41.3%; p=.0008). The KRAS G12C mutation frequency was similarly low in both cohorts. Targetable GA in BRAF and ERBB2 were infrequent in both groups as were GA in PIK3CA, PTEN and FBXW7. GA in the APC gene was significantly more frequent in the older patients (10.8% vs 3.7%; p=.007). Biomarkers of immune-oncology (IO) drug efficacy were infrequently identified in both groups including MSI-High status, TMB levels and PD-L1 expression. Conclusions: At a 7.3% incidence, AAC is a relatively infrequent form of gastrointestinal malignancy in young patients. The data analysis shows significant differences in the genomics found in younger and older patients suffering from this disease. These results can have a crucial impact on current and future clinical trials used to design novel treatments. Further exploration into this subject can change the overall approach and even treatment guidelines for this type of cancer. [Table: see text]

Increased NGS testing and real-world clinical usage of targeted therapy: All dressed up, nowhere to go.

e13758 Background: National and International recommendations mandate panel- based biomarker testing for all advanced cases of NSCLC. However, analogous to uptake of many other state of the art cancer management strategies, the uptake of NGS based testing and subsequent targeted therapy varies greatly across socio-demographic groups, explained by awareness and economic restraints. This study investigates the potential differences in uptake of NGS based testing and precision medicine in advanced NSCLC patients from India. Methods: This is a single center non-interventional study where retrospective review of patient data of biomarker driven advanced NSCLC patients was carried out. The records were recovered from electronic health records of the hospital. Single gene testing for EGFR and ALK are performed using Roche Cobas V2 and D5F3 Ventana systems respectively. A machine learning algorithm: Classification and Regression Tree (CART) was employed. Results: A total of 5894 patients of advanced NSCLC were identified. Of these 33% received NGS based biomarker testing at diagnosis. The proportion of patients who received NGS tests increased over calendar time from 2014-2023, with an average increment of 15.8% every year, and peak increase in 2022 of 51%. NGS based testing yielded a positive result in 80% cases with a median turnaround time of 18.2+/-3 days. NGS detected 10.2% cases more in EGFR, 3.2% cases less in ALK, 3.1% more in ROS1. Overall NGS was able to detect 37.8% extra cases of biomarker driven cases. Among the biomarker driven, uptake of targeted therapy was 65% for MET, 83% for ROS1, 52% for RET, 17.6% for ERBB2, 63% for BRAF V600E, 75% for EGFR and 79% for ALK at any given point in the disease. None of the G12C KRAS received selective treatment owing to drug unavailability in the country. Applying the CART model, targeted therapy was received by patients younger than 68 years of age, male gender, with ECOG status 0-2, and absence of brain metastases at diagnosis. Patients with brain metastases at diagnosis, females and those >69 years of age were less likely to opt for TKI(p<0.02*). Conclusions: This is the largest cohort from India reporting real world uptake of NGS based biomarker testing and targeted therapy. There is a clear disparity in terms of gender and age group, possibly attributable to social stigmata and taboos prevailing in rural parts of the country. Despite increased detection rates, access to targeted therapy is still a concern owing to inaccessibility to drugs/ lack of global clinical trials in India as well as lack of patient support programs/groups.

Targeting KRAS Oncogene for Patients With Colorectal Cancer: A New Step Toward Precision Medicine.

KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.

KRAS-mutated non-small cell lung cancer: new therapy strategies

Lung cancer remains one of the most dangerous and most common cancers, requiring constant improvement of diagnostic and treatment methods. The genetic heterogeneity of lung cancer forces us to search for new therapeutic targets in an attempt to achieve greater effectiveness for certain groups of patients. The purpose of the study was to update current knowledge about lung adenocarcinoma with a mutation in the KRAS gene, to consider new opportunities for personalized treatment of KRAS-mutated NSCLC and to form an image of a Russian patient who is potentially indicated for targeted therapy. Material and methods. A search of available literature sources published in the Pubmed, Cochrane Library, Elibrary database was carried out, publications covering the period from 2008 to 2023 were included. Results. The article discussed molecular genetic testing, including NGS next generation sequencing, and its role in determining the presence of KRAS gene mutations in patients with lung cancer. the effectiveness of targeted drugs, such as Sotorasib and Adagrasib was also discussed. The mechanism of action is aimed at suppressing the activity of the mutant KRAS G12C protein, which can significantly improve patient survival prognosis. We obtained data on the results of testing 935 patients with non-squamous non-small cell lung cancer from various medical centers in Russia. The KRAS gene mutation was identified in 160 (17.1 %) patients, of whom 96 (10.3 %) had KRAS G12C variant. The KRAS mutation was determined by PCR in 44 patients and by NGS (including on the FoundationOne platform) in 111 patients. Clinical characteristics, such as gender, age, smoking status, PD-L1 expression level, presence of co-mutations (TP53, STK11, KEAP1, were largely similar between patients from real-world clinical practice and patients included in the CodeBreak100 study. Conclusion. The research results confirm the high effectiveness of Sotorasib and Adagrasib for patients with the KRAS G12C mutation and open up new prospects in the treatment of lung cancer. The clinical data obtained from Russian patients demonstrate consistency with the patient profile from registration studies of these drugs. This once again demonstrates the need to expand the range of molecular genetic testing for timely identification of this group of patients and prescribing the most effective treatment for them.

Real-World Evidence Study of Patients with KRAS-Mutated NSCLC in Finland.

While KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), KRAS-mutant tumors have long been considered difficult to treat and thus, an unmet need still remains. Partly due to the lack of targeted treatments, comprehensive real-world description of NSCLC patients with KRAS mutation is still largely missing in Finland. In this study, all adult patients diagnosed with locally advanced and unresectable or metastatic NSCLC from 1 January 2018 to 31 August 2020 at the Hospital District of Helsinki and Uusimaa were first identified in this retrospective registry-based real-world study. The final cohort included only patients tested with next generation sequencing (NGS) and was stratified by the KRAS mutation status. A total of 383 patients with locally advanced and unresectable or metastatic NSCLC and with NGS testing performed were identified. Patients with KRAS mutation (KRAS G12C n = 35, other KRAS n = 74) were younger than patients without KRAS mutations, were all previous or current smokers, and had more often metastatic disease at diagnosis. Also, these patients had poorer survival, with higher age, Charlson comorbidity index (CCI) being 5 or above, and KRAS G12C being the most significant risk factors associated with poorer survival. This suggests that the patients with KRAS mutation have a more aggressive disease and/or tumors with KRAS mutation are more difficult to treat, at least without effective targeted therapies.

Synergy of EGFR and AURKA Inhibitors in KRAS-mutated Non-small Cell Lung Cancers.

The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.

D3S-001, a KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities.

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its guanosine diphosphate (GDP)- and guanosine triphosphate (GTP)-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report that D3S-001, a next-generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as epithelial growth factor and hepatocyte growth factor, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust antitumor activity preclinically and translated into promising clinical efficacy in an ongoing phase 1 trial (NCT05410145). Significance: The kinetic study presented in this work unveils, for the first time, that a GDP-bound conformation-selective KRAS G12C inhibitor can potentially deplete cellular active KRAS in the presence of growth factors and offers new insights into the critical features that drive preclinical and clinical efficacy for this class of drugs.

Precision medicine for pancreatic cancer: characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease.

Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.

KRAS G12C inhibitor combination therapies: current evidence and challenge.

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.