KRAS G12R

In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

The presence of a KRASG12 mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRASG12 status.

In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively). PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies.

Conclusions NGS-ctDNA provided clinically informative results for 26% of pts with advanced lung SCC, including 6% for whom targeted therapies are available in routine practice or clinical trials (4% ESMO ESCAT tier I and 2% ESMO ESCAT tier IIB). These results suggest that molecular profiling, including plasma NGS testing, should be considered in this population.

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2025

P1, N=29, Active, not recruiting, University of Pennsylvania | N=12 --> 29

P1, N=12, Active, not recruiting, University of Pennsylvania | Recruiting --> Active, not recruiting

P1, N=12, Recruiting, University of Pennsylvania | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

Here, we detected tumor specific KRAS mutations by liquid biopsy in bile samples from patients with confirmed malignant bile duct stenoses. Therefore, liquid biopsy from bile might be a promising approach to improve diagnostic accuracy during ERC. A larger cohort is currently being examined for further tumor-specific mutations.

Conclusions Unfortunately, NGS somatic panel seems to have limited role for the PC treatment nowadays, with few pts receiving treatment guided by the panel. The development of new targeted therapy directed to the most frequently molecular alterations, including KRAS-directed therapy other than KRAS G12C, are urgently needed to improve outcomes.

Conclusions In this study, we elucidated the genomic differences among pancreatic cancer patients with KRAS G12, non-G12, and KRAS wild-type mutations. Furthermore, we found that patients with non-G12 KRAS mutations had lower OS after receiving first-line chemotherapy compared to other patients, and these patients had higher TMB levels.

BsAb targeting BCMA (teclistamab) or GPRC5D (talquetamab) demonstrated promising efficacy in relapsed or refractory multiple myeloma (RRMM) in recent phase 1-2 studies...After 4 previous therapy lines, she received talquetamab in combination with carfilzomib, and achieved very good partial reponse for 6 months before relapse... In conclusion, we report two mechanisms of acquired talquetamab resistance resulting from genetic or epigenetic inactivation of the target. Pre-existing chromosome 12p deletion may favor the emergence of resistant subcloneswith inactivation of the second GPRC5D allele, mirroring previous results on BCMA CAR-T resistance. We anticipate that a thorough monitoring of the genetic and epigenetic status of the targets will help guiding the choice of BsAb and early detection of resistance in MM.

Patients with G12D mutations have significantly lower survival compared to G12R. Significant molecular differences were seen in MAPK pathway gene expression, markers of immune activation, and genes involved in glucose and glutamine metabolism. Intriguingly, metformin use appeared to impact survival in the KRAS G12R subgroup.

P1, N=12, Recruiting, University of Pennsylvania | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

In sporadic mutations, 18-80% of carcinomas that lack RET mutations have mutations of HRAS, KRAS or NRAS. In the case presented, chemotherapy will begin once pending mutation analysis is received.

P=N/A, N=40, Recruiting, Mandana Kamgar, MD | Not yet recruiting --> Recruiting

Pts with KRAS G12C and WT had similar overall prognosis; however, those with KRAS G12C had worse rwPFS with CT + IO tx, as opposed to a trend in the opposite direction for pts treated with IO mono. KRAS G12C imposed worse prognosis vs WT in pts with STK11 or KEAP1 mutations.Table 1. OS and rwPFS in the overall population and subgroupsPSM-based comparisonaKRAS G12CKRAS WTOSN847b1318bMedian, months (95% Cl)11.8 (10.2-14.1)12.5 (11.6-14.0)HR (95% CI);p value1.05 (0.91-1.21);0.47rwPFSN846b,c1317b,cMedian, months (95% Cl)5.5 (4.9-6.2)5.6 (5.2-5.9)HR (95% CI);p value1.06 (0.94-1.20);0.33Multivariate Cox proportional hazard modelaMultivariate HRd (95% CI), KRAS G12Cvs KRAS WT; p valueOSAll pts (N=3526)1.05 (0.92-1.10);0.47KEAP1 mutation (n=506)1.64 (1.17-2.00);<0.01STK11 mutation (n=523)1.38 (1.02-1.86);0.04IO monotherapy in 1L (n=752)0.86 (0.64-1.15);0.32CT + IO in 1L (n=1218)1.15 (0.92-1.44);0.22rwPFSAll pts (N=3526)1.06 (0.94-1.20);0.35KEAP1 mutation (n=506)1.51 (1.11-2.05);<0.01STK11 mutation (n=523)1.25 (0.97-1.61);0.09IO monotherapy in 1L (n=752)0.91 (0.71-1.17);0.46CT + IO in 1L (n=1218)1.22 (1.01-1.49);0.04aRisk factors included in PSM and the multivariate Cox model: age, gender, race, ECOG performance status, smoking status, histology, stage at initial diagnosis, presence of brain metastases, PD-L1 expression category, and 1L treatment; bAll pts in KRAS G12C and WT populations in PSM (1 to up to 2 match); cAll patients with atleast 1 progression assessment; dMultivariate Cox model HR was based on complete case analyses, i.e., pts with non-missing data.CI, confidence interval; HR, hazard ratio; PSM, propensity score matching.

In addition, the study did not meet its primary endpoint. Analysis of circulating tumor DNA (ctDNA) dynamics during study treatment is ongoing.

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

"This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel... Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways."

P=N/A, N=40, Not yet recruiting, Mandana Kamgar, MD

P1, N=12, Recruiting, University of Pennsylvania | Trial completion date: Sep 2022 --> Mar 2023 | Trial primary completion date: Sep 2022 --> Mar 2023

Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

P1, N=141, Recruiting, Revolution Medicines, Inc. | Not yet recruiting --> Recruiting

The patient was unfit for platin-based doublet chemotherapy but was offered Pemetrexed, continuing Osimertinib in standard doses...This variant is characteristic for neuroblastomas and known to be Crizotinib-resistant... Liquid biopsy-guided approach at progression in elderly patients with reduced PS may offer a feasible and effective therapy, as in this case by combining ALK- and EGFR-TKI. The treatment is ongoing and current progression-free survival is now 8 months, which is the longest under the whole treatment course. Effective combination of Osimertinib and Alectinib has been reported in single cases of disseminated EGFR-mutant NSCLC becoming resistant to Osimertinib through acquired ALK-fusions.

Through preclinical and early (ongoing) clinical trial data, our institution has shown the benefits of combining targeted synthetic long peptide vaccines with ICB and adjuvant stimulants in treatment of solid malignancies. This is a single institution, phase I study for patients with Stage III/IV unresectable KRAS-mutated NSCLC to evaluate safety of the pooled mutant-KRAS peptide vaccine with poly-ICLC adjuvant in combination with nivolumab and ipilimumab in the first line treatment setting. The secondary objectives are to assess the impact of therapy on mutant-KRAS specific T cell responses in the peripheral blood and estimate the progression free survival (PFS) for patients treated with this combination. Correlative studies will assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood, as well as evaluate dynamic genomic alterations of response and resistance through ctDNA analysis.

P1, N=141, Not yet recruiting, Revolution Medicines, Inc.

A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

P1, N=12, Recruiting, University of Pennsylvania | Trial completion date: Mar 2022 --> Sep 2022 | Trial primary completion date: Mar 2022 --> Sep 2022

Intermittent scheduling of RMC-6236 was active and permitted a higher dose intensity than daily dosing.RMC-6236 promoted anti-tumor immunity in vivo and was additive with anti-PD1 antibodies, driving durable complete responses and immunologic memory in a KRAS mutant CRC model. Furthermore, RMC-6236 treatment reversed oncogenic RAS-driven immune evasion mechanisms in a checkpoint blockade refractory KRAS mutant model, significantly transforming the tumor microenvironment in favor of anti-tumor immunity.These preclinical results support the inclusion of NSCLC, PDAC, and CRC patients in our planned clinical trial of RMC-6236 in patients with KRASG12X advanced solid tumors.

P1, N=12, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Pancreatic adenocarcinoma is an aggressive malignancy with a poor prognosis. Next-generation-sequencing may offer targeted therapy if an actionable mutation is present such as our patient's, however due to late diagnosis, rapid clinical deterioration, and next-generation sequencing delay we were unable to alter the patient's outcome.

Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial...This study illustrates a new discovery, which can potentially target 15-20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.

"Our data show that the presence of IDH1, BAP1 mutation and FGFR2 fusion supports the diagnosis of iCCA. Tumors with loss of CDKN2A/B and/or SMAD4 and ATM mutations were most likely PDC. Our results support the previous molecular findings in CCA and PDC."

P1, N=12, Recruiting, University of Pennsylvania | Trial completion date: Oct 2021 --> Mar 2022 | Trial primary completion date: Oct 2021 --> Mar 2022

The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.

The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.

A novel morphological classification system is described and used to demonstrate that PDAs with G12V/R mKRAS are enriched for the P/LD variant. Furthermore, patients with G12V/R PDAs have significantly improved OS as compared to those with G12D. Our work highlights the morphological and clinical significance of different KRAS mutations in PDA.