ROS1 mutation

P1/2, N=215, Active, not recruiting, NeoImmuneTech | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Nov 2024 | Recruiting --> Active, not recruiting

This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

In vitro, PBRM1 knockdown promoted resistance to cisplatin through boosting STAT3 signaling in cervical cancer cells, while it sensitized tumor cells to poly-ADP-ribose-polymerase inhibitor olaparib. These findings suggest that mutant PBRM1 is a potential ctDNA marker of emerging resistance to NACT and of increased sensitivity to olaparib, which warrants further clinical validation.

No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

P1/2, N=22, Active, not recruiting, Coherus Biosciences, Inc. | Recruiting --> Active, not recruiting | N=100 --> 22

P1, N=18, Active, not recruiting, Palobiofarma SL | Trial completion date: Dec 2023 --> Aug 2024 | Trial primary completion date: Oct 2023 --> May 2024

We validated multiscale radiomic signatures across tumor genotypes and immunophenotypes in a multi-institutional cohort. This imaging-based biomarker offers a non-invasive approach to select patients with NSCLC who are sensitive to targeted therapies or immunotherapy, which is promising for developing personalized treatment strategies during therapy.

Lung cancer displays differences by age at diagnosis which may have important implications for its clinical management.

P=N/A, N=100, Recruiting, Hunan Province Tumor Hospital | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

Cadonilimab 10 mg/kg Q3W plus anlotinib showed manageable safety and promising efficacy as a first-line chemo-free treatment for advanced NSCLC.

We reported a patient with lung adenocarcinoma who developed EGFR-T790M mutation after first-line treatment with icotinib and sarcoma transformation after second-line treatment with almonertinib. Sarcoma transformation can be one of the forms of drug resistance in patients with lung adenocarcinoma with EGFR-TKIs. The prognosis of patients with adenocarcinoma after transformation into sarcoma is poor.

P4, N=120, Recruiting, Shandong First Medical University Affiliated Cancer Hospital; Shandong First Medical University Affiliated Cancer Hospital

P1/2, N=238, Recruiting, NeoImmuneTech | Phase classification: P1b/2a --> P1/2

P1/2, N=242, Recruiting, Roswell Park Cancer Institute | Trial completion date: Dec 2023 --> Dec 2027 | Trial primary completion date: Dec 2023 --> Dec 2027

Furthermore, we identified DICER1 mutations, one of which is previously unreported in thyroid lesions. For these less common alterations and for patients with unknown drivers, we provide signaling information applying TCGA-derived classification.

In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.

P1, N=56, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2024 --> Oct 2023

The KRAS G12C, KRAS other and KRAS WT cohorts had similar patient and treatment patterns, although smoking history was more common in pts with a KRAS mutation. In the absence of other key driver mutations, there was no significant difference in mOS between cohorts.

NGS testing in NSCLC patients allows for the detection of multiple additional gene alterations, which have the potential to inform therapeutic decision-making. Based on the current number of actionable oncogenes and ongoing clinical trials investigating new ones, NGS is potentially cost-saving compared to sequential testing for all known targetable genomic alterations. Further studies should be conducted to validate this hypothesis.

P2, N=16, Completed, Wake Forest University Health Sciences | Trial completion date: Apr 2018 --> Oct 2022

Patients with a concordant treatment had a significant longer OS as patients with a discordant treatment. The concordance rate was higher in the group of driver-mutated patients and patients with a driver-mutation and a concordant treatment showed a longer OS as patients without. Assessment of concordance to MTB recommendations could become a meaningful and reproducible quality criterion for cancer centers in Germany.

The cohort’s clinical characteristics contrasted ROS1 -fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

P2, N=120, Not yet recruiting, Chongqing University Cancer Hospital

The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

This retrospective study aimed to evaluate the mortality risk and overall survival (OS) of metastatic NSCLC patients who received first-line pembrolizumab plus carboplatin doublet chemotherapy or pembrolizumab alone — aligned with KEYNOTE-189 and KEYNOTE-024 trials, in the real-world setting of oncology practice in Australia. The real-world survival outcomes for metastatic NSCLC patients was inferior in the pembrolizumab-chemotherapy group but pembrolizumab alone conveyed survival benefit comparable to trial results.

A molecular subset (∼13%) has ROS1 mutations, which is an actionable driver mutation. ROS1-mutated patients have improved overall survival likely due to high mutational burden.

P2, N=16, Completed, Wake Forest University Health Sciences | Active, not recruiting --> Completed

P3, N=643, Active, not recruiting, Shanghai Henlius Biotech | Recruiting --> Active, not recruiting | Trial primary completion date: Feb 2023 --> Oct 2023

Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Conclusions We identified that ROS1 mutation predicted the resistance to ICIs in HNSCs. The clinical delivery of ICIs should be cautious in those patients.

This study represents a comprehensive clinical investigation of LUAD patients with tumors harboring <5%, 5-45%, and 50% of acinar separately. The results show that LUAD patients with 50% acinar have significantly worse OS than patients with 5-45% acinar. This study also shows that having at least a 5% acinar component is an independent indicator of poor prognosis in LUAD.

Patients with a concordant treatment had a significant longer OS as patients with a discordant treatment. The concordance rate was higher in the group of driver-mutated patients and patients with a driver-mutation and a concordant treatment showed a longer OS as patients without. Assessment of concordance to MTB recommendations could become a meaningful and reproducible quality criterion for cancer centers in Germany.

We have established a model that can predict the efficacy of ICIs immunotherapy in PD-L1 positive patients. The model consists of ROS1 gene mutations, KRAS gene mutations, tumor staging, and endocrine system disease history, and has good predictive ability.

There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib...To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.

Conclusion ROS1 IHC assessment in lung cancer as a screening tool is helpful to suspect molecular alterations in positive cases, revealing ROS1 rearrangement and/or other oncogenic driver mutations.Evaluation with the FISH technique should be performed.In discordant cases with no molecular correlation of ROS1, ALK, KRAS, or EGFR; NGS or RT-PCR for ROS1 can be run to exclude rare mutations or undetected fusion partners with FISH. ROS-1 rearrangement can have co-mutations with EGFR, KRAS, and ALK setting a challenge for medical treatment.

P=N/A, N=698, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1/2, N=100, Recruiting, Coherus Biosciences, Inc. | Not yet recruiting --> Recruiting

Selection criteria included: Tempus xT targeted NGS, known PD-L1 status, absence of EGFR, ALK and ROS1 mutations, and treatment with chemotherapy (CT) + pembrolizumab (P), or P only... This largest RWD analysis to date demonstrates that 1L KRAS G12C NSCLC patients with TPS

P1, N=60, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway...All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations.Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +Afatinib sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++PI3K/ mTOR inhibitorAll cell lines sensitiveCDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1NGSCCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutationSTK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutationKRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutationCDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutationCCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutationCCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutationCDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutationCCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutationFAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B lossOutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)Potential treatmentsAll sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried(1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics(1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi & CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi(1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,& p53 reactivator(1) Taxane &5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi(1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator(1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/ DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp... Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC.

In this study, after excluding NSCLC patients harboring driven oncogenes as EGFR, ALK and ROS1 mutation, twenty NSCLC patents with higher Programmed cell death 1 ligand 1 (PD-L1) expression (PD-L1 ≧ 50%, immunohistochemical stained by SP263 or 22C3) were administered with Pembrolizumab alone as first-line immunotherapy...In conclusion, NGS analysis was recommended even the NSCLC patients with higher PD-L1 expression before immunnotherapy. First-line ICIs monotherapy should be cautious for oncogene-driven NSCLC patients.