ROS1 mutation

P4, N=100, Not yet recruiting, Anhui Chest Hospital; Anhui Chest Hospital

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

Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.

Identifying ctDNA mutations by targeted sequencing in plasma is feasible, showing the clinical value of ctDNA-targeted sequencing in NSCLC patients when tumor tissue sampling is insufficient or even impossible.

Conclusions : The integration of ODxTT alongside single gene tests provides significant additional information without compromising the performance of single gene tests. With ODxTT's high success rate, this integration expands the scope of comprehensive therapeutic strategies for advanced lung cancer.

No abstract available

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