ROS1 rearrangement

P3, N=878, Recruiting, AstraZeneca | Trial completion date: Mar 2030 --> Nov 2030 | Trial primary completion date: May 2029 --> Nov 2030

This multicentre real-world cohort describes longitudinal ROS1 management with evolving treatments. Favourable survival likely reflects reflex molecular testing, access to ROS1i, and high clinical trial enrolment.

Clinical courses were heterogeneous: one patient achieved a durable partial response using combined osimertinib and crizotinib. A second patient, intolerant to dual TKI therapy due to QTc prolongation and grade 3 edemas, achieved a sustained partial response with platinum-pemetrexed chemotherapy...However, its biological significance, driver versus passenger role, and therapeutic relevance remain uncertain. Combined EGFR and ROS1 inhibition may be considered in selected cases, but further validation is required.

The efficacy of tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, lorlatinib, entrectinib, and repotrectinib was systematically evaluated. Our findings underscore that although G2032R and L2026M mutations reside within the kinase active site, their impact extends far beyond steric hindrance, altering overall kinase domain dynamics. Collectively, these data establish a robust panel of patient-derived ROS1 cell lines that recapitulate clinical resistance patterns and, together with complementary computational modeling, provide a valuable framework to dissect ROS1 tumor biology and support rational design of next-generation inhibitors.

P2, N=33, Completed, University Health Network, Toronto | N=50 --> 33 | Recruiting --> Completed

We present the case of a 60-year-old non-smoking woman previously treated for luminal B human epidermal growth factor receptor 2 (HER2)-positive invasive breast carcinoma with surgery, AC60 chemotherapy, trastuzumab, breast radiotherapy, and hormone therapy at the Mohammed VI Oncology Center in Casablanca, Morocco. The patient received neoadjuvant vinorelbine-cisplatin chemotherapy followed by volumetric modulated arc therapy (VMAT) thoracic radiotherapy at 66 Gy, achieving clinical and radiological stabilization. This case highlights the occurrence of a second driver-negative primary lung adenocarcinoma in a non-smoker and underscores the importance of integrated histopathological, immunohisto chemical, and targeted molecular evaluation in distinguishing primary tumors from metastases, as well as the potential role of post-therapeutic carcinogenesis.

The rate of bone metastasis was significantly higher in ROS1 rearrangement-positive than in ROS1 rearrangement-negative patients. ROS1 rearrangement plays a significant prognostic role in advanced progression of LUAD; however, the generally favorable survival outcomes of early-stage LUAD may obscure its prognostic value.

In this cohort of surgically resected NSCLC, preoperative corrected serum calcium and smoking exposure were more closely associated with tumor metabolic activity than with specific molecular alterations. These findings suggest that simple clinical and biochemical parameters may provide complementary information, although their utility for discriminating individual molecular subgroups appears limited.

P1, N=16, Recruiting, Memorial Sloan Kettering Cancer Center

Immunostaining for ALK was negative, and there was no expression of PD-L1 22C3 IHC. This case report highlights an unexpected ROS1 IHC staining associated with a rare ROS1 gene rearrangement.

P=N/A, N=3400, Not yet recruiting, AstraZeneca

In the Cox model, CYP4F2 (HR = 2,846; IC 95%: 1,102-7,352; p = 0,031) and TPSB2 (HR = 3,089; IC95%: 1,053-9,060; p = 0,040) were independently biomarkers associated with shorter OS (χ² =13,128; p = 0.004), and CYP4F2 (HR = 3,167; IC95%: 1,384-7,244; p = 0,006) remained an independent predictor of shorter PFS (χ² =11.116; p = 0.011). This proof-of-concept study demonstrates that WES of ctDNA processed through the AIRGenomics platform is viable in real-world cases of advanced NSCLC treated with immunotherapy, detecting new potential candidate genes and pathways like predictive biomarkers, such as CYP4F2, ARSD, and TPSB2.