ALK-ROS1 fusion

P1/2, N=381, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Dec 2025 | Trial primary completion date: Sep 2023 --> Dec 2025

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

P1, N=115, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2024 --> Aug 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P2, N=85, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2024 --> Dec 2025

Importantly, this assay is adaptable to highly degraded RNA samples with low input amounts. Future steps involve expanding the testing to include a broader range of clinical samples as well as cell-free RNAs to further validate its applicability and reliability.

New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.

A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

Bevacizumab through an IPC resulted in a significantly improved prognosis for NSCLC patients with MPE and actionable mutations. However, patients without actionable mutations do not benefit from bevacizumab through IPC.

P1, N=115, Recruiting, Daiichi Sankyo, Inc. | Phase classification: P1b --> P1 | Trial primary completion date: Dec 2023 --> Feb 2024

P1, N=150, Recruiting, Ascentage Pharma Group Inc.

This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

P1; Trial completion date: Nov 2023 --> Dec 2025 | Trial primary completion date: Aug 2023 --> Dec 2024

P4, N=30, Not yet recruiting, Beijing Hospital; Beijing Hospital

P2, N=80, Recruiting, CSPC ZhongQi Pharmaceutical Technology Co., Ltd. | Not yet recruiting --> Recruiting

The optimized probe design of the GenMineTOP (RUO) panel significantly improves sensitivity and limit of detection for gene fusions in FFPE specimens with limited amounts of degraded RNA. The assay is also analytically and clinically validated (CAP/CLIA) for single nucleotide variants, indels, copy number variants, tumor mutation burden, etc., and is available for clinical service as GenMineTOP in Japan.

Among the 19 HTG-assay false negative samples, the preanalytical conditions were identified as the major factors impacting the assay efficiency. Overall, the HTG EdgeSeq assay offers comparable sensitivities and specificity than other RNA sequencing techniques, with the advantage that it can be used on very small and old samples collected multicentrically.

Concurrent testing in tissue and liquid biopsy in NSCLC increased the detection of EGFR mutations (47% to 64%). This has substantial implications in deciding treatment and administration targeted therapy and the consequent overall survival.

P1, N=271, Active, not recruiting, Daiichi Sankyo, Inc. | Trial completion date: Dec 2023 --> Dec 2024

The test detected all the expected ALK, RET, NTRK1, and ROS1 fusion isoforms and MET exon 14-skipping splice variants. The average TAT from extracted nucleic acids to the final variant report was 18.3 h. The Oncomine Dx Express Test in combination with the Ion Torrent Genexus System is a CE-IVD-compliant, performant, and multicenter reproducible method for NGS detection of actionable biomarkers from a range of tumor samples, providing results in a short TAT that could support timely decision- making for targeted therapeutic interventions.

RNA-based NGS can be used to detect gene fusions in NSCLC cytology cases with high concordance with FISH results. However, RNA-based NGS may have high failure rates and therefore a low threshold for reflexing inadequate cases to an orthogonal testing method is essential for comprehensive genomic profiling.

A MIG6 deletion was also found in a patient after progressing to ROS1 inhibition. Collectively, this study identifies MIG6 as a novel regulator for EGFR-mediated adaptive and acquired resistance to ALK/ROS1 inhibitors and suggests EGFR to MIG6 ratios and MIG6 damaging alterations as biomarkers to predict responsiveness to ALK/ROS1 and EGFR inhibitors.

In clinical practice, results of cfDNA NGS are highly concordant with those of tissue SOC testing in aNSCLC patients. Plasma analysis identified actionable alterations that were missed or not evaluated by tissue testing, enabling the initiation of targeted therapy. Results from this study add to the body of evidence in the support routine use of cfDNA NGS for patients with aNSCLC.

Clinical trials such as Larotrectinib for NTRK fusions show high response rates to molecularly targeted therapy (MTT) matched to TKFs in pediatric and AYA STSs... To our knowledge, this is the first systematic review of TKFs in pediatric and AYA STSs. While STSs are a heterogeneous group of diseases with distinct histologies, we observe a significant overlap of TKFs across diseases demonstrating a broad need for relevant therapies in these patients. We also observe a discordance between the percentage of pediatric and AYA patients < 18 years old with actionable TKFs and available trials, particularly evident in the ALK and ROS1 TKF-positive patient population.

P1, N=279, Active, not recruiting, Jazz Pharmaceuticals | Trial completion date: Aug 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Gene co-occurrence survival analysis showed that mPFS of pts harboring FAT3/FAT4 mutations were significantly shorter than those without FAT3/FAT4 mutations (8.9 mo vs 16.5 mo, p=0.012). Conclusions Clinical utility of ctDNA was demonstrated, not only at baseline by identifying fusion types and subgroups of ALK+ NSCLC pts that may benefit more from SAF-189s, but also at progression by tracking ALK-resistant mutations.

Despite achieving 5-year survival, two-thirds did not achieve 10-year survival. The increase of deaths from non-lung cancer in the long-term survivor, emphasizing the importance of monitoring and managing cardiovascular and other cancer complications.

More importantly, CGP-matched guideline-recommended treatment is associated with improved rwOS. Future studies are needed to understand the gap in compliance with matched targeted therapy.

Patients with NSCLC and RET fusions have a high incidence of thromboembolic events with 45% of patients experiencing a TE. Ischemic stroke was common in more than 18% of patients, particularly in males and before RET inhibitors. Anticoagulant therapy did not prevent stroke in most cases, however one third were asymptomatic.

CARMA-BROS is an adaptive observational basket-umbrella study platform suitable for generating high-quality RWD for regulatory and health funding agencies, for clinical evidence generation, and for quality assessments in health care. Though not originally specific for lung cancer, CARMA-BROS has many key elements that benefit lung cancer RWD evidence collection.

Although precision medicine based on liquid NGS remains challenging due to the low PPA for fusion genes, alectinib is active in highly selected NSCLC populations with ALK rearrangement detected by both tissue-based assays and liquid NGS. Additional analysis on resistance mechanisms using paired blood samples will be presented.

In this European cohort of patients with mNSCLC having disease progression on anti-PD-1/anti-PD-L1 and PDC, treatment regimens were heterogenous and predominantly included non-platinum chemotherapies. Poor clinical outcomes demonstrate an unmet clinical need that warrant more efficacious therapies for anti-PD-1/anti-PD-L1 and PDC-refractory patients.

Germline testing in this prospective cohort of driver positive NSCLC was able to identify PGV in 19.5% of patients which is slightly higher than what has been reported in general LC population (8-11%).

P1; Trial completion date: May 2023 --> Nov 2023 | Trial primary completion date: Mar 2023 --> Aug 2023

P1/2, N=353, Recruiting, Hutchmed | Unknown status --> Recruiting | Phase classification: P1b --> P1/2 | N=208 --> 353 | Trial completion date: Jul 2021 --> Sep 2023 | Trial primary completion date: Mar 2021 --> Sep 2023

As lung adenocarcinoma patients significantly benefit from targeted therapy, the assessment of mutational profiles using NGS could become a crucial approach in the routine management of oncological patients.

The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

Patients with co-occurring TP53/CDKN2A/B variations and ALK/RET/ROS1 rearrangements are associated with high TMB, more neoantigens, an immunosuppressive microenvironment and a worse prognosis.

P2, N=80, Not yet recruiting, CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

Three key metrics across the three groups, turnaround time (TAT), inadequacy rates and detection of actionable mutations, are shown in the Table. Overall, only 2% of specimens, diagnostic and resected tumours, failed in-house profiling due to inadequacy or for technical reasons. The improvement since centralisation of genomics in the parameters considered here is attributable to obsessive attention to tissue stewardship, increased efficiency in the pathway generally, (including at the GLH) and, in particular, modest expansion of our in-house profiling to include testing for EGFR mutations, which means that crucial information on common actionable mutations applicable in the first-line setting is available to clinicians early in the pathway. We suggest that the formal devolution and funding of some of the testing involved in the entire analytical process would streamline the pathway, reduce pressure on GLHs and, ultimately, improve the service for patients.

First line therapy was crizotinib, chemotherapy followed by maintenance crizotinib, ceritinib, Alectinib in 40(77%), 4(7.7%), 6(11.5%) and 2(3.8%) patients respectively. ALK and ROS1 positivity was seen in 8.1% and 2.8% of advanced NSCLC patients. Majority of patients were never smokers. Opposite lung and bone were the most common site of metastases.