ALK rearrangement

P1, N=40, Recruiting, Astellas Pharma Global Development, Inc.

After about 20 years of exciting improvements in treatment efficacy outcomes of advanced epidermal growth factor receptor (EGFR) mutant and anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC), also combined with a progressively better safety profile, from chemotherapy to new generation tyrosine kinase inhibitors (TKIs) (osimertinib, alectinib, brigatinib), the recent MARIPOSA and CROWN trials have changed this trend. The story would be easy and totally positive if these two innovative, amazing treatments were not associated with new peculiar features in safety profiles that must be discussed with patients, because they potentially affect their quality of life. When treating these patient populations, the peculiar safety profiles of amivantamab plu lazertinib and lorlatinib require a well-structured shared decision making, "where and when", both the high probability of a longer survival and the risk of worse quality of life must be well announced and explained to our patients before the shared final treatment choice.

In addition, germline mutations are present in a subset of patients with mesothelioma and primarily involve genes in the DNA repair and cell cycle regulation and are more common in patients who are young, with family history of mesothelioma, or with peritoneal mesothelioma. In this review, we discuss the considerable heterogeneity of mesothelioma, the diversity of radiologic and gross presentation, various morphologic features with distinctive histologies and ultimately, we individually describe subsets of tumors characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion, as well as the implications of these findings on the diagnostic workup.

The use of immunotherapy in real life in 2020 in France shows an apparent gap with national guidelines that is more marked in cases of squamous cell NSCLC or with PD-L1 expression<50% with less exposure of patients to the immunotherapy-chemotherapy combination compared to current recommendations. This gap could be partly explained by the progressive reimbursement schedule of pembrolizumab and by other factors not documented in KBP-2020-CPHG.

RNA sequencing revealed an in-frame fusion between TPM4 Exon 8 and ALK Exon 20. Conservative excision was performed and recurrence has not been observed at one-year follow-up.

Outcomes with targeted therapy, primarily in the adjuvant setting, for NSCLC harboring EGFR mutations or ALK rearrangements are summarized, and the importance of identifying these patients upfront is emphasized. Throughout, pending results and active areas of investigation are highlighted.

ALK+ squamous and adenosquamous NSCLCs are rare, but biologically distinct, with inferior outcomes on 1L ALK TKI, highlighting the need for further research to develop effective treatment strategies.

Emerging targeted therapies and immunotherapeutic strategies show promise for these rare RCCs, emphasizing the need for subtype-specific clinical research. This review provides a comprehensive overview of the histological and molecular rare variants of RCC, highlights diagnostic innovations, and discusses the implications of these insights for precision medicine and future therapeutic development in kidney cancer.

This is the largest NSCLC dataset analyzed for biomarker distribution across histologies, age, sex and genetic ancestry. This dataset confirms sufficient enough biomarker prevalence across many histological subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

AI shows promising potential to support diagnosis, prognostication, and treatment assessment in ALK-rearranged lung cancer. However, methodological heterogeneity, limited external validation, and a lack of prospective studies currently constrain clinical translation.