Immunotherapy in non-small cell lung cancer harbouring driver mutations

Addeo, Alfredo; Passaro, Antonio; Malapelle, Umberto; Banna, Giuseppe Luigi; Subbiah, Vivek; Friedlaender, Alex

doi:10.1016/j.ctrv.2021.102179

Cited by 76 publications

(53 citation statements)

References 98 publications

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“…Data related to TMB among patients with RET fusion-positive NSCLC are limited. Among the available studies, most have reported a presence of low/intermediate TMB (often defined as either ≤5, <10 or <20 mutations per megabase) in majority of the included patients with RET fusion-positive NSCLC [19,22,33,[49][50][51][52]. Likewise, data related to the level of PD-L1 expression in this patient population are not consistent.…”

Section: Discussionmentioning

confidence: 85%

Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer

et al. 2021

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Aim: To describe outcomes of patients with RET fusion-positive non-small-cell lung cancer (NSCLC) who received immune checkpoint inhibitor (ICI)-based treatments in the US. Patients & methods: Using de-identified Flatiron Health-Foundation Medicine NSCLC Clinico-Genomic and Guardant Health databases, treatment patterns and outcomes of 69 patients with advanced/metastatic RET fusion-positive NSCLC who received ICI-based treatment were described. Results: Median real-world progression-free survival and overall survival months were 4.2 (95% CI: 1.4–8.4) and 19.1 (6.9–not reached), respectively, among patients in Clinico-Genomic database (n = 17) receiving first-line ICI-based therapy. In the Guardant Health database, progression-free survival was unavailable, and the median overall survival was not reached (n = 29). Conclusion: Outcomes associated with ICI-based treatments in the first-line setting among patients with RET fusion-positive NSCLC are consistent with unselected populations reported in literature.

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Section: Discussionmentioning

confidence: 85%

Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer

et al. 2021

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“…RET + NSCLC usually occurs in patients with a history of no tobacco use or minimal smokers, which could be the link to lower TMB. This lower TMB renders them as ‘cold tumors’ that have an immune-poor microenvironment, rich in regulatory T cells, and poor in activated T cells, responding less to checkpoint inhibitors [ 65 ]. However, TMB and tumor microenvironment (TME) are dynamic as T cell-inflamed TME seems to positively correlate with responsiveness to ICIs and adoptive cell therapy.…”

Section: Treating Ret -Altered Cancersmentioning

confidence: 99%

“…However, TMB and tumor microenvironment (TME) are dynamic as T cell-inflamed TME seems to positively correlate with responsiveness to ICIs and adoptive cell therapy. Therefore, future studies should look into opportunities to convert these ‘cold’ oncogene-driven tumors to hot tumors [ 65 ].…”

Section: Treating Ret -Altered Cancersmentioning

confidence: 99%

Precision therapy for RET-altered cancers with RET inhibitors

et al. 2021

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Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks. HighlightsRearranged during transfection (RET) is an oncogenic driver activated by either RET fusions or mutations. RET fusions occur predominantly in 2% of lung cancers and 10-20% of thyroid cancers and in low frequency in an increasing number of diverse cancers.Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been successfully translated to the clinic and are FDA approved.Data on acquired resistance to RETspecific inhibitors are rapidly emerging but not fully understood. However recent studies have suggested on-target mutations at non-gatekeeper sites or emergence of off-target alterations such as MET amplification or NTRK fusion as mechanisms of acquired resistance.

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“…Roles for RET in the more recently proposed 'emerging hallmarks' and 'enabling characteristics' remain to be more directly examined, but at least early reports suggests RET-driven cancers (both MTC and NSCLC) have a low tumor-mutational burden and characterized by lower PD-L1 expression (37,38). In addition studies have shown modifications of tumor microenvironment associated to RET-familial MTC/multiple endocrine neoplasia 2 and -associated oncoproteins (39) Herein, it is highly possible that RET-driven cancers are biologically 'cold' (40). Thus, the impact of RET on oncogenesis goes well beyond simply enhancing cell proliferation.…”

Section: Ret and The Hallmarks Of Cancermentioning

confidence: 99%

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

Adashek

Desai

Andreev-Drakhlin³

et al. 2021

Molecular Cancer Therapeutics

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Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers.Herein, we review the registrational data from the selective RETinhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRAS G12C inhibition.

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Immunotherapy in non-small cell lung cancer harbouring driver mutations

Cited by 76 publications

References 98 publications

Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer

Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer

Precision therapy for RET-altered cancers with RET inhibitors

Hallmarks of RET and Co-occuring Genomic Alterations inRET-aberrant Cancers

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