A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with <i>RET</i>-altered cancers.

Drilon, Alexander; Subbiah, Vivek; Oxnard, Geoffrey R.; Bauer, Todd M.; Velcheti, Vamsidhar; Lakhani, Nehal; Besse, Benjamin; Park, Keunchil; Patel, Jyoti D.; Cabanillas, Maria E.; Johnson, Melissa L.; Reckamp, Karen L.; Boni, Valentina; Loong, Herbert H.; Schlumberger, Martin; Solomon, B.; Cruickshank, Scott; Rothenberg, S. Michael; Shah, Manisha H.; Wirth, Lori J.

doi:10.1200/jco.2018.36.15_suppl.102

Cited by 100 publications

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“…This suggests that future analyses of ATC samples and outcomes should focus on genes with targeted therapy options available. RET and NTRK inhibitors have shown promise in early clinical trials, despite their low prevalence of these GA in our dataset, thyroid cancers with fusions involving ALK , RET , or NTRK may respond to targeted therapy . RET genomic abnormalities have special therapeutic significance, as novel RET inhibitors show promising results.…”

Section: Discussionmentioning

confidence: 85%

“…RET and NTRK inhibitors have shown promise in early clinical trials, 22 despite their low prevalence of these GA in our dataset, thyroid cancers with fusions involving ALK, RET, or NTRK may respond to targeted therapy. 23 RET genomic abnormalities have special therapeutic significance, as novel RET inhibitors show promising results. RET E511K is specifically associated with increased oncogenic potential in thyroid cancer 24 and is considered an activating mutation permitting enrollment onto ongoing clinical trials of RET inhibitors (NCT03157128).…”

Section: Discussionmentioning

confidence: 99%

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Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

Xie

Gerber

et al. 2019

Head & Neck

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Introduction Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Those ATC with genomic alterations (GAs) in TSC2, ALK, and BRAF may respond to targeted therapies. Methods Comprehensive genomic profiling on 90 ATC specimens identified base substitutions, short insertions and deletions, amplifications, copy number alterations, and genomic rearrangements in up to 315 cancer‐related genes and 28 genes commonly rearranged in cancer. Results Median patient age was 65 (range, 33‐86) years, 50 patients were male. There was a mean of 4.2 GA per case, range 1‐11. The most common GA were TP53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), and NRAS (26%). BRAF V600E and NRAS/HRAS/KRAS alteration were mutually exclusive. BRAF, CDKN2A, PIK3CA, and JAK2 were more frequent in patients >70 years of age; while myc, PTEN, and NRAS were more common in those ≤50 years. Conclusion ATC shows many GA with potential therapeutic significance and suggesting different molecular pathways can lead to ATC.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

Xie

Gerber

et al. 2019

Head & Neck

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“…Not listed [28] PIK3CA inhibitors such as alpelisib [26] Breast cancer PI3K-AKT-mTOR pathway activation ALK TPM3-ALK, TPM4-ALK Inflammatory myofibroblastic tumor ∼ 50% [29] ALK inhibitors [30] such as alectinib [31] Non-small cell lung cancer ALK pathway activation [32] NOTCH1 Loci not specified Aging esophagus 12-80% [33] No specific inhibitors approved Colon cancer Wnt-betacatenin pathway activation [34] KRAS G12V or G12D Arteriovenous malformations in brain ∼ 63% [35,36] MEK inhibitors such as trametinib [16] Colorectal and pancreatic cancer RAS-RAF-MEK-ERK pathway upregulation [15] G12C, G12V, G12A, G12D, G12R…”

Section: H1047l H1047rmentioning

confidence: 99%

“…Interestingly, there is also growing evidence that the canonical theory of renegade clonal expansion in carcinogenesis [116] may not be the only manner in which malignant development proceeds. The theory of clonal Melanocytic nevi 70-88% [3][4][5][6][7][8][9][10][11][12] BRAF and/or MEK inhibitors such as dabrafenib and trametanib [13,14] Melanoma RAS-RAF-MEK-ERK pathway upregulation [15] NRAS Q61K Giant congenital melanocytic nevi 6-14% [10,11] MEK inhibitors [12] such as trametinib [16] Melanoma RAS-RAF-MEK-ERK pathway upregulation [15] Q61K and Q61R…”

Section: Introductionmentioning

confidence: 99%

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The paradox of cancer genes in non-malignant conditions: implications for precision medicine

et al. 2020

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Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate nonmalignant illnesses and/or to prevent the emergence of cancer.

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

875

697

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers.

Cited by 100 publications

References 0 publications

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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