The genomic landscape of gene fusions across solid tumors and clinical outcome of targeted therapies: A real-world retrospective analysis.

3132 Background: Oncogenic gene fusions can be observed across numerous solid tumor types with therapies targeting fusion events emerging as important treatment modalities. The occurrence of rare fusion events and response to targeted therapy inclusive of off-label drug use has not been fully elucidated. We describe a real-world (RW) landscape of gene fusions in solid tumors and treatment outcomes of targeted therapies. Methods: Patients with solid tumors harboring a gene fusion or rearrangement were retrospectively identified through review of a clinical molecular database housing sequencing data on 6,800 patients from a single-center between 1/1/2015 – 12/31/2019. Patients who received targeted therapy for gene fusions were divided into three arms: off-label, on-label, and clinical trial use. Clinical characteristics were summarized using descriptive statistics. Overall survival (OS) and Progression free survival (PFS) between the three arms were compared using the Kaplan-Meier estimates. Results: A total of 336 (4.9%) patients had a fusion positive solid tumor with 197 (2.9%) having a fusion event predicted to be oncogenic and could be targeted with a drug. Thirty different cancer types had targetable fusions with the three most common types being lung adenocarcinoma (41%), glioblastoma (10.2%), and melanoma (7.1%). The most common observed targetable fusions included ALK (21.3%), RET (11.7%), ROS1 (9.1%), and FGFR2 (8.1%). A total of 71 patients received targeted therapy; 37 (52%) received therapies on-label, 20 (28%) off-label, and 14 (20%) on-trial (Table). The median PFS was 4 months for off-label, 16 months for on-label, and 9 months for on trial-therapy (p=0.02). The median OS was 8 months for off-label, 51 months for on-label, and 11 months for on-trial therapy (p=0.001). Seven out of twenty patients (35%) in the off-label group had PFS for at least 6 months. Three patients had a response for more than one year. However, higher toxicity related discontinuation rate was observed (30%, 8%, 7% for off-label, on-label, and on-trial, p=0.03). Conclusions: Off-label targeted therapy had shorter PFS and OS when compared to on-label therapy. However, 35% patients in the off-label group had at least 6 months PFS. Off-label therapy remained a valuable option for patients who were not candidate for clinical trials or with rare fusions. Further studies are needed to determine which patients are most likely to benefit from targeting gene fusion events.[Table: see text]

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Off-label targeted therapy (TT) use in recurrent/metastatic NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18688 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18688-e18688

Author(s):

Victoria Wang ◽

Chenming Cui ◽

Lei Yang ◽

Gerald Li ◽

Alexa Betzig Schrock ◽

...

Keyword(s):

Targeted Therapy ◽

Clinical Efficacy ◽

Real World ◽

Survival Advantage ◽

Genomic Alteration ◽

Genomic Profiling ◽

Off Label ◽

Number Of Patients ◽

Tier System ◽

Line Of Therapy

e18688 Background: Comprehensive genomic profiling (CGP) is an established diagnostic approach to select patients for TT. As CGP gains wide adoption, an increasing number of patients are found to harbor driver mutations for which no approved TT is available. This is often addressed through use of matched TKI and mAb approved for other mutations or anatomic sites. In this work, we examined the clinical efficacy of off-label TT in R/M NSCLC. Methods: Using a de-identified NSCLC clinico-genomic database (CGDB), we identified 6590 NSCLC patients who underwent Foundation Medicine CGP, of whom 17.8% harbored an actionable genomic alteration (GA) for which an FDA-approved TT was available and 2% (133) whose GA (MET ex-14, uncommon EGFRm, EGFR ex20ins, HER2 amp/mut, RET fusion, BRAF class 2/3) lacked an FDA-approved TT (62 in 1L and 71 in ≥2L ) who received matched off-label TT. ESMO Scale for Clinical Actionability (ESCAT) was used to grade levels of evidence. For patients who progressed on initial chemotherapy (range 2 – 9 lines, median 3), we calculated clinical efficacy using the ratio of real world PFS on targeted therapy (rw-PFS2) to rw-PFS on the last prior line of therapy (rw-PFS1) and used a cut-off of PFS2/PFS1 > 1.3 to determine off-label drug efficacy. Results: Of the 133 patients reviewed, 72 were classified as ESCAT level IB (uncommon EGFRm, MET-ex14), 45 IIB (HER2m/amp, EGFR ex-20ins), 7 IC (RET fusions). PFS varied significantly by mutation and line of therapy (table 1) with uncommon EGFRm+ and MET-ex14 exhibiting best response while EGFR ex20 ins, BRAF class 2/3 and HER2 amp fared significantly worse. 55.8% of the patients (39 of 71) reached a PFS2/PFS1 ratio > 1.3 (two-sided 95% CI, 45.3 % – 68.7 %), ranging from 93% in uncommon EGFRm+ down to 20% in HER2 amp and 44% in ex20ins. Conclusions: We provide real-world evidence to assess off-label TT in NSCLC. Clinical benefit derived from off-label TT is unevenly distributed across various mutations with most survival advantage accruing to specific mutations (MET-ex14 and uncommon EGFRm) at the expense of others (HER2 amp). Survival advantage was highly influenced by two factors: A) the timing of CGP with the earlier recipients of genomic profiling achieving better outcome, B) the identity of the driver mutation, highlighting the role of clinical actionability tier system to define level of evidence supporting such intervention.[Table: see text]

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Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

JCO Precision Oncology ◽

10.1200/po.16.00046 ◽

2017 ◽

pp. 1-19 ◽

Cited By ~ 12

Author(s):

W. Brian Dalton ◽

Patrick M. Forde ◽

Hyunseok Kang ◽

Roisin M. Connolly ◽

Vered Stearns ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Targeted Therapies ◽

Progression Free Survival ◽

Molecular Profiling ◽

Tumor Board ◽

Free Survival ◽

Off Label ◽

Tumor Boards ◽

Molecular Tumor Board

Purpose Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. Methods A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration–approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. Results One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months ( 95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43% (95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. Conclusion The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

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Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20568 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20568-e20568

Author(s):

Michael Gregory Cushion ◽

Bhavani Krishnan ◽

Jeff Paul Hodge ◽

Jaya Chandra Balusu ◽

Joseph Wagner ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Targeted Therapy ◽

Real World ◽

Targeted Therapies ◽

Claims Data ◽

Molecular Testing ◽

Insurance Claims ◽

Insurance Claims Data ◽

Nsclc Patients

e20568 Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]

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Targeted therapy in gastrointestinal stromal tumor (GIST): A nationwide database analysis from Taiwan.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.437 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 437-437

Author(s):

I-Jen Chiang ◽

Wen-Yi Shau ◽

Wei-Tse Fang ◽

Chi-Hui Fang ◽

Yen-Yang Chen

Keyword(s):

Targeted Therapy ◽

Gastrointestinal Stromal Tumor ◽

Dose Escalation ◽

Targeted Therapies ◽

Standard Dose ◽

Stromal Tumor ◽

Treatment Modalities ◽

Research Database ◽

Line Treatment ◽

First Line

437 Background: Gastrointestinal stromal tumor (GIST) is a visceral sarcoma that arises from the gastrointestinal tract. Currently, imatinib (first-line) and sunitinib (second-line) are two reimbursed targeted therapies for GIST in Taiwan. This study aimed to evaluate the real world data of targeted therapies in GIST treatment among Taiwanese population. Methods: We conducted a nationwide retrospective cohort study based on data from the National Health Insurance Research Database (NHIRD) between January 2005 and December 2010. NHIRD is a comprehensive database of administrative and claim data which covers over 99% of entire population in Taiwan. Patients were selected with ICD codes and targeted therapy utilization, imatinib (IMA) or sunitinib (SUN). Time to treatment discontinuation (DC) due to any reasons (such as death, intolerance and disease progression) was estimated using Kaplan-Meier analysis. Results: From 2005 to 2010, the incidence rate of GIST in Taiwan was between 20 and 30 cases per million. A total of 3,436 GIST patients were identified; the mean age was 63.2 years and 57 % were male. Most patients (94.7%) received standard dose IMA (…400mg/day). Among these patients, 136 patients (4.0%) required IMA dose escalation and 44 (1.3%) patients switched to SUN after IMA. The probability of the 1st-line treatment DC was 20%, 30.7%, 38.9%, 43.2%, and 47.1% for years 1 to 5, respectively. The probability of a change in treatment pattern (defined as either IMA dose escalation or switch to SUN) was 4% 6.8%, 9.6%, 10.5% and 11.7% for years 1 to 5. Lastly, the probability of the 2nd-line treatment DC was 20.5%, 33.7%, 41.1%, 44.8%, 51.7% for years 1 to 5, respectively. Conclusions: First-line IMA plus other treatment modalities may provide additional benefits to progression-free survival. Taiwanese GIST patients who failed first-line treatment still gained benefit from either IMA dose escalation or a switch to SUN. Additional analysis is required for the detailed comparison in different treatment patterns.

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Clinical Benefit and Agenda for Clinical Sequencing Using Cancer Panel Testing: A Retrospective Clinical Study

10.21203/rs.3.rs-44809/v1 ◽

2020 ◽

Author(s):

Sadaaki Nishimura ◽

Atsushi Sugimoto ◽

Shuhei Kushiyama ◽

Shingo Togano ◽

Kenji Kuroda ◽

...

Keyword(s):

Targeted Therapy ◽

Clinical Study ◽

Solid Tumors ◽

Gene Panel ◽

Off Label Use ◽

Clinical Sequencing ◽

Off Label ◽

Panel Testing ◽

Retrospective Clinical Study ◽

Label Use

Abstract Background: Clinical sequencing using a multiplex gene panel has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using multiplex gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospitalMethods: A total of 28 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 26 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors.Results: Pathogenic alterations were detected in 20 (77%) of the 26 patients. The most common mutation was TP53 (6/26, 35%), followed by KRAS (5/26, 19%), and the highest frequency of gene amplification was ERBB2 (5/26, 19%). Five of the 26 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but none of the cases had an advantage for novel targeted therapy following the genetic tests; the reasons were clinical deterioration, refusal for off-label use, and complexity of clinical trial access.Conclusions: Our current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.Trial registration: This study was performed as a part of clinical study approved by Ethical Committee of Osaka City University Graduate School of Medicine (Permission number: 4199, 3925)

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Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15072 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15072-e15072

Author(s):

Libin Xu ◽

Ming Liu ◽

Jingxian Duan ◽

Tao Wang

Keyword(s):

Cancer Patients ◽

Solid Tumors ◽

Solid Tumor ◽

Coiled Coil ◽

Genetic Alterations ◽

Chinese Patients ◽

Driver Mutations ◽

Gene Fusions ◽

Fgfr3 Gene ◽

Tumor Types

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]

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Targeted Therapy Recommendations for Therapy Refractory Solid Tumors—Data from the Real-World Precision Medicine Platform MONDTI

Journal of Personalized Medicine ◽

10.3390/jpm10040188 ◽

2020 ◽

Vol 10 (4) ◽

pp. 188

Author(s):

Hossein Taghizadeh ◽

Matthias Unseld ◽

Martina Spalt ◽

Robert M. Mader ◽

Leonhard Müllauer ◽

...

Keyword(s):

Targeted Therapy ◽

Precision Medicine ◽

Solid Tumors ◽

Real World ◽

Molecular Profile ◽

Tumor Type ◽

Therapy Recommendations ◽

Dismal Prognosis ◽

Advanced Therapy ◽

Therapy Recommendation

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

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Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets

Journal of Clinical Pathology ◽

10.1136/jclinpath-2015-203394 ◽

2015 ◽

Vol 69 (5) ◽

pp. 403-408 ◽

Cited By ~ 23

Author(s):

Hwajeong Lee ◽

Kai Wang ◽

Adrienne Johnson ◽

David M Jones ◽

Siraj M Ali ◽

...

Keyword(s):

Targeted Therapy ◽

Intrahepatic Cholangiocarcinoma ◽

Targeted Therapies ◽

Genomic Profiling ◽

Gene Fusions ◽

Single Patient ◽

Genomic Alterations ◽

Extrahepatic Cholangiocarcinoma ◽

Long Tail ◽

Comprehensive Genomic Profiling

AimWe queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy.MethodsComprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma.ResultsThere were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0–13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified.ConclusionsComprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies.

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