HALT: targeted therapy with or without dose-intensified radiotherapy in oligo-progressive disease in oncogene addicted lung tumours

511 Background: The aim of the present study was to profile the metastatic lesion of pts using high throughput technologies, and to treat them accordingly. Methods: SAFIR01 trial aimed to include 400 pts with MBC, selected for not presenting a progressive disease at the time of biopsy. A biopsy was done in a metastatic site. DNA was extracted if the tumor contained >50% cancer cells, and sent to one of the 5 genomic centers who performed array CGH (copy number changes) and sanger sequencing on PIK3CA (exon 10/21) and AKT1 (exon 3). A targeted therapy matched to the genomic alteration was expected to be proposed at the time of progressive disease. The primary endpoint was the % of pts who received a targeted therapy according to the genomic alteration. Results: A biopsy of metastatic site was done successfully in 408 out of the 423 included pts. Biopsy was complicated by a serious adverse event in 9 pts. A discrepancy between primary and metastatic lesion was observed in 8% and 19% of pts for Her2 and HR. Array CGH and sequencing were successfully obtained in 277 (68%) and 295 (72%) pts. The main reason for failure of genomic test was the low cellularity (n=93). A targetable genomic alteration was identified in 204 pts. The most frequent genomic alterations were PIK3CA mutations, CCND1, FGF4 and FGFR1 amplifications. 76 pts presented a rare targetable genomic alteration (<5%), including AKT1 mutations, EGFR, FGFR2, PIK3CA, MDM2 amplifications. Early Feb 2013, 4 6 out of 277 pts with genomic analyses (17%) had received a targeted therapy matched to the genomic alteration, covering twelve different targets. Updated results on number of pts treated, together with efficacy data will be presented. Next generation sequencing on metastatic lesions is ongoing and results will be presented. Conclusions: This trial evaluated the concept of personalized medicine for MBC and provided a large scale genomic analysis of metastatic tissue. This study suggests that assessing the biology of metastatic tissue could allow driving pts to targeted therapy. A randomized trial (SAFIR02) testing this approach is expected to start during summer 2013. Clinical trial information: NCT01414933.

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125: HALT: Targeted therapy beyond progression with or without dose-intensified radiotherapy in oligoprogressive disease in oncogene addicted lung tumours

Lung Cancer ◽

10.1016/s0169-5002(17)30175-7 ◽

2017 ◽

Vol 103 ◽

pp. S57 ◽

Cited By ~ 1

Author(s):

F. McDonald ◽

M. Guckenberger ◽

S. Popat ◽

N. Andratschke ◽

L. Kilburn ◽

...

Keyword(s):

Targeted Therapy ◽

Lung Tumours

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Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

Cancers ◽

10.3390/cancers13112725 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2725

Author(s):

Sandra N. Freiberger ◽

Patrick Turko ◽

Martin Hüllner ◽

Reinhard Dummer ◽

Grégoire B. Morand ◽

...

Keyword(s):

Targeted Therapy ◽

Cutaneous Melanoma ◽

Primary Tumor ◽

Progressive Disease ◽

Causal Relation ◽

Resistance Mechanisms ◽

Mucosal Melanoma ◽

Recurrent Event ◽

Driver Mutations ◽

Molecular Testing

Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.

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Hypoalbuminaemia as a Prognostic Biomarker of First-Line Treatment Resistance in Metastatic Non-small Cell Lung Cancer

Frontiers in Nutrition ◽

10.3389/fnut.2021.734735 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mark Stares ◽

Amanda Swan ◽

Kirsten Cumming ◽

Tze-En Ding ◽

James Leach ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Progressive Disease ◽

Treatment Resistance ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Metastatic Nsclc ◽

Pre Treatment

Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC.Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined.Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23–2.7) (p =0.003) and HR2.55 (95%CI 1.78–3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20–41.72, p = 0.003) and RR3.60 (95%CI 1.74–6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86–4.46) (p < 0.001) and HR2.67 (95%CI 1.74–4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61–3.82) (p < 0.001) and HR2.87 (95%CI 1.91–4.31) (p < 0.001) respectively).Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.

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Targeted Therapy With or Without Dose-intensified Radiotherapy in Oligoprogressive Disease in Oncogene Addicted Lung Tumours

Clinical Oncology ◽

10.1016/j.clon.2018.02.062 ◽

2018 ◽

Vol 30 (6) ◽

pp. e64-e65

Author(s):

F. McDonald ◽

M. Guckenberger ◽

S. Popat ◽

C. Faivre-Finn ◽

N. Andratschke ◽

...

Keyword(s):

Targeted Therapy ◽

Lung Tumours

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LGG-16. TO BE PRECISE - KNOW YOUR TARGETS: INSTITUTIONAL EXPERIENCE WITH TUMOR TARGETED THERAPY FOR RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA AND PLEXIFORM NEUROFIBROMA

Neuro-Oncology ◽

10.1093/neuonc/noab090.140 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i35-i35

Author(s):

Mackenzie Silverman ◽

Joseph Piatt ◽

Andrew Walter ◽

Rahul Nikam ◽

Gurcharanjeet Kaur

Keyword(s):

Targeted Therapy ◽

Targeted Therapies ◽

Progressive Disease ◽

Plexiform Neurofibroma ◽

Cns Tumors ◽

Low Grade ◽

Therapy Initiation ◽

Community Oncology ◽

Institutional Experience ◽

Pediatric Cns Tumors

Abstract Introduction The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG). Methods We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years. Results Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology. Conclusion Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.

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Update on Targeted Therapy in Medullary Thyroid Cancer

Frontiers in Endocrinology ◽

10.3389/fendo.2021.708949 ◽

2021 ◽

Vol 12 ◽

Author(s):

Christian Okafor ◽

Julie Hogan ◽

Margarita Raygada ◽

Barbara J. Thomas ◽

Srivandana Akshintala ◽

...

Keyword(s):

Thyroid Cancer ◽

Targeted Therapy ◽

Progressive Disease ◽

Medullary Thyroid Cancer ◽

Kinase Inhibitors ◽

Mechanisms Of Resistance ◽

Medullary Thyroid ◽

Resistant Disease ◽

Sporadic Cases ◽

Novel Therapeutic

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that accounts for 2-4% of all thyroid cancers. All inherited MTC and approximately 50% of sporadic cases are driven by mutations in the REarranged during Transfection (RET) proto-oncogene. The recent expansion of the armamentarium of RET-targeting tyrosine kinase inhibitors (TKIs) has provided effective options for systemic therapy for patients with metastatic and progressive disease. However, patients that develop resistant disease as well as those with other molecular drivers such as RAS have limited options. An improved understanding of mechanisms of resistance to TKIs as well as identification of novel therapeutic targets is needed to improve outcomes for patients with MTC.

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