Complete therapeutic response to anti-PD1 therapy in patient with advanced melanoma and resistance to targeted therapy of BRAF inhibitors

Objective: To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression. Data Source: An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection and Data Extraction: All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies. Data Synthesis: The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression. Conclusions: Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

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EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

Neuro-Oncology ◽

10.1093/neuonc/noaa215.370 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii90-ii90

Author(s):

Nikita Dhir ◽

Sheila Chandrahas ◽

Chibuzo O’Suoji ◽

Mohamad Al-Rahawan

Keyword(s):

Targeted Therapy ◽

Brain Tumors ◽

Tumor Regression ◽

Case Series ◽

Pediatric Brain Tumors ◽

Braf V600e ◽

Cns Tumors ◽

Braf Inhibitors ◽

Pediatric Brain ◽

Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

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A systematic review and network meta-analysis of immunotherapy and targeted therapy for advanced melanoma

Cancer Medicine ◽

10.1002/cam4.1001 ◽

2017 ◽

Vol 6 (6) ◽

pp. 1143-1153 ◽

Cited By ~ 17

Author(s):

Joao Paulo da Silveira Nogueira Lima ◽

Mina Georgieva ◽

Benjamin Haaland ◽

Gilberto de Lima Lopes

Keyword(s):

Systematic Review ◽

Targeted Therapy ◽

Meta Analysis ◽

Advanced Melanoma

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Advanced melanoma, a pharmacological evaluation

European Journal of Public Health ◽

10.1093/eurpub/ckab120.091 ◽

2021 ◽

Vol 31 (Supplement_2) ◽

Author(s):

Anabela Andrade ◽

Jorge Balteiro

Keyword(s):

Overall Survival ◽

Targeted Therapy ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Mek Inhibitor ◽

Advanced Melanoma ◽

New Drugs ◽

High Rate ◽

Free Survival ◽

Dismal Prognosis

Abstract Background Cutaneous melanoma is an aggressive cancer that occurs in melanocytes, located in the epidermis. Historically it has a high rate of morbidity and mortality, due to the resistance and toxicity of traditional therapies. Its incidence has increased annually by 4% to 8%. Until 2011 it was still considered a devastating and almost always fatal disease in a few months. Advances in therapies have significantly improved the results of most patients with advanced melanoma, especially those with a BRAFV600 mutation, which account for almost 50% of tumors. Before the recent evolution in treatment, the prognosis and overall survival were considered very bad. The introduction of new drugs has improved progression-free survival and overall survival, as well as producing faster clinical responses. Methods Comparison of endpoints such as progression-free survival and overall melanoma survival from the Summary of Product Characteristics (SPC) studies of each drug in the therapeutic groups under assessment used in the disease. The variables used were the Endpoints Global Survival at various times (12 months, 24 months, 36 months and the median) and Progression-Free Survival. Results Combined immunotherapy (Nivolumab and Ipilimumab) improves overall survival and progression-free survival, achieving better results than targeted therapy. In this, the combination of a BRAF inhibitor and a MEK inhibitor, presents better results with the combination of Encorafenib and Binimetinib. Conclusions Both targeted therapy and immunotherapy transform melanoma with a dismal prognosis into a life-threatening illness.

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Therapeutic response monitoring after targeted therapy in an orthotopic rat model of hepatocellular carcinoma using contrast-enhanced ultrasound: Focusing on inter-scanner, and inter-operator reproducibility

PLoS ONE ◽

10.1371/journal.pone.0244304 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244304

Author(s):

Hwaseong Ryu ◽

Jung Hoon Kim ◽

Seunghyun Lee ◽

Joon Koo Han

Keyword(s):

Hepatocellular Carcinoma ◽

Targeted Therapy ◽

Treatment Group ◽

Rat Model ◽

Therapeutic Response ◽

Response Monitoring ◽

Control Group ◽

Rat Models ◽

Significant Change ◽

Operator Reproducibility

Purpose To assess therapeutic response monitoring after targeted therapy in an orthotopic rat model of hepatocellular carcinoma (HCC) using CEUS with focusing on inter-scanner and inter-operator reproducibility. Materials and methods For reproducibility, CEUS was performed using two different US scanners by two operators in sixteen rat models of HCC. Using perfusion analysis software (VueBox ®), eleven parameters were collected, and intra-class correlation coefficient (ICC) was used to analyze reproducibility. Then seventeen rat models of HCC were divided into treatment group (n = 8, 30 mg/kg/day sorafenib for five days) and control group (n = 9). CEUS was performed at baseline and 14 days after first treatment, and changes of perfusion parameters were analyzed. Results In treatment group, CEUS perfusion parameters showed a significant change. The peak enhancement (PE, 2.50 x103±1.68 x103 vs 5.55x102±4.65x102, p = 0.010) and wash-in and wash out AUC (WiWoAUC, 1.07x105±6.48 x104 vs 2.65x104±2.25x104, p = 0.009) had significantly decreased two weeks after treatment. On the contrary, control group did not show a significant change, including PE (1.15 x103±7.53x102 vs 9.43x102± 7.81 x102, p = 0.632) and WiWoAUC (5.09 x104±3.25x104 vs 5.92 x104±3.20x104, p = 0.646). For reproducibility, the various degrees of inter-scanner reproducibility were from poor to good (ICC: <0.01–0.63). However, inter-operator reproducibility of important perfusion parameters, including WiAUC, WoAUC, and WiWoAUC, ranged from fair to excellent (ICC: 0.59–0.93) in a different scanner. Conclusion Our results suggest that CEUS is useful for assessment of the treatment response after targeted therapy and with fair to excellent inter-operator reproducibility.

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A Longitudinal Analysis of IDO and PDL1 Expression during Immune- or Targeted Therapy in Advanced Melanoma

Neoplasia ◽

10.1016/j.neo.2017.12.002 ◽

2018 ◽

Vol 20 (2) ◽

pp. 218-225 ◽

Cited By ~ 13

Author(s):

Lukas Krähenbühl ◽

Simone M Goldinger ◽

Joanna Mangana ◽

Katrin Kerl ◽

Ines Chevolet ◽

...

Keyword(s):

Targeted Therapy ◽

Longitudinal Analysis ◽

Advanced Melanoma

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Chemotherapeutic, Immunologic, and Molecularly Targeted Therapy for the Treatment of Advanced Melanoma

Frontiers in Clinical Drug Research - Anti-Cancer Agents ◽

10.2174/9781681082899116030005 ◽

2016 ◽

pp. 217-270

Author(s):

Said C. Azoury ◽

David M. Straughan ◽

Robert D. Bennett ◽

Vivek Shukla

Keyword(s):

Targeted Therapy ◽

Advanced Melanoma ◽

Molecularly Targeted Therapy

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Metastatic Pancreatic Cancer with BRAF and P53 Mutations: Case Report of Therapeutic Response to Doublet Targeted Therapy

Case Reports in Oncology ◽

10.1159/000510096 ◽

2020 ◽

Vol 13 (3) ◽

pp. 1239-1243

Author(s):

Shenthol Sasankan ◽

Lorraine Rebuck ◽

Gloria Darrah ◽

Moises Harari Turquie ◽

Ian Rabinowitz

Keyword(s):

Pancreatic Cancer ◽

Case Report ◽

Targeted Therapy ◽

Therapeutic Response ◽

Case Reports ◽

Clinical History ◽

P53 Mutation ◽

Metastatic Pancreatic Cancer ◽

First Case ◽

History Of

We report on the clinical history of a 49-year-old female with metastatic pancreatic cancer. She was initially treated with standard chemotherapy as per current guidelines. She was found to have both a BRAF and P53 mutation, and received dabrafenib and trametinib with deep responses, both radiographically and biochemically (CA19-9). Her response has been more clinically relevant than responses in previous case reports of patients with BRAF-positive pancreatic cancer treated with targeted therapy. To the best of our knowledge, this is the first case report showing a dramatic therapeutic response to combination therapy with dabrafenib and trametinib in metastatic pancreatic cancer.

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Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells

Cancers ◽

10.3390/cancers12082218 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2218

Author(s):

Sabrina Rizzolio ◽

Simona Corso ◽

Silvia Giordano ◽

Luca Tamagnone

Keyword(s):

Targeted Therapy ◽

Kinase Inhibitors ◽

Combined Treatment ◽

Melanoma Cells ◽

Drug Resistant ◽

Braf Inhibitors ◽

Autocrine Signaling ◽

Melanoma Tumor ◽

Neuropilin 1 ◽

Soluble Ligand

Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.

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