scholarly journals Uncommon BRAF Mutations Associated with Durable Response to Immunotherapy in Patients with Metastatic Melanoma

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Brenen P. Swofford ◽  
Jade Homsi
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Disease Process ◽  
Complete Response ◽  
Therapeutic Benefit ◽  
Braf Mutations ◽  
Durable Response ◽  
Melanoma Patients ◽  
Potential Therapeutic Benefit

Melanoma is a disease process which has been increasing in incidence over the past three decades and metastatic melanoma carries a poor prognosis. Through genetic studies of this disease, it has been determined that the BRAF V600 mutation plays a major role in the pathophysiology of the disease and this has led to the utilization of targeted therapy (BRAF and MEK inhibitors) in its treatment. Other BRAF mutations (non-V600 mutations) are rare in melanoma and targeted therapy is not indicated for patients with these mutations due to reduced response rates. An emerging option for metastatic melanoma with uncommon BRAF mutations is immunotherapy using checkpoint inhibitors such as PD-1 inhibitors or CTLA-4 inhibitors. Currently, it is unknown how patients with BRAF non-V600 mutations respond to immunotherapy. This report will examine the effect of immunotherapy on two distinct metastatic melanoma patients, each with uncommon BRAF mutations, occurring outside the V600 locus (E586K and G469E). These patients were noted to have a durable, complete response when treated with immunotherapy and continue to exhibit a response 9 and 15 months after discontinuing therapy. Further research and clinical trials are needed to study patients with uncommon BRAF mutations and the potential therapeutic benefit of immunotherapy.

scholarly journals 90. Fecal Microbiota Transplantation in Metastatic Melanoma Patients Resistant to Anti-PD-1 Treatment

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S7-S7 ◽  
Author(s):  
Ilan Youngster ◽  
Erez Baruch ◽  
Lior Katz ◽  
Adi Lahat ◽  
Tal Brosh-Nissimov ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Metastatic Melanoma ◽  
Cell Activity ◽  
Complete Response ◽  
Fecal Microbiota ◽  
Post Treatment ◽  
Response To Treatment ◽  
Durable Response ◽  
Melanoma Patients

Abstract Background Most metastatic melanoma patients treated with Programed cell Death (PD)-1 blockers fail to achieve a durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT) have been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first patients treated in a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods FMT donors were two metastatic melanoma patients who achieved a durable complete response to treatment. FMT recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopic and oral administration, followed by anti-PD-1 re-treatment. Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results Five patients with treatment-resistant metastatic melanoma were recruited. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis was performed. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, P = 0.04, FDR q = 0.22) between the two recipient–donor groups. Specific taxonomic dynamics included post-FMT increased abundance of Paraprevotellaceae, previously associated in descriptive studies with responsiveness to treatment, and significant reductions in abundance of β-proteobacteria, previously associated with reduced response to treatment. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T-test, P = 0.008) and in the tumor (P = 0.0076). Post-treatment intra-tumoral CD8+ T-cell infiltration was also increased. Three patients had a partial or complete response to treatment post-FMT. Conclusion FMT in metastatic melanoma patients seems to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, and conferred clinical and radiological benefit in several recipients previously unresponsive to treatment. Disclosures All Authors: No reported Disclosures.

scholarly journals Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2312
Author(s):  
Henner Stege ◽  
Maximilian Haist ◽  
Michael Schultheis ◽  
Maria Isabel Fleischer ◽  
Peter Mohr ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Checkpoint Inhibitors ◽  
Patient Characteristics ◽  
Complete Response ◽  
Second Line ◽  
Treatment Cessation ◽  
Durable Response ◽  
Ongoing Treatment ◽  
Number Of Patients ◽  
The Impact

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.

Concurrent Vogt–Koyanagi–Harada disease and impressive response to immune checkpoint blockade in metastatic melanoma

Immunotherapy ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 439-444 ◽  
Author(s):  
T Gambichler ◽  
C Seifert ◽  
M Lehmann ◽  
C Lukas ◽  
C Scheel ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
High Dose ◽  
Ocular Ultrasound ◽  
Melanoma Patients ◽  
Dose Corticosteroid

Background: Vogt–Koyanagi–Harada disease (VKHD)-like symptoms have previously been reported in 11 melanoma patients treated with immune checkpoint inhibitors. Materials & methods: We report a female patient with multilocular metastatic melanoma who was treated with nivolumab. Results: Following the first nivolumab dose, she experienced bilateral blurry vision, hearing loss, vertigo and ataxia. Ocular ultrasound was consistent with the diagnosis of uveitis. Audiography revealed severe bilateral sensorineural hearing loss. A high-dose corticosteroid regimen was initiated under which the patient developed generalized vitiligo. Abdominal and thoracic CT scans showed an almost complete response to nivolumab therapy. This patient fulfilled all criteria of VKHD which is characterized pathogenetically by an antimelanocytic autoimmune process. Conclusion: The present case showed an impressive response to antimelanoma immunotherapy. Based on these data, the occurrence of VKHD in melanoma patients appears to be a strong indicator for immune checkpoint inhibitor efficacy.

scholarly journals Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
L. Warburton ◽  
T. M. Meniawy ◽  
L. Calapre ◽  
M. Pereira ◽  
A. McEvoy ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Residual Disease ◽  
Complete Response ◽  
Digital Pcr ◽  
Disease Recurrence ◽  
Prolonged Treatment ◽  
Durable Response ◽  
Longitudinal Plasma ◽  
Melanoma Patients

Abstract BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/− MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20–74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8–36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.

Evolution of Molecular Targets in Melanoma Treatment

2020 ◽  
Vol 26 (4) ◽  
pp. 396-414 ◽  
Author(s):  
Khanh B. Tran ◽  
Christina M. Buchanan ◽  
Peter R. Shepherd
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Durable Response ◽  
History Of ◽  
Melanoma Treatment ◽  
Melanoma Patients

Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.

scholarly journals Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response

2021 ◽  
Vol 149 ◽  
pp. 37-48
Author(s):  
Florentia Dimitriou ◽  
Anne Zaremba ◽  
Clara Allayous ◽  
Katharina C. Kähler ◽  
Camille L. Gerard ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Complete Response ◽  
Melanoma Patients

Analysis of metastatic melanoma treated with immune checkpoint inhibitors and the rates of adverse events of colitis and hepatitis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21591-e21591
Author(s):  
Emily Horan ◽  
Melissa Arneil ◽  
Wen Xu ◽  
Victoria Atkinson
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Complete Response ◽  
Treatment Regimens ◽  
Organ Systems ◽  
Oral Steroids ◽  
Intravenous Steroids

e21591 Background: Immune checkpoint inhibitors (CPI) are widely used in metastatic melanoma (MM), where it has markedly improved survival outcomes. ICI induced autoimmune adverse reactions (irAE) manifest in all organ systems and are due to over-activation of the immune system. Clinically relevant irAE are colitis and hepatitis as drivers of morbidity and mortality. Methods: Data was collected from a single centre (Princess Alexandra Hospital) from the electronic medical records system and immunotherapy prescribing software. Patient demographics, treatments, complications and outcomes were recorded from 2016-2019. Eligible patients had to have received immunotherapy (pembrolizumab, ipilimumab, or nivolumab) and experienced colitis or hepatitis toxicity. Trial patients were excluded. Results: The cohort of 337 patients who had received immune therapy, 18% (n = 61) had hepatitis or colitis, mean age was 56 years, 64% male. The majority were stage 4d 28% (n = 17). Braf wildtype accounted for 56% (n = 34). The highest rates of irAE occurred on combination ipilimumab and nivolumab 56% (n = 34), 10% nivolumab (n = 6), 3% (n = 2) ipilimumab, and 31% (n = 19) pembrolizumab monotherapy. Colitis affected 61% of patients (n = 37), 30% (n = 18) were grade 3 severity. Hepatitis affected 48% (n = 29), 18% (n = 32) were grade 1. The majority required oral steroids (80%, n = 49), followed by intravenous steroids (51%, n = 31), infliximab (18%, n = 11) and mycophenolate in 5% (n = 3). Hospitalisation occurred in 56% (n = 34), 20% (n = 12) requiring treatment cessation. Progressive disease occurred in 62% (n = 38), and 13% (n = 8) had a complete response. Conclusions: The findings of this analysis mirror current literature with immunotherapies used, rates and severity of irAE. The management of irAE also aligned with current guidelines. Further research is required to investigate patient factors increasing the risk of developing irAE, and ideal treatment regimens. Analysing this large cohort, the incidence of toxicity was 17%, predominantly colitis followed by hepatitis. Patients were severely impacted requiring significant interventions to manage toxicity, hospitalisation and morbidity.

Complete responses to two different anti-PD1 agents in a metastatic melanoma patient

2019 ◽  
Vol 26 (2) ◽  
pp. 496-499 ◽  
Author(s):  
Saadettin Kilickap ◽  
Deniz C Guven ◽  
Oktay H Aktepe ◽  
Burak Y Aktas ◽  
Omer Dizdar
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
Complete Response ◽  
Duration Of Treatment ◽  
Treatment Protocols ◽  
Real Life Data ◽  
Heavily Pretreated ◽  
Drug Free

In the last decade, immune checkpoint inhibitors changed the landscape of metastatic melanoma. However, the optimal duration of treatment and treatment cessation in responders is largely unknown. Herein, we represent a heavily pretreated metastatic melanoma case who had a complete response to pembrolizumab and also a complete response with nivolumab after progression during drug-free follow-up. We think that reinduction with a different anti-PD1 antibody may be used in patients with metastatic melanoma responders. Clinical trials with prespecified sequential treatment protocols and large real-life data can further delineate this subject.

scholarly journals Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Caitlyn N. Myrdal ◽  
Srinath Sundararajan
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Optimal Sequencing ◽  
The Right

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

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