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

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.

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Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study

Annals of Oncology ◽

10.1093/annonc/mdw641 ◽

2017 ◽

Vol 28 (3) ◽

pp. 634-641 ◽

Cited By ~ 74

Author(s):

G.A. McArthur ◽

M. Maio ◽

A. Arance ◽

P. Nathan ◽

C. Blank ◽

...

Keyword(s):

Brain Metastases ◽

Multicentre Study ◽

Metastatic Melanoma ◽

Phase 2 ◽

Open Label ◽

Melanoma Patients

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Multicentric ipilimumab experience in Turkish patients with metastatic melanoma: MIPI-TURK.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19024 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19024-e19024

Author(s):

Alper Sevinc ◽

Hande Turna ◽

Mustafa Ozdogan ◽

Suleyman Buyukberber ◽

Gokhan Demir ◽

...

Keyword(s):

Side Effects ◽

Metastatic Melanoma ◽

Muscle Weakness ◽

Cytotoxic T Lymphocyte ◽

Complete Response ◽

Response Evaluation ◽

Gastrointestinal Side Effects ◽

Clinical Responses ◽

Melanoma Patients ◽

Turkish Patients

e19024 Background: Ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen) monoclonal antibody has been shown to enhance immune responses and induce durable clinical responses in patients with metastatic melanoma. The authors report retrospectively on metastatic melanoma patients treated under Expanded Access Program in Turkey among 13 centers. Methods: Patients with metastatic melanoma were treated with ipilimumab 3 mg/kg for 4 doses on weeks 1, 4, 7, 10 as induction. Response evaluation was done on week 12. Patients with complete response (CR), partial response (PR) and stable disease (SD) at week 12 were eligible for re-induction. Results: A total of 75 patients enrolled with 70 evaluable. Ipilumumab treatment was given as 2nd, 3rd and 4th line in 20.0%, 64.3% and 15.7% of patients respectively. The numbers of patients receiving ipilimumab for 1, 2, 3 and 4 doses were 9, 12, 13 and 36, respectively. Seven of 70 patients were eligible for re-induction. G1/2 adverse events were reported in 32.8% (23/70) of patients whereas G3/4 was 14.3% (10/70). The most common G1/2 immune related adverse event was skin rash (14.3%) followed by muscle weakness (10.0%) and gastrointestinal side effects (8.6%). There were seven G3 side effects (diarrhea in 4, muscle weakness in 1, hypothyroidism in 1 and GI bleeding in 1 patient). There was one reversible G4 thrompocytopenia and two deaths were associated with hepatic AEs. Thirty-six of 70 patients (51.4%) completed 4 doses ipilimumab treatment were available for response evaluation. There was no CR. The disease control rate (DCR) was 36.1% (PR: 8.3% and SD 27.8%). Median time to progression (TTP) was 2.7 months (95% CI, 2.1-4.2 months). Median overall survival was not reached with 61.3% of patients surviving within 12 months of follow up period. Conclusions: As a conclusion, ipilimumab treatment resulted in favorable clinical benefit for metastatic melanoma patients. Data generated by our 13 centers revealed an efficacy and safety profile consistent with the currently avaliable knowledge.

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Chemotherapy for patients with brain metastases from melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e19012 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e19012-e19012

Author(s):

David R. Naskhletashvili ◽

Vera A. Gorbunova ◽

Mark B. Bychkov ◽

Ali H. Bekyashev ◽

Vladislav B. Karahan ◽

...

Keyword(s):

Partial Response ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Objective Response ◽

Complete Response ◽

Combined Chemotherapy ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

The Brain

e19012 Background: There have not been standards of chemo- and chemo-radiotherapy for treatment for patients with brain metastases. The patients (pts) with brain metastases (BM) from melanoma have poor prognoses. The main goal of this trial is to assess the efficacy of nitrosoureas (CCNU or FCNU), temozolomide (TMZ) as monotherapy, TMZ combined with whole brain irradiation (WBI), or combined chemotherapy of TMZ and cisplatin in pts with BM from melanoma. Methods: 78 pts were included in this study. 21 pts were treated with WBI (3Gy/30Gy) and concomitant TMZ therapy (75 mg/m2/day orally on days 1-14), 19 pts were treated with TMZ (150 mg/m2/day orally on days 1-5, every 4 weeks) as monotherapy, 17 pts pts were treated with nitrosoureas (CCNU or FCNU), 21 pts were treated with combined chemotherapy of TMZ (150/mg/m2/day orally on days 1-5, every 4 weeks) + cisplatin (20/mg/m2/day intravenous on days 1-5, every 4 weeks). The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (mOS), 1-year and 2-year survival. Results: Observations were as follows: in the TMZ + WBI treated pts, 4 OR (19,0%) in 21 pts group in the brain and 1 OR (6,7%) in 15 pts group in ES. The mOS was 6.0 months, 1-year survival was 23,8%. In the TMZ monotherapy treated pts there were 5 OR (26,3%) in 19 pts group in the brain and no OR in 13 pts group in ES. The mOS was 6 months, 1-year survival was 21,1%. In the nitrisoureas treated pts we achieved 2 OR (11,8%) in 17 pts group in the brain and 1 OR (9,1%) in 11 pts group in ES. The mOS was 5 months, 1-year survival was 17,6%. In the TMZ + cisplatin treated pts there were 7 OR (33.3%) in 21 pts group in the brain and 7 OR (35,0%) in 20 pts group in ES. The mOS was 8 months, 1-year survival was 33,3%. 2-year survival (19,0%) was achieved only in TMZ and cisplatin group. Conclusions: Previous results of our study showed promising higher efficacy of TMZ and cisplatin, especially in OR in ES (p<0.05) and in 2-year survival (p<0.05), in comparison with TMZ alone, nitrosoureas or TMZ with whole brain irradiation in patients with metastatic melanoma with BM. Control of extracranial lesions is important factor for patients with BM. Further investigation is to be expected.

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Complete response to immunotherapy in a nonagenarian patient with metastatic melanoma

BMJ Case Reports ◽

10.1136/bcr-2020-235472 ◽

2020 ◽

Vol 13 (7) ◽

pp. e235472

Author(s):

Tiffany Foo ◽

Gonzalo Tapia Rico ◽

Michael P Brown

Keyword(s):

Elderly Patients ◽

Metastatic Melanoma ◽

Eastern Cooperative Oncology Group ◽

Death Receptor ◽

Complete Response ◽

Response To Treatment ◽

Group Score ◽

Programmed Death ◽

Melanoma Patients ◽

Reduced Mobility

Despite the increasing incidence of metastatic melanoma in the older population, there are relatively limited data for those older than 75 years of age. Elderly patients are often under-represented in clinical trials. In addition, elderly patients in trials often have a lower Eastern Cooperative Oncology Group score and fewer comorbidities and may thus not truly reflect the realities of day-to-day clinical practice. We present a case of a 95-year-old woman who had extensive and unresectable subcutaneous and dermal deposits of metastatic melanoma of her right leg, which caused oedema and reduced mobility. She was treated concurrently with pembrolizumab and radiotherapy to her leg lesions of melanoma. She has had an excellent response to treatment, with complete resolution of the subcutaneous and dermal metastatic deposits and has not developed any immune-related toxicities. Our experience demonstrates that anti-programmed-death-receptor-1 therapy can be given safely and effectively even in very elderly metastatic melanoma patients.

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Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab

Melanoma Management ◽

10.2217/mmt-2019-0020 ◽

2020 ◽

Vol 7 (1) ◽

pp. 7-15

Author(s):

Quaovi H Sodji ◽

Paulina M Gutkin ◽

Susan M Swetter ◽

Sunil A Reddy ◽

Susan M Hiniker ◽

...

Keyword(s):

Radiation Therapy ◽

Metastatic Melanoma ◽

Combined Treatment ◽

Prospective Trial ◽

Complete Response ◽

The Third ◽

Long Term Follow Up ◽

Melanoma Patients

Aim: We previously reported a prospective trial evaluating the safety and efficacy of combining ipilimumab and radiation therapy in patients with metastatic melanoma. Herein, we provide a long-term update on patients with complete response (CR) or partial response (PR). Patients & methods: We continued to follow these patients with serial imaging including computed tomography, PET or MRI. Results: Two of the three patients with CR are still alive and without evidence of melanoma but with chronic treatment-induced hypophysitis. The third patient died of hepatocellular carcinoma, but with no evidence of melanoma. Among the three patients with PR, two achieved CR after pembrolizumab monotherapy. Conclusion: This long-term follow up reveals the striking durability of the CRs, which appears to correlate with a grade 2–3 hypophysitis.

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

Immunotherapy ◽

10.2217/imt-2019-0206 ◽

2020 ◽

Vol 12 (7) ◽

pp. 439-444 ◽

Cited By ~ 2

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.

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

Case Reports in Oncological Medicine ◽

10.1155/2017/8241624 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

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.

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Single Center Experience Study with Pembrolizumab in Patients with BRAF Mutant Negative Metastatic Melanoma

Acta Facultatis Medicae Naissensis ◽

10.2478/afmnai-2018-0028 ◽

2018 ◽

Vol 35 (4) ◽

pp. 267-272

Author(s):

Ivica Pejčić ◽

Ivan Petković ◽

Ana Cvetanović ◽

Irena Conić

Keyword(s):

Metastatic Melanoma ◽

Disease Progression ◽

Performance Status ◽

Progression Free Survival ◽

Complete Response ◽

Wild Type ◽

Free Survival ◽

Good Performance Status ◽

Melanoma Patients ◽

Braf Mutant

Abstract The aim of the paper was to determine the efficacy, toxicity and progression free survival with anti-PD-1 immunotherapy pembrolizumab in BRAF wild type metastatic melanoma patients with good performance status (ECOG PS 0-1). From February 2017 to April 2018, 17 patients with BRAF mutant wild type metastatic melanoma were enrolled in the study. Only 3/17 patient had received chemotherapy previously. The aim of the study was to confirm the efficacy of pembrolizumab immunotherapy in patients with good performance status (ECOG 0-1). Treatment consisted of pembrolizumab 2 mg/kg Q3 weeks continued until disease progression or intolerable toxicity. Secondary end points included toxicity and progression-free survival (defined as the time from randomization to documented disease progression according to RECIST). The overall response rate (ORR) was 11/17 (53.0 %), with complete response (CR) 0, partial response (PR) 3 (18 %), stable disease (SD) 8 (47%), and progressive disease (PD) 6 (35%). A total number of 97 consecutive cycles were administered. Adverse effects were mild. The most common toxicity was pneumonitis grade 1. None of the patients in the study demonstrated grade 2, 3 and 4 toxicity. No treatment-related deaths occurred. The median time to disease progression was 5.8 months. Anti-PD-1 pembrolizumab immunotherapy appeared to be a beneficial therapeutic approach with less toxicity for metastatic BRAF wild type melanoma patients with good PS.

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