In patients with melanomas containing activating
BRAF
mutations, the combination of a BRAF inhibitor and a MEK inhibitor improved overall survival, as compared with a BRAF inhibitor alone, and was ...associated with many fewer second skin tumors.
The treatment of metastatic melanoma is rapidly evolving. The potent and specific BRAF inhibitors vemurafenib and dabrafenib, as compared with chemotherapy, have significantly improved response rates, along with progression-free and overall survival, in patients with metastatic melanoma with
BRAF
V600E or V600K mutations.
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However, acquired resistance to BRAF inhibitors frequently develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway, resulting in a median progression-free survival of 6 to 8 months.
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In addition, the use of BRAF inhibitors may result in the development of secondary skin tumors, originating from a paradoxical activation of the MAPK pathway in cells . . .
Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we ...present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study.
Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety.
At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy.
Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg ...in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 10% of 364 patients in the 10 mg/kg group vs 21 6% of 362 patients in the 3 mg/kg group), colitis (19 5% vs nine 2%), increased alanine aminotransferase (12 3% vs two 1%), and hypophysitis (ten 3% vs seven 2%). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.
Summary Background In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib ...and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. Methods COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy—Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov , number NCT01597908 , and is ongoing for the primary endpoint, but is not recruiting patients. Findings From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (–13·20, −8·05, −8·82, −12·69, −12·46, −11·41, and −10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001). Interpretation From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population. Funding GlaxoSmithKline.
To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous ...cell carcinoma of the skin (SCCS).
Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors RECIST criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated.
Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes.
As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.
IMPORTANCE: The activating mutation of MYD88 L265P is a frequent feature of primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL-LT), reported in up to 69% of the cases. Whether patients ...with MYD88 mutation display specific clinical and evolutive features has not been evaluated. OBJECTIVE: To identify the clinical characteristics associated with MYD88 mutation, confirm its high prevalence, and evaluate its effect on prognosis in patients with PCLBCL-LT. DESIGN, SETTING, AND PARTICIPANTS: A retrospective multicenter study was conducted using the medical records of patients from dermatology departments belonging to the French Study Group for Cutaneous Lymphomas. Sixty-one patients with a diagnosis of PCLBCL-LT made between 1988 and 2010 who were available for molecular study were included. Of these, 58 patients displaying interpretable results constituted the study group. Median follow-up was 33 months, and 39 patients (67%) were monitored until death. MAIN OUTCOMES AND MEASURES: Clinical features (age, sex, number of skin lesions, tumor stage, and location as leg vs elsewhere), MYD88 mutation (allele-specific TaqMan polymerase chain reaction assay), treatment regimen, and outcome were recorded. Baseline characteristics and outcome were compared according to the status of MYD88. RESULTS: The median age of the patients was 79 years, and 59% were female. Skin lesions were located on the leg in 76% of the cases. Thirty-four of 58 patients (59%) harbored the MYD88 L265P mutation. Patients had similar clinical characteristics at presentation regardless of their MYD88 status, except that those harboring the MYD88 mutation were older (P = .006) and had more frequent involvement of the leg (P = .008). Patients harboring the MYD88 mutation had 3- and 5-year–specific survival rates of 65.7% and 60.2% vs 85.4% and 71.7% in patients with the wild-type allele. The MYD88 mutation was significantly associated with shorter disease-specific survival in univariate (P = .03) and multivariate (odds ratio, 3.01; 95% CI, 1.03-8.78; P = .04) analysis. There was no significant difference between the groups in their treatment regimens. Considering overall survival, in univariate (P = .002) and multivariate (odds ratio, 2.94; 95% CI, 1.18-7.30; P = .02) analysis, MYD88 L265P mutation was an independent adverse prognostic factor. CONCLUSIONS AND RELEVANCE: This study confirms the high prevalence of MYD88 L265P mutation in PCLBCL-LT and shows its association with shorter survival. The clinical effect of MYD88 mutation activating the nuclear factor-κB pathway supports the use of targeted therapies at the time of relapse after conventional therapies.
Aggressive primary cutaneous T-cell lymphomas include advanced-stage mycosis fungoides (stage ≥ IIB mycosis fungoides), Sézary syndrome, gamma/delta cutaneous lymphoma, nasal type lymphoma, ...aggressive epidermotropic CD8+ T-cell lymphoma and some cutaneous lymphomas not otherwise specified. To evaluate their long-term prognosis, we conducted a retrospective cohort study of 85 patients diagnosed between 2005 and 2020 with advanced-stage mycosis fungoides (n = 48), Sézary syndrome (n = 28) or aggressive non-mycosis fungoides/Sézary syndrome subtypes (n = 9). The median survival times in these 3 groups were 118.7, 45.7 and 11.2 months, respectively, and the 5-year survival rates were 55.3%, 27.8% and 33.3%, respectively. Multivariate analyses in patients with mycosis fungoides/Sézary syndrome identified age ≥ 70 years, Eastern Cooperative Oncology Group Performance Status ≥ 2, and the high-risk group according to the Cutaneous Lymphoma International Consortium prognostic model, as adverse prognostic factors. Seven patients in this mycosis fungoides/ Sézary syndrome group were in complete long-term remission after treatment with bexarotene, including 4 patients living without any treatment for 16-101 months.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ABSTRACTAn 86-year-old woman was referred for a rare but aggressive subtype of primary cutaneous lymphoma of the right lower limbdiffuse large B-cell lymphoma leg type. Initial evaluation by ...whole-body F-FDG PET/CT showed intense hypermetabolic activity of multiple cutaneous and subcutaneous nodules of the distal third of the right leg. Follow-up evaluations by F-FDG PET/CT showed complete response after 4 and 8 cycles of appropriate rituximab combination with polychemotherapy. Although no specific recommendations are available, our case stresses the major role of F-FDG PET/CT for initial extension and treatment response evaluation in clinical practice of primary cutaneous diffuse large B-cell lymphoma leg type.
Primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL) is a rare form of primary cutaneous lymphoma characterized by a clonal proliferation of mature γ/δ T lymphocytes. PCGDTCL is usually considered ...an aggressive and rapidly evolving malignancy. Contrasting with this patter, we hereby report 2 unusual cases with a protracted indolent evolution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•Pretreatment skewness at coarse texture scale in metastases from skin melanoma is an independent predictor of response to treatment.•Variation of entropy between baseline and first control CT ...examinations in metastases from skin melanoma is an independent predictor of favorable response to anti-PD-1 monoclonal antibodies.•In patients with metastatic skin melanoma treated with anti-PD-1 monoclonal antibodies, texture analysis performed on pretreatment CT and on first control CT after treatment may serve as a useful tool to predict favorable response to treatment.
The purpose of this study was to determine whether texture analysis features on pretreatment contrast-enhanced computed tomography (CT) images and their evolution can predict treatment response of metastatic skin melanoma (SM) treated with anti-PD1 monoclonal antibodies.
Sixty patients (29 men, 31 women; median age, 56 years; age range: 27–91 years) with metastatic SM treated with pembrolizumab (43/60; 72%) or nivolumab (17/60; 28%) were included. Texture analysis of SM metastases was performed on baseline and first post-treatment evaluation CT examinations. Mean gray-level, entropy, kurtosis, skewness, and standard deviation values were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales, ranging from fine to coarse. Lasso penalized Cox regression analyses were performed to identify independent variables associated with favorable response to treatment.
A total of 127 metastases were analyzed, with a median of two metastases per patient. Skewness at fine texture scale (spatial scale filtration SSF = 2; Hazard ratio HR: 3.51; 95% CI: 2.08–8.57; P = 0.010), skewness at medium texture scale (SSF = 3; HR: 0.56; 95% CI: 0.11–1.59; P = 0.014), variation of entropy at fine texture scale (SSF = 2; HR: 37.76; 95% CI: 3.48–496.22; P = 0.008) and LDH above the threshold of 248 UI/L (HR: 3.56; 95% CI: 1.78–21.35; P = 0.032 were independent predictors of response to treatment.
Pretreatment CT texture analysis-derived tumor skewness and variation of entropy between baseline and first control CT examination may be used as predictors of favorable response to anti-PD1 monoclonal antibodies in patients with metastatic SM.
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