Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a ...clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
•First report on PD-L1 therapy and radiotherapy in a HIV positive patient with metastatic Merkel cell carcinoma.•The patient has been tolerated the treatments reasonably well.•The patient has been in ...complete remission for one year to date.
This case report presents a HIV-positive 60-year old male with Merkel cell carcinoma of his right forearm and pulmonary sarcoidosis, who, after excisions and irradiations of the primary tumour site and subsequent lymph node metastases developed distant metastases. He received radiotherapy to symptomatic mediastinal lymph node metastases followed by Doxorubicin and, after two cycles, by the PD-1 inhibitor Pembrolizumab due to mixed response. Re-staging showed a para-mediastinal, radiotherapy-induced pneumonitis, which was treated by prednisolone due to clinical symptoms. In September 2017, the patient developed a solitary lymph node metastasis next to the right atrium, for which he received stereotactic radiotherapy. The systemic treatment with Pembrolizumab was replaced by the PD-L1 inhibitor Avelumab and is being continued since. The patient has been in complete remission for one year now and the HIV-infection is well-controlled.
Systemic therapy of metastatic melanoma Rauschenberg, Ricarda; Garzarolli, Marlene; Dietrich, Ursula ...
Journal der Deutschen Dermatologischen Gesellschaft,
12/2015, Letnik:
13, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Summary
For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and ...high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70 %, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects.
Showing long‐term survival rates of approximately 20 %, the anti‐CTLA‐4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune‐mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti‐PD‐1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45 % and one‐year survival rates of > 70 %. The combination of ipilimumab and nivolumab has shown response rates of up to 58 % and a median progression‐free survival of > 11 months. While this combination is expected to result in a rapid and long‐lasting response, this potential benefit comes at the expense of a high level of toxicity.
Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long‐term survival a possibility, not only acute but also long‐term therapeutic side effects must be taken into account.
Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. ...However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence.
Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS.
The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P < .001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 95% confidence interval {CI} 9.3–15.1; 9.8 95% CI 6.9–12.6 versus 5.1 95% CI 2.7–7.5; P = .03).
SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies.
•Two hundred eight patients with melanoma brain metastases are reported.•Patients were treated with radiotherapy (RT) and systemic therapy (ST).•Stereotactic radiosurgery and immunotherapy achieved highest overall survival (OS) rates.•For RT and targeted therapy, treatment sequencing is critical.•Whole brain RT and ST achieved unprecedentedly high OS rates.
Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates ...of 50–75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic factors in order to establish the best treatment for each patient. Although the management of MBM has dramatically improved, a substantial number of patients still progress and die from brain metastases. Therefore, there is an urgent need for prospective studies in patients with MBM that focus on treatment combinations and sequences, new treatment strategies, and biomarkers of treatment response. Moreover, further research is needed to decipher brain-specific mechanisms of therapy resistance.
Summary
Background
This study aimed to explore the information‐seeking behavior (ISB) of melanoma patients (MPs) and MP subgroups, in order to provide data for needs‐based adaptation of information ...provision.
Methods
In a cross‐sectional survey in 27 German skin cancer centers, we explored characteristics of the ISB of MPs with the aid of a standardized questionnaire. Subgroup differences were determined with the chi‐squared test and predictors of media preferences with logistic regression.
Results
67 % of the 529 participating MPs had clinical stage III or IV melanoma. Most of the participants (81 %) reported medical consultations as their regularly or frequently used information resource (IR). 58 % wished to have more advice about IRs from their physician. Only 8 % of MPs used the services of self‐help groups and 12 % of MPs took advantage of the services of cancer counseling centers. The internet (63 %) and booklets (58 %) were reported to be the preferred media. Age, educational level, general need for information and lack of awareness of their own condition proved to be predictors for media preferences.
Conclusions
Most MPs expected their physician to advise them about IRs they could use in addition to medical consultations. Peer support services were quite underused by MPs. The various preferences of media by MPs should be considered when developing and providing IRs.
Zusammenfassung
Hintergrund
Mit dieser Studie sollte das Informationsverhalten (IV) von Melanompatienten (MP) und deren Subgruppen untersucht werden, um Daten für eine bedarfsgerechte Anpassung der ...Informationsversorgung zu erhalten.
Methoden
In einer Querschnittserhebung an 27 deutschen Hautkrebszentren untersuchten wir mithilfe eines standardisierten Fragebogens das IV von MP. Unterschiede zwischen Subgruppen wurden mithilfe des Chi‐Quadrat‐Tests, Prädiktoren für die Präferenzen verschiedener Medien mithilfe logistischer Regression ermittelt.
Ergebnisse
67 % der 529 Teilnehmer waren von einem Melanom im klinischen Stadium III oder IV betroffen. Die meisten der Teilnehmer (81 %) gaben Gespräche mit dem Arzt als regelmäßig oder häufig genutzte Informationsquelle (IQ) an. 58 % wünschten sich von ihrem Arzt mehr Beratung zu IQ. Nur 8 % der MP nutzten die Angebote von Selbsthilfegruppen (SHG) und 12 % die Angebote von Krebsberatungsstellen (KBS). Das Internet (63 %) und Broschüren (58 %) wurden als bevorzugte Medien angegeben. Alter, Bildungsstatus das generelle Informationsbedürfnis und mangelnde Kenntnis des eigenen Erkrankungsstandes erwiesen sich als Prädiktoren für die Präferenzen verschiedener Medien.
Schlussfolgerungen
Die meisten MP erwarteten von ihrem Arzt, über IQ beraten zu werden, die sie zusätzlich und außerhalb der Klinik nutzen können. SHG und KBS wurden von MP vergleichsweise selten konsultiert. Die unterschiedlichen Präferenzen verschiedener Medien sollten bei der Entwicklung und Bereitstellung von IQ für MP berücksichtigt werden.
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