| 1. |
- Arance, Ana, et al.
(författare)
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Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination.
- 2023
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:1, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
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| 2. |
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| 3. |
- Costa Svedman, Fernanda
(författare)
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Molecular markers for prediction of response and progression free survival to novel therapies in cutaneous malignant melanoma
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drugs inhibiting the MAPK-pathway (MAPKi) and immune checkpoint inhibitors (ICI) have changed the clinical outcome of metastatic cutaneous malignant melanoma (CMM) in a significant way. Nonetheless, many patients have primary resistance or develop acquired resistance to these therapies within a relatively short period of time. This thesis was performed to explore mechanisms of resistance and possible predictive biomarkers to further improve treatment outcome and to help individualize treatment in this patient population. In Paper I, we compared mRNA and protein expression in MAPKi resistant and sensitive melanoma cell lines. By applying gene expression and proteome profiling we identified two previously described (MET and EPHA2) and two novel (FLI1 and CD13/ANPEP) candidate biomarkers that, when overexpressed, were associated with treatment resistance to MAPKi. The overexpression of MET and EPHA2 was confirmed in melanoma samples from patients with metastatic CMM when comparing samples taken before and after treatment with MAPKi. In cell lines, we demonstrated that an inhibitor of EPHA2 (the multikinase inhibitor dasatinib), re-sensitized cells to MAPKi treatment. In Paper II, we analyzed plasma samples from 28 patients with metastatic CMM before and during treatment with MAPKi. Micro-RNA (miRNA) was extracted from plasmatic extra cellular microvesicles (EVs) and miRNA profiling was performed by microarray, using a panel with 372 human miRNAs. We assessed the association of the miRNA levels with response to treatment and progression free survival (PFS) and found that an increased level of let-7g-5p during treatment, compared to before treatment, was correlated with better response. A high level of miRNA 497-5p during treatment was associated with longer PFS. In Paper III, we investigated if plasmatic proteins were related to response and PFS to MAPKi or ICI in 109 patients with metastatic CMM. Proteomic profiling of plasma samples collected before and during treatment was performed by mass spectroscopy and the abundance of proteins was then correlated with treatment response and PFS. We identified that the plasma levels of 43 proteins, either before or during treatment, were prognostic/predictive of treatment outcome. An inverse correlation between acute-phase inflammatory proteins and apolipoproteins was observed. Patients with high levels of acute-phase inflammatory proteins and low levels of apolipoproteins had worse outcome to therapy. In Paper IV, we analyzed mRNA expression by targeted RNA sequencing of pre-treatment tumor samples from 28 patients with metastatic CMM who underwent treatment with MAPKi or ICI. Transcriptomic data was correlated with treatment response and PFS in gene set enrichment analysis (GSEA). Enrichment of genes in IFN-gamma and inflammatory response was associated with longer PFS to MAPKi therapy, and decreased expression of proliferative genes and increased expression of immune genes correlated with longer PFS to ICI. Finally, lower expression of proliferation genes and immune evasion genes was associated with increased response to ICI. In summary, we have identified possible mechanisms of resistance and potential predictive biomarkers to novel therapies in patients with metastatic CMM. Our studies were performed in small cohorts of patients and further studies to validate our findings are warranted.
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| 4. |
- Holmsten, Karin, et al.
(författare)
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Treatment Patterns and Efficacy of Chemotherapy After Pembrolizumab in Advanced Urothelial Cancer-a Real-World Study in the pre-Antibody-Drug Conjugate Era
- 2023
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Ingår i: Clinical Genitourinary Cancer. - : Elsevier. - 1558-7673 .- 1938-0682. ; 21:6, s. E438-E448
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Tidskriftsartikel (refereegranskat)abstract
- This retrospective real-world study shows that vinflunine and platinum-combinations were the most common regimens after previous pembrolizumab in patients with metastatic urothelial cancer (mUC). The median progression-free and overall survival were 3.3 and 7.7 months respectively. Conventional chemotherapy after immunotherapy may remain to be a late-stage treatment option for selected patients in the era of targeted precision medicine of mUC. Background: Immune checkpoint inhibitors (ICIs) have been established as a routine treatment in patients with metastatic urothelial cancer (mUC). However, there has been no standard of care after progression on ICIs. We investigated real-world treatment patterns and efficacy of chemotherapy (CHT) after pembrolizumab, in the era before introduction of maintenance avelumab and antibody-drug conjugates (ADC). Patients and Methods: An observational, retrospective study was conducted at twelve Nordic centers. Patients with mUC were treated according to investigator s ' choice of CHT after pembrolizumab. Primary endpoint was overall response (ORR) and disease control rate (DCR); secondary endpoints were progression-free (PFS) and overall survival (OS). Results: In total, 102 patients were included whereof 23 patients received CHT after pembrolizumab as second line treatment (subcohort A) and 79 patients in third line (subcohort B). Platinum-gemcitabine combinations were the most common regimens in subcohort A, and vinflunine in subcohort B. The ORR and DCR were 36% and 47%, respectively. Presence of liver metastases was independently associated with lower ORR and DCR. The PFS and OS were 3.3 months and 7.7 months, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS) and number of previous cycles of pembrolizumab were found to be independent prognostic factors associated with OS. Conclusion: In a real-world setting, CHT showed clinically
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| 5. |
- Karlsson, Max J., et al.
(författare)
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Inflammation and Apolipoproteins Are Potential Biomarkers for Stratification of Cutaneous Melanoma Patients for Immunotherapy and Targeted Therapy
- 2021
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:9, s. 2545-2555
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cutaneous melanoma is one of the most common cancers in young adults. During the last decade, targeted and immunotherapies have significantly increased the overall survival of patients with malignant cutaneous melanoma. Nevertheless, disease progression is common, and a lack of predictive biomarkers of patient response to therapy hinders individualized treatment strategies. To address this issue, we performed a longitudinal study using an unbiased proteomics approach to identify and quantify proteins in plasma both before and during treatment from 109 patients treated with either targeted or immunotherapy. Linear modeling and machine learning approaches identified 43 potential prognostic and predictive biomarkers. A reverse correlation between apolipoproteins and proteins related to inflammation was observed. In the immunotherapy group, patients with low pretreatment expression of apolipoproteins and high expression of inflammation markers had shorter progression-free survival. Similarly, increased expression of LDHB during treatment elicited a significant impact on response to immunotherapy. Overall, we identified potential common and treatment-specific biomarkers in malignant cutaneous melanoma, paving the way for clinical use of these biomarkers following validation on a larger cohort. Significance: This study identifies a potential biomarker panel that could improve the selection of therapy for patients with cutaneous melanoma.
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| 6. |
- Svedman, Fernanda Costa, et al.
(författare)
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Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.MATERIALS AND METHODS: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.RESULTS: Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P <0.000061).CONCLUSIONS: EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.
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| 7. |
- Villabona Lisa Villabona, Lisa, et al.
(författare)
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Immunrelaterade biverkningari tarm, lever, lungor och njurar : BIVERKNINGAR I SAMBAND MED IMMUNTERAPI MOT CANCER, DEL 1 [Overview of immune-related side effects from immune checkpoint inhibitors. Part 1: Gastrointestinal, lung and kidney toxicity]
- 2021
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Ingår i: Läkartidningen. - : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 118
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Forskningsöversikt (refereegranskat)abstract
- In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis of those occurring in gastrointestinal organs, lungs and kidneys.
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