619 results on '"Kirkwood JM"'
Search Results
2. Improved survival with vemurafenib in melanoma with BRAF V600E mutation
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Chapman, Pb, Hauschild, A, Robert, C, Haanen, Jb, Ascierto, P, Larkin, J, Dummer, R, Garbe, C, Testori, A, Maio, M, Hogg, D., Lorigan, P, Lebbe, C, Jouary, T, Schadendorf, D, Ribas, A, O'Day, Sj, Sosman, Ja, Kirkwood, Jm, Eggermont, Amm, Dreno, B, Nolop, K, Li, J, Nelson, B, Hou, J, Lee, Rj, Flaherty, Kt, Mcarthur, Ga, BRIM-3 Study Group, Cognetti, F, University of Zurich, Surgery, Erasmus MC other, and Cell biology
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Oncology ,Adult ,Male ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Keratoacanthoma ,Indoles ,Dacarbazine ,Medizin ,Ipilimumab ,610 Medicine & health ,Antineoplastic Agents ,2700 General Medicine ,Disease-Free Survival ,adult ,aged ,aged, 80 and over ,antineoplastic agents ,dacarbazine ,disease-free survival ,female ,humans ,indoles ,intention to treat analysis ,male ,melanoma ,middle aged ,mutation ,proto-oncogene proteins B-raf ,sulfonamides ,survival analysis ,vemurafenib ,young adult ,chemistry.chemical_compound ,Young Adult ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Humans ,Vemurafenib ,Melanoma ,Survival analysis ,Aged ,Cobimetinib ,Aged, 80 and over ,Sulfonamides ,business.industry ,10177 Dermatology Clinic ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,Intention to Treat Analysis ,chemistry ,Mutation ,Female ,business ,V600E ,medicine.drug - Abstract
BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P < 0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
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- 2011
3. Prognostic significance of autoimmunity during treatment of melanoma with interferon
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Gogas, H Ioannovich, J Dafni, U Stavropoulou-Giokas, C and Frangia, K Tsoutsos, D Panagiotou, P Polyzos, A and Papadopoulos, O Stratigos, A Markopoulos, C Bafaloukos, D and Pectasides, D Fountzilas, G Kirkwood, JM
- Abstract
BACKGROUND: Immunotherapy for advanced melanoma induces serologic and clinical manifestations of autoimmunity. We assessed the prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b. METHODS: We enrolled 200 patients in a substudy of a larger, ongoing randomized trial. Blood was obtained before the initiation of intravenous interferon therapy, after 1 month of therapy, and at 3, 6, 9, and 12 months. Serum was tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo. RESULTS: The median duration of follow-up was 45.6 months. Relapse occurred in 115 patients, and 82 patients died. The median relapse-free survival was 28.0 months, and the median overall survival was 58.7 months. Autoantibodies and clinical manifestations of autoimmunity were detected in 52 patients (26 percent). The median relapse-free survival was 16.0 months among patients without autoimmunity (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P
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- 2006
4. Establishing A Mark-Recapture Program For Dugongs In Moreton Bay, South-East Queensland
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Lanyon, JM, primary, Sneath, HL, additional, Kirkwood, JM, additional, and Slade, RW, additional
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- 2002
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5. PP34. Economic analysis of adjuvant interferon-ALFA 2B (IFN) in high risk melanoma using projections from ECOG (E) 1684
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Hillner, BE, primary, Kirkwood, JM, additional, Atkins, MB, additional, Johnson, ER, additional, and Smith, TJ, additional
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- 1997
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6. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases.
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Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, Cascinelli N, Cochran AJ, Coit DG, Eggermont AM, Johnson T, Kirkwood JM, Leong SP, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sondak VK, Balch, Charles M, and Gershenwald, Jeffrey E
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- 2010
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7. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma.
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Hersey P, Sosman J, O'Day S, Richards J, Bedikian A, Gonzalez R, Sharfman W, Weber R, Logan T, Buzoianu M, Hammershaimb L, Kirkwood JM, and Etaracizumab Melanoma Study Group
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- 2010
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8. Inter-clinician agreement on the recognition of clinical pigmentary characteristics of patients with cutaneous malignant melanoma. Studies of melanocytic nevi, VI
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Roush, GC, primary, Barnhill, RL, additional, Ernstoff, MS, additional, and Kirkwood, JM, additional
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- 1991
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9. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma.
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Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, and Keilholz U
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- 2009
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10. Phase I/II trial of tremelimumab in patients with metastatic melanoma.
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Camacho LH, Antonia S, Sosman J, Kirkwood JM, Gajewski TF, Redman B, Pavlov D, Bulanhagui C, Bozon VA, Gomez-Navarro J, Ribas A, Camacho, Luis H, Antonia, Scott, Sosman, Jeffrey, Kirkwood, John M, Gajewski, Thomas F, Redman, Bruce, Pavlov, Dmitri, Bulanhagui, Cecile, and Bozon, Viviana A
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- 2009
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11. Predictors of response to interferon therapy.
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Gogas H and Kirkwood JM
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- 2009
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12. A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma.
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Tarhini AA, Millward M, Mainwaring P, Kefford R, Logan T, Pavlick A, Kathman SJ, Laubscher KH, Dar MM, and Kirkwood JM
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- 2009
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13. Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients participating in Intergroup Trial ECOG 1694.
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Tarhini AA, Stuckert J, Lee S, Sander C, Kirkwood JM, Tarhini, Ahmad A, Stuckert, Joseph, Lee, Sandra, Sander, Cindy, and Kirkwood, John M
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- 2009
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14. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial...
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Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM, Atkins, Michael B, Hsu, Jessie, Lee, Sandra, Cohen, Gary I, Flaherty, Lawrence E, Sosman, Jeffrey A, Sondak, Vernon K, Kirkwood, John M, and Eastern Cooperative Oncology Group
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- 2008
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15. Next generation of immunotherapy for melanoma.
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Kirkwood JM, Tarhini AA, Panelli MC, Moschos SJ, Zarour HM, Butterfield LH, Gogas HJ, Kirkwood, John M, Tarhini, Ahmad A, Panelli, Monica C, Moschos, Stergios J, Zarour, Hassane M, Butterfield, Lisa H, and Gogas, Helen J
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- 2008
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16. Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma.
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Sosman JA, Carrillo C, Urba WJ, Flaherty L, Atkins MB, Clark JI, Dutcher J, Margolin KA, Mier J, Gollob J, Kirkwood JM, Panka DJ, Crosby NA, O'Boyle K, LaFleur B, Ernstoff MS, Sosman, Jeffrey A, Carrillo, Carole, Urba, Walter J, and Flaherty, Lawrence
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- 2008
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17. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group.
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Testori A, Richards J, Whitman E, Mann GB, Lutzky J, Camacho L, Parmiani G, Tosti G, Kirkwood JM, Hoos A, Yuh L, Gupta R, Srivastava PK, C-100-21 Study Group, Testori, Alessandro, Richards, Jon, Whitman, Eric, Mann, G Bruce, Lutzky, Jose, and Camacho, Luis
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- 2008
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18. Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy.
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Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS, Tarhini, Ahmad A, Kirkwood, John M, Gooding, William E, Cai, Chao, and Agarwala, Sanjiv S
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- 2007
19. Ctla-4-blocking immunotherapy with ipilimumab for advanced melanoma.
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Tarhini AA and Kirkwood JM
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- 2010
20. Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy.
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Kirkwood JM and Tarhini AA
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- 2009
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21. Resolving 'kinks' of chemotherapy in melanoma.
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Moschos SJ, Chaudhary PM, and Kirkwood JM
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- 2008
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22. Response to 'helping melanoma patients decide whether to choose adjuvant high-dose interferon-alpha2b'.
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Tarhini AA, Shipe-Spotloe J, DeMark M, Agarwala SS, and Kirkwood JM
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- 2006
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23. New observations on vitiligo and ocular disease
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James J. Nordlund, Kirkwood Jm, Aaron B. Lerner, Daniel M. Albert, Bernadette M. Forget, and Michael D. Wagoner
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Adult ,Male ,medicine.medical_specialty ,Visual acuity ,Adolescent ,Eye Diseases ,medicine.medical_treatment ,Population ,Visual Acuity ,Vitiligo ,Uveitis ,Depigmentation ,medicine ,Humans ,Psoriasis ,skin and connective tissue diseases ,education ,Child ,PUVA Therapy ,Aged ,education.field_of_study ,integumentary system ,business.industry ,Incidence (epidemiology) ,Middle Aged ,medicine.disease ,Dermatology ,Ophthalmology ,Child, Preschool ,PUVA therapy ,Female ,sense organs ,medicine.symptom ,business ,Poliosis - Abstract
We examined 223 consecutive patients with vitiligo for ocular disease and 154 consecutive patients with uveitis for vitiligo to better determine the nature of the relationship between vitiligo and ocular disease. Of the 129 patients whose uveitis had an unknown cause, seven (5.4%) had cutaneous depigmentation, poliosis, or early graying of hair. The incidence is 0.5% in the general population (P less than .02). None of the 25 patients whose uveitis had a known cause had vitiligo. Eleven (4.8%) of 223 patients with vitiligo had uveitis at the time of the study or had had it within the previous two years. Of 27 patients in whom vitiligo was associated with cutaneous melanoma, five (18.5%) had had uveitis within the previous two years. In three of these five, the uveitis began within one month of the appearance of cutaneous changes. Evidence of old chorioretinal scars were present in 69 of 223 patients with vitiligo (30.9%) but in only two of 148 control patients (P less than .001). Sixty of 223 patients with vitiligo (26.9%) had evidence of hypopigmentation or atrophy of the retinal pigment epithelium, or both, not related to old chorioretinitis or macular degeneration but only six of 148 controls did (P less than .001).
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- 1983
24. Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment.
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Ascierto PA, Napolitano M, Celentano E, Simeone E, Gentilcore G, Daponte A, Capone M, Caracò C, Calemma R, Beneduce G, Cerrone M, De Rosa V, Palmieri G, Castello G, Kirkwood JM, Marincola FM, Mozzillo N, Ascierto, Paolo A, Napolitano, Maria, and Celentano, Egidio
- Abstract
Background: High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen.Methods: Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.Results: Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b.Conclusions: Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present. [ABSTRACT FROM AUTHOR]- Published
- 2010
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25. Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.
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Ribas A, Kirkwood JM, Atkins MB, Whiteside TL, Gooding W, Kovar A, Gillies SD, Kashala O, Morse MA, Ribas, Antoni, Kirkwood, John M, Atkins, Michael B, Whiteside, Theresa L, Gooding, William, Kovar, Andreas, Gillies, Stephen D, Kashala, Oscar, and Morse, Michael A
- Abstract
Background: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.Methods: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.Results: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.Conclusion: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine. [ABSTRACT FROM AUTHOR]- Published
- 2009
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26. Adjuvant therapy of melanoma with interferon: lessons of the past decade.
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Ascierto PA and Kirkwood JM
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- 2008
27. A systematic approach to biomarker discovery; preamble to "the iSBTc-FDA taskforce on immunotherapy biomarkers".
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Butterfield LH, Disis ML, Fox BA, Lee PP, Khleif SN, Thurin M, Trinchieri G, Wang E, Wigginton J, Chaussabel D, Coukos G, Dhodapkar M, Håkansson L, Janetzki S, Kleen TO, Kirkwood JM, Maccalli C, Maecker H, Maio M, and Malyguine A
- Abstract
The International Society for the Biological Therapy of Cancer (iSBTc) has initiated in collaboration with the United States Food and Drug Administration (FDA) a programmatic look at innovative avenues for the identification of relevant parameters to assist clinical and basic scientists who study the natural course of host/tumor interactions or their response to immune manipulation. The task force has two primary goals: 1) identify best practices of standardized and validated immune monitoring procedures and assays to promote inter-trial comparisons and 2) develop strategies for the identification of novel biomarkers that may enhance our understating of principles governing human cancer immune biology and, consequently, implement their clinical application. Two working groups were created that will report the developed best practices at an NCI/FDA/iSBTc sponsored workshop tied to the annual meeting of the iSBTc to be held in Washington DC in the Fall of 2009. This foreword provides an overview of the task force and invites feedback from readers that might be incorporated in the discussions and in the final document. [ABSTRACT FROM AUTHOR]
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- 2008
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28. Prognostic significance of autoimmunity during treatment of melanoma with interferon.
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Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A, Markopoulos C, Bafaloukos D, Pectasides D, Fountzilas G, Kirkwood JM, Gogas, Helen, Ioannovich, John, Dafni, Urania, Stavropoulou-Giokas, Catherine, and Frangia, Konstantina
- Abstract
Background: Immunotherapy for advanced melanoma induces serologic and clinical manifestations of autoimmunity. We assessed the prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b.Methods: We enrolled 200 patients in a substudy of a larger, ongoing randomized trial. Blood was obtained before the initiation of intravenous interferon therapy, after 1 month of therapy, and at 3, 6, 9, and 12 months. Serum was tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo.Results: The median duration of follow-up was 45.6 months. Relapse occurred in 115 patients, and 82 patients died. The median relapse-free survival was 28.0 months, and the median overall survival was 58.7 months. Autoantibodies and clinical manifestations of autoimmunity were detected in 52 patients (26 percent). The median relapse-free survival was 16.0 months among patients without autoimmunity (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P<0.001).Conclusions: The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with interferon alfa-2b is associated with statistically significant improvements in relapse-free survival and overall survival in patients with melanoma. [ABSTRACT FROM AUTHOR]- Published
- 2006
29. The adjuvant therapy of early breast cancer: update of the Naples (GUN) study
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BIANCO AR, DE PLACIDO S, PERRONE F, DEL MASTRO L, DE LAURENTIIS M, CARLOMAGNO C, PETRELLA G, DELRIO P, GALLO, Ciro, MANTOVANI G, BONAVIDA B, DEL GIACCO GS, GRANGER GA, KIRKWOOD JM, Bianco, Ar, DE PLACIDO, S, Perrone, F, DEL MASTRO, L, DE LAURENTIIS, M, Carlomagno, C, Petrella, G, Delrio, P, and Gallo, Ciro
- Published
- 1991
30. LAG-3 and PD-1 synergize on CD8 + T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.
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Andrews LP, Butler SC, Cui J, Cillo AR, Cardello C, Liu C, Brunazzi EA, Baessler A, Xie B, Kunning SR, Ngiow SF, Huang YJ, Manne S, Sharpe AH, Delgoffe GM, Wherry EJ, Kirkwood JM, Bruno TC, Workman CJ, and Vignali DAA
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- Animals, Mice, Autocrine Communication, Humans, Melanoma immunology, Melanoma drug therapy, Female, Cell Line, Tumor, Melanoma, Experimental immunology, T-Cell Exhaustion, Lymphocyte Activation Gene 3 Protein, Programmed Cell Death 1 Receptor metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Interferon-gamma metabolism, Mice, Inbred C57BL, Antigens, CD metabolism
- Abstract
Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8
+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy., Competing Interests: Declaration of interests D.A.A.V. and C.J.W. have patents covering LAG-3, with others pending, and are entitled to a share of net income generated from licensing of these patent rights for commercial development. D.A.A.V. is cofounder and stock holder of Novasenta, Potenza, Tizona, and Trishula; stock holder of Oncorus and Werewolf; has patents licensed and royalties from BMS and Novasenta; is a scientific advisory board member at Tizona, Werewolf, F-Star, Bicara, Apeximmune, and T7/Imreg Bio; is a consultant for BMS, Incyte, Regeneron, Ono Pharma, Peptone, and Avidity Partners; and receives funding from BMS and Novasenta. E.J.W. is an advisor for Danger Bio, Marengo, Janssen, New Limit, Pluto Immunotherapeutics Related Sciences, Rubius Therapeutics, Santa Ana Bio, Synthekine, and Surface Oncology. E.J.W. is a founder of and holds stock in Surface Oncology, Danger Bio, and Arsenal Biosciences. A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis and has research funding from IOME, AbbVie, and Taiwan Bio unrelated to the submitted work. A.H.S. serves on advisory boards for Selecta, Elpiscience, Monopteros, Bicara, Fibrogen, IOME, BioEntre, Corner, and Alixia Therapeutics. She also is on scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, Johns Hopkins Bloomberg Kimmel Institute for Cancer Immunotherapy, Gladstone Institute, Glaxo Smith Kline, Amgen, and Janssen. She is an academic editor for the Journal of Experimental Medicine. A.R.C. is a consultant for Abound Bio., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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31. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8 + T cells to promote antitumor immunity.
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Cillo AR, Cardello C, Shan F, Karapetyan L, Kunning S, Sander C, Rush E, Karunamurthy A, Massa RC, Rohatgi A, Workman CJ, Kirkwood JM, Bruno TC, and Vignali DAA
- Subjects
- Humans, Antigens, CD metabolism, Antigens, CD genetics, Basic-Leucine Zipper Transcription Factors metabolism, Basic-Leucine Zipper Transcription Factors genetics, Cell Differentiation, Cytotoxicity, Immunologic, High Mobility Group Proteins, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Nivolumab therapeutic use, Nivolumab pharmacology, Positive Regulatory Domain I-Binding Factor 1 metabolism, Positive Regulatory Domain I-Binding Factor 1 genetics, Signal Transduction, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Lymphocyte Activation Gene 3 Protein antagonists & inhibitors, Melanoma immunology, Melanoma drug therapy, Melanoma genetics, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8
+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+ TIM3+ CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies., Competing Interests: Declaration of interests A.R.C. is a consultant for AboundBio. J.M.K. is on consulting or scientific advisory boards of Ankyra Therapeutics, Axio Research LLC, Bristol Myers Squibb, Cancer Network, CytomX Therapeutics, DermTech, iOnctura, Iovance Biotherapeutics, IQVIA, Istari Oncology, Jazz Pharmaceuticals Inc., Lytix Biopharma AS, Magnolia Innovation LLC, Merck, Natera Inc., Novartix Pharmaceuticals, OncoCyte Corporation, PathAI Inc., Pfizer Inc., Piper Sandler & Co., PyrOjas Corporation, Regeneron Pharmaceuticals, Replimune Inc., Scopus BioPharma Inc., Takeda, and Valar Labs. J.M.K. received research trial support to institution from Amgen Inc., Bristol Myers Sqiubb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore Ltd., Iovance Biotherapeutics, Lion Biotechnologies Inc., Lytix Biopharma AS, Novartis Pharmaceuticals, Takeda, and Verastem Inc. T.C.B. is a consultant for Galvanize Therapeutics, Tallac Therapeutics, Mestag Therapeutics, Attivare Therapeutics, and Kalivir Therapeutics, and is on the scientific advisory board of Tabby Therapeutics. D.A.A.V. is a cofounder and stockholder of Novasenta, Potenza, Tizona, and Trishula; is a stockholder of Oncorus and Werewolf; has patents licensed and royalties with BMS and Novasenta; is a scientific advisory board member of Tizona, Werewolf, F-Star, Bicara, Apeximmune, and T7/Imreg Bio; and is a consultant for BMS, Incyte, G1 Therapeutics, Inzen Therapeutics, Regeneron, and Avidity Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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32. Automated Quantitative CD8+ Tumor-Infiltrating Lymphocytes and Tumor Mutation Burden as Independent Biomarkers in Melanoma Patients Receiving Front-Line Anti-PD-1 Immunotherapy.
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Fortman D, Karunamurthy A, Hartman D, Wang H, Seigh L, Abukhiran I, Najjar YG, Pantanowitz L, Zarour HM, Kirkwood JM, and Davar D
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- Humans, Female, Male, Middle Aged, Aged, Adult, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Aged, 80 and over, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Melanoma immunology, Lymphocytes, Tumor-Infiltrating immunology, CD8-Positive T-Lymphocytes immunology, Mutation, Biomarkers, Tumor genetics, Immunotherapy methods
- Abstract
Background: CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response., Methods: Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied., Results: Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density ≥222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response., Conclusions: An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade., (© The Author(s) 2024. Published by Oxford University Press.)
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- 2024
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33. NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.
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Dong B, Obermajer N, Tsuji T, Matsuzaki J, Bonura CM, Sander C, Withers H, Long MD, Chavel C, Olejniczak SH, Minderman H, Kirkwood JM, Edwards RP, Storkus WJ, Romero P, and Kalinski P
- Abstract
CTL recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells but also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM-1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes (TIL) and long-term survival of melanoma patients. Using MART-1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM-1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior costimulatory effects of DNAM-1 over CD28 involved enhanced TCR signaling, CTL killer function and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in the antigen specificity and selectivity of killer function. In addition, the elevation of NKR-Ligand expression on cancer cells by chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAA. Our data help to explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.
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- 2024
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34. Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.
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Long GV, Hauschild A, Santinami M, Kirkwood JM, Atkinson V, Mandala M, Merelli B, Sileni VC, Nyakas M, Haydon A, Dutriaux C, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Larkin J, Tan M, Adnaik SB, Burgess P, Jandoo T, and Dummer R
- Abstract
Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)
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- 2024
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35. GZ17-6.02 kills PDX isolates of uveal melanoma.
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Booth L, Roberts JL, Spasojevic I, Baker KC, Poklepovic A, West C, Kirkwood JM, and Dent P
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- Humans, Animals, Mice, Cell Line, Tumor, Signal Transduction drug effects, Autophagy drug effects, Ubiquitin Thiolesterase metabolism, Ubiquitin Thiolesterase genetics, Doxorubicin pharmacology, Doxorubicin therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, TOR Serine-Threonine Kinases metabolism, Tumor Suppressor Proteins metabolism, Tumor Suppressor Proteins genetics, Melanoma drug therapy, Melanoma metabolism, Melanoma pathology, Melanoma genetics, Uveal Neoplasms drug therapy, Uveal Neoplasms metabolism, Uveal Neoplasms pathology, Uveal Neoplasms genetics, Xenograft Model Antitumor Assays
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GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.
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- 2024
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36. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study.
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Luke JJ, Ascierto PA, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, Spagnolo F, Mackiewicz J, Chiarion-Sileni V, Kirkwood JM, Robert C, Grob JJ, de Galitiis F, Schadendorf D, Carlino MS, Wu XL, Fukunaga-Kalabis M, Krepler C, Eggermont AMM, and Long GV
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- Humans, Female, Male, Middle Aged, Chemotherapy, Adjuvant, Aged, Double-Blind Method, Adult, Disease-Free Survival, Aged, 80 and over, Melanoma drug therapy, Melanoma mortality, Melanoma pathology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Neoplasm Staging, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms mortality, Antineoplastic Agents, Immunological therapeutic use
- Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.
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- 2024
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37. Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma: A Pooled Analysis.
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Mangla A, Lee C, Mirsky MM, Wang M, Rothermel LD, Hoehn R, Bordeaux JS, Carroll BT, Theuner J, Li S, Fu P, and Kirkwood JM
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- Female, Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Ipilimumab therapeutic use, Ipilimumab administration & dosage, Ipilimumab adverse effects, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors administration & dosage, Melanoma drug therapy, Melanoma immunology, Melanoma pathology, Neoadjuvant Therapy adverse effects, Nivolumab therapeutic use, Nivolumab administration & dosage, Nivolumab adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Importance: Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known., Objective: To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM., Design, Setting, and Participants: In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM., Interventions: Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab., Main Outcomes and Measures: The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered., Results: Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy., Conclusion and Relevance: In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.
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- 2024
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38. Plain language summary of the CheckMate 76K study results: nivolumab given after stage 2B/2C melanoma is removed by surgery.
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Kirkwood JM, Vecchio MD, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, and Long GV
- Subjects
- Humans, Nivolumab, Ipilimumab therapeutic use, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Randomized Controlled Trials as Topic, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms surgery, Skin Neoplasms etiology
- Abstract
What Is This Summary About?: In this article, we summarize results from the ongoing phase 3 CheckMate 76K clinical study published online in Nature Medicine in October 2023. The study goal was to learn whether nivolumab works as an adjuvant therapy (that is, helps to keep cancer from coming back when it is given after surgery) for stage 2 melanoma (skin cancer) that has not spread to other parts of the body. Nivolumab is an immunotherapy that activates a person's immune system so it can destroy cancer cells. In melanoma, staging describes the severity of the cancer. Melanoma staging ranges from 0 (very thin and confined to the upper layer of the skin) to 4 (spread to distant parts of the body), with earlier stages removed by surgery. The people in this study had stage 2 melanoma that had not spread to the lymph nodes or other organs in the body., How Was the Study Designed?: People 12 years and older with stage 2 melanoma that had not spread and had been removed by surgery were included in CheckMate 76K. People were randomly assigned to receive either nivolumab (526 patients) or placebo (264 patients). A placebo resembles the test medicine but does not contain any active medicines. The researchers assessed whether people who received nivolumab lived longer without their cancer returning and/or spreading to other parts of their bodies (compared with placebo) and if nivolumab was well tolerated., What Were the Results?: Researchers found that people who received nivolumab were 58% less likely to have their cancer return and 53% less likely of having their cancer spread to distant parts of their body, compared with placebo. These reductions in risk with nivolumab were seen in different subgroups of people with a range of characteristics, and regardless of how deep the melanoma had gone into the skin. People taking nivolumab had more side effects than those taking placebo, but most were mild to moderate and manageable., What Do the Results Mean?: Results from CheckMate 76K support the benefit of using nivolumab as a treatment option for people with stage 2 melanoma post-surgery.
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- 2024
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39. Radiomic analysis of patient and inter-organ heterogeneity in response to immunotherapies and BRAF targeted therapy in metastatic melanoma.
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Tompkins A, Gray ZN, Dadey RE, Zenkin S, Batavani N, Newman S, Amouzegar A, Ak M, Ak N, Pak TY, Peddagangireddy V, Mamindla P, Behr S, Goodman A, Ploucha DL, Kirkwood JM, Zarour HM, Najjar YG, Davar D, Colen R, Luke JJ, and Bao R
- Abstract
Background: Variability in treatment response may be attributable to organ-level heterogeneity in tumor lesions. Radiomic analysis of medical images can elucidate non-invasive biomarkers of clinical outcome. Organ-specific radiomic comparison across immunotherapies and targeted therapies has not been previously reported., Methods: We queried UPMC Hillman Cancer Center registry for patients with metastatic melanoma (MEL) treated with immune checkpoint inhibitors (ICI) (anti-PD1/CTLA4 [ipilimumab+nivolumab; I+N] or anti-PD1 monotherapy) or BRAF targeted therapy. Best overall response was measured using RECIST v1.1. Lesions were segmented into discrete volume-of-interest with 400 radiomics features extracted. Overall and organ-specific machine-learning models were constructed to predict disease control (DC) versus progressive disease (PD) using XGBoost., Results: 291 MEL patients were identified, including 242 ICI (91 I+N, 151 PD1) and 49 BRAF. 667 metastases were analyzed, including 541 ICI (236 I+N, 305 PD1) and 126 BRAF. Across cohorts, baseline demographics included 39-47% female, 24-29% M1C, 24-46% M1D, and 61-80% with elevated LDH. Among patients experiencing DC, the organs with the greatest reduction were liver (-88%±12%, I+N; mean±S.E.M.) and lung (-72%±8%, I+N). For patients with multiple same-organ target lesions, the highest inter-lesion heterogeneity was observed in brain among patients who received ICI while no intra-organ heterogeneity was observed in BRAF. 267 patients were kept for radiomic modeling, including 221 ICI (86 I+N, 135 PD1) and 46 BRAF. Models consisting of optimized radiomic signatures classified DC/PD across I+N (AUC=0.85) and PD1 (0.71) and within individual organ sites (AUC=0.72∼0.94). Integration of clinical variables improved the models' performance. Comparison of models between treatments and across organ sites suggested mostly non-overlapping DC or PD features. Skewness, kurtosis, and informational measure of correlation (IMC) were among the radiomic features shared between overall response models. Kurtosis and IMC were also utilized by multiple organ-site models., Conclusions: Differential organ-specific response was observed across BRAF and ICI with within organ heterogeneity observed for ICI but not for BRAF. Radiomic features of organ-specific response demonstrated little overlap. Integrating clinical factors with radiomics improves the prediction of disease course outcome and prediction of tumor heterogeneity.
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- 2024
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40. Correction: Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study.
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Munster P, Iannotti N, Cho DC, Kirkwood JM, Villaruz LC, Gibney GT, Hodi FS, Mettu NB, Jones M, Bowman J, Smith M, Lakshminarayanan M, and O'Day S
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- 2024
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41. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial.
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Schadendorf D, Luke JJ, Ascierto PA, Long GV, Rutkowski P, Khattak A, Del Vecchio M, de la Cruz-Merino L, Mackiewicz J, Sileni VC, Kirkwood JM, Robert C, Grob JJ, Dummer R, Carlino MS, Zhao Y, Kalabis M, Krepler C, Eggermont A, and Scolyer RA
- Subjects
- Humans, Adjuvants, Immunologic therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Combined Modality Therapy, Adolescent, Adult, Melanoma pathology, Skin Neoplasms pathology
- Abstract
Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics., Methods: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm
2 (median) vs ≥5 per mm2 ), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present)., Results: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2 and 0.57 (0.40 to 0.80) for ≥5 per mm2 ; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS., Conclusions: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma., Trial Registration Number: ClinicalTrials.gov, NCT03553836., Competing Interests: Competing interests: DS reports being an invited speaker for BMS, Merck Serono, MSD, Novartis, Roche, and Sanofi; having advisory board roles with BMS, Immunocore, MSD, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, and Sanofi/Regeneron; research grants from BMS and MSD; being a steering committee member for BMS, MSD, and Novartis; being a coordinating PI for BMS, MSD, Novartis, and Pierre Fabre; being a local PI for Philogen and Sanofi; and being member of the board of directors for EORTC-MG (non-financial). JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; having two provisional patents (serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)); participating on a data safety monitoring board or advisory board for AbbVie, Immutep, and Evaxion; having leadership or a fiduciary role in the Society for Immunotherapy of Cancer; and having stock or stock options in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest. PAA reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, and Bayer; support for attending meetings and/or travel from Pfizer, Bio-Al Health, and Replimmune; and participating on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, and Erasca. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, and Regeneron. PR reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicine; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, AstraZeneca, Philogen and Blueprint Medicine. AK reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing or educational events from MSD and support for attending meetings and/or travel from MSD. MDV reports consulting fees from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Immunocore. LdlC-M reports grants or contracts from Roche, Celgene, and MSD; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, MSD-Merck, Novartis, Roche, AstraZeneca, Incyte, and Gilead; and support for attending meetings and/or travel from Gilead. JM reports payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; support for attending meetings and/or travel from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis; and participation on a data safety monitoring board or advisory board for MSD, Bristol Myers Squibb, and Novartis. VCS reports consulting fees from Pierre Fabre, Novartis, Merck-Serono, and Bristol Myers Squibb; support for attending meetings and/or travel from Pierre Fabre and Bristol Myers Squibb; and participation on a data safety monitoring board or advisory board for Merck Sharp and Dohme and Pierre Fabre. JMK reports consulting fees from Amgen Inc., Ankyra Therapeutics, Applied Clinical Intelligence LLC, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore LLC, iOnctura, Iovance Biotherapeutics, Istari Oncology, Jazz Pharmaceuticals Inc., Magnolia Innovation LLC, Merck, Natera Inc, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc, PathAI Inc, Pfizer Inc, Regeneron Pharmaceuticals Inc, Replimune Inc, Scopus BioPharma Inc, SR One Capital Management LP, and Takeda; research trial support to institution from Amgen Inc, Bristol Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co, Immunocore Ltd, Iovance Biotherapeutics, Lion Biotechnologies Inc, Novartis Pharmaceuticals, Takeda, and Verastem Inc; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS; support for attending meetings and/or travel from Checkmate Pharmaceuticals, BMS, Regeneron, Ankyra Therapeutics, and Iovance Biotherapeutics; and participation on a data safety monitoring board or advisory board for Axio Research and IQVIA. CR reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Merck, MSD, Sun Pharma, and AstraZeneca; participation on a data safety monitoring board or advisory board for BMS, Roche, Pierre Fabre, Novartis, Sun Pharma, Sanofi, Merck, MSD, and AstraZeneca; and stock or stock options in Ribonexus. J-JG reports grants or contracts from Pierre Fabre (institution); consulting fees from Novartis, BMS, MSD, Pierre Fabre, Amgen, Sanofi, and Philogen; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS, Novartis, and Pierre Fabre; support for attending meetings and/or travel from BMS, Novartis, MSD, and Pierre Fabre; and participation on a data safety monitoring board or advisory board for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Philogen. RD reports consulting fees from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and TouchIME; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, and touchIME. MSC reports consulting fees from MSD, BMS, Novartis, Amgen, Eisai, Ideaya, Nektar, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, and Sanofi; and payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from MSD, BMS, and Novartis. YZ reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. MK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. CK reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and stock ownership in Merck & Co., Inc., Rahway, New Jersey, USA. AE reports consulting fees from Agenus, BioInvent, BioNTech, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GenOway, IO Biotech, IQVIA, ISA Pharmaceuticals, MSD, Pierre Fabre, Pfizer, Scorpion Pharmaceuticals, Sairopa, Sellas, SkylineDX, TigaTx, and Trained Therapeutics; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing, or educational events from BMS and MSD; support for attending meetings and/or travel from BMS; participation on a data safety monitoring board or advisory board for BioNTeck, IQVIA, and Pfizer; and stock or stock options in IO Biotech, Sairopa, and SkylineDX. RAS reports consulting fees from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, MSD, NeraCare, Amgen Inc., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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42. Author Correction: Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.
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Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, and Long GV
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- 2024
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43. Publisher Correction: Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.
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Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, and Long GV
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- 2024
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44. Real-world outcomes with immuno-oncology therapies in advanced melanoma: final results of the OPTIMIzE registry study.
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Kirkwood JM, Kottschade LA, McWilliams RR, Khushalani NI, Jang S, Hallmeyer S, McDermott DF, Tawbi H, Che M, Lee CH, Ritchings C, Le TK, Park B, and Ramsey S
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- Humans, Nivolumab adverse effects, Ipilimumab adverse effects, Quality of Life, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Registries, Melanoma drug therapy
- Abstract
Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.
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- 2024
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45. Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study.
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Munster P, Iannotti N, Cho DC, Kirkwood JM, Villaruz LC, Gibney GT, Hodi FS, Mettu NB, Jones M, Bowman J, Smith M, Lakshminarayanan M, and O'Day S
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- Humans, Diarrhea, Nausea, Programmed Cell Death 1 Receptor therapeutic use, Neoplasms drug therapy
- Abstract
Purpose: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]., Experimental Design: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks)., Results: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR., Conclusions: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors., Significance: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations., (© 2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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46. Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.
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Hassel JC, Piperno-Neumann S, Rutkowski P, Baurain JF, Schlaak M, Butler MO, Sullivan RJ, Dummer R, Kirkwood JM, Orloff M, Sacco JJ, Ochsenreither S, Joshua AM, Gastaud L, Curti B, Piulats JM, Salama AKS, Shoushtari AN, Demidov L, Milhem M, Chmielowski B, Kim KB, Carvajal RD, Hamid O, Collins L, Ranade K, Holland C, Pfeiffer C, and Nathan P
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- Adult, Humans, HLA-A Antigens, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Melanoma drug therapy, Melanoma mortality, Melanoma secondary, Uveal Neoplasms drug therapy, Uveal Neoplasms mortality, Uveal Neoplasms secondary, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins adverse effects, Recombinant Fusion Proteins therapeutic use
- Abstract
Background: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug., Methods: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival., Results: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred., Conclusions: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)., (Copyright © 2023 Massachusetts Medical Society.)
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- 2023
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47. Prognostic gene expression profile testing to inform use of adjuvant therapy: A survey of melanoma experts.
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Fastner S, Shen N, Hartman RI, Chu EY, Kim CC, Kirkwood JM, and Grossman D
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- Humans, Prognosis, Transcriptome, Gene Expression Profiling methods, Surveys and Questionnaires, Neoplasm Staging, Melanoma genetics, Melanoma therapy, Melanoma pathology, Skin Neoplasms pathology
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Objectives: To investigate current practices and attitudes regarding use of adjuvant immunotherapy and prognostic gene expression profile (GEP) testing among melanoma medical and surgical oncologists., Methods: An anonymous RedCap-based survey was emailed to ~300 melanoma experts., Results: Respondents generally favored adjuvant immunotherapy over observation (73% for all Stage IIIA, 50% for Stage IIB/IIC) and cited a minimum 10-year recurrence risk of 11%-20% (48%) or 21%-30% (33%) to justify treatment, but acknowledged that risks of serious adverse events may outweigh potential benefits for some Stage IIB/IIC patients. While GEP test results did not strongly influence decision-making regarding follow-up or intervention, most were receptive to randomized trials using GEP testing to identify subsets of Stage IIB/IIC (74%) and Stage IB/IIA (54%) patients who may not or may, respectively, benefit from adjuvant therapy., Conclusion: Although most respondents do not routinely use GEP testing, many would participate in clinical trials to determine clinical utility., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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48. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.
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Kirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, Loquai C, Dutriaux C, Chiarion-Sileni V, Mackiewicz J, Rutkowski P, Arenberger P, Quereux G, Meniawy TM, Ascierto PA, Menzies AM, Durani P, Lobo M, Campigotto F, Gastman B, and Long GV
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- Humans, Adjuvants, Immunologic, Antineoplastic Combined Chemotherapy Protocols adverse effects, Double-Blind Method, Neoplasm Staging, Nivolumab, Melanoma, Cutaneous Malignant, Melanoma drug therapy, Melanoma surgery, Skin Neoplasms drug therapy, Skin Neoplasms surgery
- Abstract
Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 ., (© 2023. The Author(s).)
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- 2023
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49. Systemic Therapy for Melanoma: ASCO Guideline Update.
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Seth R, Agarwala SS, Messersmith H, Alluri KC, Ascierto PA, Atkins MB, Bollin K, Chacon M, Davis N, Faries MB, Funchain P, Gold JS, Guild S, Gyorki DE, Kaur V, Khushalani NI, Kirkwood JM, McQuade JL, Meyers MO, Provenzano A, Robert C, Santinami M, Sehdev A, Sondak VK, Spurrier G, Swami U, Truong TG, Tsai KK, van Akkooi A, and Weber J
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- Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Ipilimumab therapeutic use, Nivolumab therapeutic use, Proto-Oncogene Proteins B-raf genetics, Melanoma, Cutaneous Malignant, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Oncolytic Virotherapy, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma., Methods: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature., Results: The updated review identified 21 additional randomized trials., Updated Recommendations: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF -mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.
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- 2023
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50. Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis.
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Pradhan AK, Modi J, Maji S, Kumar A, Bhoopathi P, Mannangatti P, Guo C, Afosah DK, Mochel MC, Mukhopadhyay ND, Kirkwood JM, Wang XY, Desai UR, Sarkar D, Emdad L, Das SK, and Fisher PB
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- Animals, Humans, Syntenins chemistry, Signal Transduction, Peptides metabolism, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism
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Genome-wide gene expression analysis and animal modeling indicate that melanoma differentiation associated gene-9 (mda-9, Syntenin, Syndecan binding protein, referred to as MDA-9/Syntenin) positively regulates melanoma metastasis. The MDA-9/Syntenin protein contains two tandem PDZ domains serving as a nexus for interactions with multiple proteins that initiate transcription of metastasis-associated genes. Although targeting either PDZ domain abrogates signaling and prometastatic phenotypes, the integrity of both domains is critical for full biological function. Fragment-based drug discovery and NMR identified PDZ1i, an inhibitor of the PDZ1 domain that effectively blocks cancer invasion in vitro and in vivo in multiple experimental animal models. To maximize disruption of MDA-9/Syntenin signaling, an inhibitor has now been developed that simultaneously binds and blocks activity of both PDZ domains. PDZ1i was joined to the second PDZ binding peptide (TNYYFV) with a PEG linker, resulting in PDZ1i/2i (IVMT-Rx-3) that engages both PDZ domains of MDA-9/Syntenin. IVMT-Rx-3 blocks MDA-9/Syntenin interaction with Src, reduces NF-κB activation, and inhibits MMP-2/MMP-9 expression, culminating in repression of melanoma metastasis. The in vivo antimetastatic properties of IVMT-Rx-3 are enhanced when combined with an immune-checkpoint inhibitor. Collectively, our results support the feasibility of engineering MDA-9 dual-PDZ inhibitors with enhanced antimetastatic activities and applications of IVMT-Rx-3 for developing novel therapeutic strategies effectively targeting melanoma and in principle, a broad spectrum of human cancers that also overexpress MDA-9/Syntenin., (©2023 American Association for Cancer Research.)
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- 2023
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