Features and Long-Term Outcomes of Stage IV Melanoma Patients Achieving Complete Response Under Anti-PD-1-Based Immunotherapy.
Journal
American journal of clinical dermatology
ISSN: 1179-1888
Titre abrégé: Am J Clin Dermatol
Pays: New Zealand
ID NLM: 100895290
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
accepted:
25
03
2023
medline:
22
5
2023
pubmed:
5
5
2023
entrez:
4
5
2023
Statut:
ppublish
Résumé
Immune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI. We evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined. A total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52-58) and the median time from CR to therapy end was 10 months (IQR 1-17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities. Response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders.
Sections du résumé
BACKGROUND
BACKGROUND
Immune checkpoint inhibition (ICI) has changed the melanoma treatment spectrum. Few studies have examined the characteristics and long-term outcomes of patients achieving complete response (CR) under ICI.
MATERIALS AND METHODS
METHODS
We evaluated patients with unresectable stage IV melanoma treated with first-line ICI. The characteristics of those achieving CR were compared with those not achieving CR. Progression-free survival (PFS) and overall survival (OS) were assessed. Late-onset toxicities, response to second-line treatment, the prognostic value of clinicopathologic features, and blood markers were examined.
RESULTS
RESULTS
A total of 265 patients were included; 41 (15.5%) achieved CR, while 224 (84.5%) had progressive disease, stable disease, or partial response. At the therapy start, those who had CR were more likely to be older than 65 years of age (p = 0.013), have a platelet-to-lymphocyte ratio below 213 (p = 0.036), and have lower lactate dehydrogenase levels (p = 0.008) than those not achieving a CR. For those who discontinued therapy after CR, the median follow-up time after CR was 56 months (interquartile range [IQR] 52-58) and the median time from CR to therapy end was 10 months (IQR 1-17). Five-year PFS after CR was 79% and 5-year OS was 83%. Most complete responders had a normalization of S100 at the time of CR (p < 0.001). In simple Cox regression analysis, age below 77 years at CR (p = 0.04) was associated with better prognosis after CR. Eight patients received second-line ICI; disease control was seen in 63%. Late immune-related toxicities occurred in 25% of patients, most being cutaneous immune-related toxicities.
CONCLUSIONS
CONCLUSIONS
Response, according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, is, until now, the most important prognostic factor, and CR is a valid surrogate marker for long-term survival in patients treated with ICI. Our results highlight the importance of investigating the optimal therapy duration in complete responders.
Identifiants
pubmed: 37142875
doi: 10.1007/s40257-023-00775-7
pii: 10.1007/s40257-023-00775-7
pmc: PMC10195722
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
453-467Informations de copyright
© 2023. The Author(s).
Références
McDermott D, Lebbé C, Hodi FS, Maio M, Weber JS, Wolchok JD, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40(9):1056–64.
pubmed: 25060490
Ribas A, Hodi FS, Kefford R, Hamid O, Daud A, Wolchok JD, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol. 2014;32(15 Suppl):LBA9000-LBA.
Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94.
pubmed: 25667295
pmcid: 5089162
van Zeijl MCT, van den Eertwegh AJM, Wouters M, de Wreede LC, Aarts MJB, van den Berkmortel F, et al. Discontinuation of anti-PD-1 monotherapy in advanced melanoma-outcomes of daily clinical practice. Int J Cancer. 2022;150(2):317–26.
pubmed: 34520567
Marron TU, Ryan AE, Reddy SM, Kaczanowska S, Younis RH, Thakkar D, et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J Immunother Cancer. 2021;9(3): e001901.
pubmed: 33653801
pmcid: 7929825
Mäkelä S, Kohtamäki L, Laukka M, Juteau S, Hernberg M. Limited-duration anti-PD-1 therapy for patients with metastatic melanoma. Acta Oncol. 2020;59(4):438–43.
pubmed: 32000554
Asher N, Israeli-Weller N, Shapira-Frommer R, Ben-Betzalel G, Schachter J, Meirson T, et al. Immunotherapy discontinuation in metastatic melanoma: lessons from real-life clinical experience. Cancers (Basel). 2021;13(12):3074.
pubmed: 34203061
pmcid: 8234591
Betof Warner A, Palmer JS, Shoushtari AN, Goldman DA, Panageas KS, Hayes SA, et al. Long-term outcomes and responses to retreatment in patients with melanoma treated with PD-1 blockade. J Clin Oncol. 2020;38(15):1655–63.
pubmed: 32053428
pmcid: 7238490
Jansen YJL, Rozeman EA, Mason R, Goldinger SM, GeukesFoppen MH, Hoejberg L, et al. Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann Oncol. 2019;30(7):1154–61.
pubmed: 30923820
Jansen Y, van der Veldt AAM, Awada G, Neyns B. Anti-PD-1: when to stop treatment. Curr Oncol Rep. 2022;24(7):905–15.
pubmed: 35347590
Robert C, Long G, Larkin J, Wolchok JD, Hassel J, Schadendorf D, et al. 1082MO 5-year characterization of complete responses in patients with advanced melanoma who received nivolumab plus ipilimumab (NIVO+IPI) or NIVO alone. Ann Oncol. 2020;31:S734–5.
Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol. 2018;36(17):1668–74.
pubmed: 29283791
Dimitriou F, Zaremba A, Allayous C, Kähler KC, Gerard CL, Festino L, et al. Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response. Eur J Cancer. 2021;149:37–48.
pubmed: 33823361
Saiag P, AitMehdi R, Blom A, Longvert C, Emile J-F, Boru B, et al. Discontinuation of anti-PD-1 mAb after complete response in advanced melanoma pts. J Clin Oncol. 2018;36(15 Suppl): e21549.
De Risi I, Sciacovelli AM, Guida M. Checkpoint inhibitors immunotherapy in metastatic melanoma: when to stop treatment? Biomedicines. 2022;10(10):2424.
pubmed: 36289687
pmcid: 9599026
Dutheil A, Belkadi D, Antigny M, Roy S, Lupu J, Vallet A, et al. Complete responders to checkpoint inhibitors in advanced melanoma: relapse risk factors, and patients’ outcomes. J Clin Oncol. 2021;39(15 Suppl):9550.
Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472–92.
pubmed: 29028110
pmcid: 5978683
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
pubmed: 19097774
Kugel CH III, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res. 2018;24(21):5347–56.
pubmed: 29898988
pmcid: 6324578
Machiraju D, Schäfer S, Hassel JC. Potential reasons for unresponsiveness to anti-PD1 immunotherapy in young patients with advanced melanoma. Life (Basel). 2021;11(12):1318.
pubmed: 34947849
pmcid: 8707626
Wu Q, Wang Q, Tang X, Xu R, Zhang L, Chen X, et al. Correlation between patients’ age and cancer immunotherapy efficacy. Oncoimmunology. 2019;8(4): e1568810.
pubmed: 30906662
pmcid: 6422380
Espinosa E, Márquez-Rodas I, Soria A, Berrocal A, Manzano JL, Gonzalez-Cao M, et al. Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM). Ann Transl Med. 2017;5(19):389.
pubmed: 29114547
pmcid: 5653511
Weide B, Elsässer M, Büttner P, Pflugfelder A, Leiter U, Eigentler TK, et al. Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis. Br J Cancer. 2012;107(3):422–8.
pubmed: 22782342
pmcid: 3405231
Amaral T, Seeber O, Mersi E, Sanchez S, Thomas I, Meiwes A, et al. Primary resistance to PD-1-based immunotherapy: a study in 319 patients with stage IV melanoma. Cancers. 2020;12(4):1027.
pubmed: 32331243
pmcid: 7226601
Qi Y, Zhang Y, Fu X, Wang A, Yang Y, Shang Y, et al. Platelet-to-lymphocyte ratio in peripheral blood: a novel independent prognostic factor in patients with melanoma. Int Immunopharmacol. 2018;56:143–7.
pubmed: 29414644
Zhou X, Du Y, Huang Z, Xu J, Qiu T, Wang J, et al. Prognostic value of PLR in various cancers: a meta-analysis. PLoS ONE. 2014;9(6): e101119.
pubmed: 24968121
pmcid: 4072728
Kim J-Y, Jung EJ, Kim J-M, Lee HS, Kwag S-J, Park J-H, et al. Dynamic changes of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio predicts breast cancer prognosis. BMC Cancer. 2020;20(1):1206.
pubmed: 33287745
pmcid: 7720486
Guida M, Bartolomeo N, Quaresmini D, Quaglino P, Madonna G, Pigozzo J, et al. Basal and one-month differed neutrophil, lymphocyte and platelet values and their ratios strongly predict the efficacy of checkpoint inhibitors immunotherapy in patients with advanced BRAF wild-type melanoma. J Transl Med. 2022;20(1):159.
pubmed: 35382857
pmcid: 8981693
Lee JC, Green MD, Huppert LA, Chow C, Pierce RH, Daud AI. The liver-immunity nexus and cancer immunotherapy. Clin Cancer Res. 2022;28(1):5–12.
pubmed: 34285059
pmcid: 8897983
Chatziioannou E, Aydin SA, Forchhammer S, Sinnberg T, Eigentler T. Makrophagen im Melanom—von molekularen Signalen zur therapeutischen Anwendung. Die Dermatologie. 2022;73(12):915–28.
pubmed: 36394590
Pires da Silva I, Lo S, Quek C, Gonzalez M, Carlino MS, Long GV, et al. Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy. Cancer. 2020;126(1):86–97.
pubmed: 31584722
Stein JE, Soni A, Danilova L, Cottrell TR, Gajewski TF, Hodi FS, et al. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019;30(4):589–96.
pubmed: 30689736
pmcid: 6503625
Borm FJ, Smit J, Oprea-Lager DE, Wondergem M, Haanen J, Smit EF, et al. Response prediction and evaluation using PET in patients with solid tumors treated with immunotherapy. Cancers (Basel). 2021;13(12):3083.
pubmed: 34205572
pmcid: 8234914
Dimitriou F, Lo SN, Tan AC, Emmett L, Kapoor R, Carlino MS, et al. FDG-PET to predict long-term outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol. 2022;33(1):99–106.
pubmed: 34687894
Schank TE, Forschner A, Sachse MM, Dimitrakopoulou-Strauss A, Sachpekidis C, Stenzinger A, et al. Complete metabolic response in FDG-PET-CT scan before discontinuation of immune checkpoint inhibitors correlates with long progression-free survival. Cancers (Basel). 2021;13(11):2616.
pubmed: 34073477
pmcid: 8198795
Ellebaek E, Schina A, Andersen R, Hendel HW, Svane IM, Donia M. Clinical value of routine [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography scans as a decision tool for early immunotherapy discontinuation in advanced melanoma. Int J Cancer. 2022;150(11):1870–8.
pubmed: 35001363
Coen O, Corrie P, Marshall H, Plummer R, Ottensmeier C, Hook J, et al. The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma. BMC Cancer. 2021;21(1):761.
pubmed: 34210290
pmcid: 8246129
Mulder E, de Joode K, Litière S, Ten Tije AJ, Suijkerbuijk KPM, Boers-Sonderen MJ, et al. Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial. BMC Cancer. 2021;21(1):323.
pubmed: 33765967
pmcid: 7993897
Hirsch I, Goldstein DA, Tannock IF, Butler MO, Gilbert DC. Optimizing the dose and schedule of immune checkpoint inhibitors in cancer to allow global access. Nat Med. 2022;28(11):2236–7.
pubmed: 36202999
Amrane K, Le Goupil D, Quere G, Delcroix O, Gouva S, Schick U, et al. Prediction of response to immune checkpoint inhibitor therapy using 18F-FDG PET/CT in patients with melanoma. Medicine (Baltimore). 2019;98(29): e16417.
pubmed: 31335691
Kitajima K, Watabe T, Nakajo M, Ishibashi M, Daisaki H, Soeda F, et al. Tumor response evaluation in patients with malignant melanoma undergoing immune checkpoint inhibitor therapy and prognosis prediction using (18)F-FDG PET/CT: multicenter study for comparison of EORTC, PERCIST, and imPERCIST. Jpn J Radiol. 2022;40(1):75–85.
pubmed: 34287739
Tan L, Sandhu S, Lee RJ, Li J, Callahan J, Ftouni S, et al. Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann Oncol. 2019;30(5):804–14.
pubmed: 30838379
pmcid: 6551451
Vanni I, Tanda ET, Spagnolo F, Andreotti V, Bruno W, Ghiorzo P. The current state of molecular testing in the BRAF-mutated melanoma landscape. Front Mol Biosci. 2020. https://doi.org/10.3389/fmolb.2020.00113 .
doi: 10.3389/fmolb.2020.00113
pubmed: 32850962
pmcid: 7396525
Boyer M, Cayrefourcq L, Dereure O, Meunier L, Becquart O, Alix-Panabières C. Clinical relevance of liquid biopsy in melanoma and merkel cell carcinoma. Cancers. 2020;12:960.
pubmed: 32295074
pmcid: 7226137
Kamińska P, Buszka K, Zabel M, Nowicki M, Alix-Panabières C, Budna-Tukan J. Liquid biopsy in melanoma: significance in diagnostics, prediction and treatment monitoring. Int J Mol Sci 2021;22(18).
Pitcovski J, Shahar E, Aizenshtein E, Gorodetsky R. Melanoma antigens and related immunological markers. Crit Rev Oncol Hematol. 2017;115:36–49.
pubmed: 28602168
Hasan Ali O, Diem S, Markert E, Jochum W, Kerl K, French LE, et al. Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer. OncoImmunology. 2016;5(11): e1231292.
pubmed: 27999741
pmcid: 5139632
Failla CM, Carbone ML, Fortes C, Pagnanelli G, Datri S. Melanoma and vitiligo: in good company. Int J Mol Sci. 2019;20(22):5731.
pubmed: 31731645
pmcid: 6888090
Byrne KT, Turk MJ. New perspectives on the role of vitiligo in immune responses to melanoma. Oncotarget. 2011;2(9):684–94.
pubmed: 21911918
pmcid: 3248219
Zhao J-J, Wen X-Z, Ding Y, Li D-D, Zhu B-Y, Li J-J, et al. Association between immune-related adverse events and efficacy of PD-1 inhibitors in Chinese patients with advanced melanoma. Aging. 2020;12(11):10663–75.
pubmed: 32516130
pmcid: 7346077
Wu C-E, Yang C-K, Peng M-T, Huang P-W, Chang C-F, Yeh K-Y, et al. The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies. BMC Cancer. 2020;20:1018.
pubmed: 33087090
pmcid: 7579996
Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51.
pubmed: 26501224
Carlet C, Dalle S, Leccia M-T, Mortier L, Dalac-Rat S, Dutriaux C, et al. Late-onset adverse events of anti-PD1 therapy in melanoma patients: an observational study from MELBASE, a nationwide prospective cohort. J Am Acad Dermatol. 2022;86(2):345–52.
pubmed: 34153388