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. 2023 May;24(3):453-467.
doi: 10.1007/s40257-023-00775-7. Epub 2023 May 4.

Features and Long-Term Outcomes of Stage IV Melanoma Patients Achieving Complete Response Under Anti-PD-1-Based Immunotherapy

Eftychia Chatziioannou  1 , Ulrike Leiter  1 , Ioannis Thomas  1 , Ulrike Keim  1 , Olivia Seeber  1 , Andreas Meiwes  1 , Isabell Boessenecker  1 , Stephanie Sanchez Gonzalez  1 , Francisco Merraz Torres  1 , Heike Niessner  1   2 , Tobias Sinnberg  1   2   3 , Andrea Forschner  1 , Lukas Flatz  1   4 , Teresa Amaral  5   6
Affiliations

Features and Long-Term Outcomes of Stage IV Melanoma Patients Achieving Complete Response Under Anti-PD-1-Based Immunotherapy

Eftychia Chatziioannou et al. Am J Clin Dermatol. 2023 May.

Abstract

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: 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: 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: 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.

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Conflict of interest statement

Ulrike Leiter reports research support from MSD; consulting fees and honoraria from Sun Pharma, Sanofi (personal and institutional), MSD (personal and institutional), Novartis, Roche, and Almirall Hermal; support for attending meetings from Sun Pharma; and participation on a Data Safety Monitoring Board or Advisory Board from Sun Pharma, Sanofi, MSD, Novartis, Roche, and Almirall Hermal, outside the submitted work. Ioannis Thomas reports honoraria for talks or advisory boards from BMS and Pierre Fabre; and research funding (institutional) from BMS, Pfizer, MSD, Amgen, ARGN-X, LEO, Novartis, UCB, 4SC, AstraZeneca, BioNTech, Genentech, Roche, Biotech, CureVac, HUYA, Incyte, Idera, Iovance, InflaRx, Cerpass, Kartos, Nektar, Philogen, Pierre Fabre, Regeneron, Replimune, and Sanofi. Heike Niessner reports institutional funding from Novartis and Pierre Fabre outside the submitted work. Tobias Sinnberg reports institutional funding from Novartis and Pierre Fabre outside the submitted work. Andrea Forschner served as a consultant to Roche, Novartis, MSD, BMS, and Pierre Fabre; received travel support from Roche, Novartis, BMS, and Pierre Fabre; received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT; and reports institutional research grants from BMS Stiftung Immunonkologie. Lukas Flatz reports grants or contracts from Hookipa Pharma, SAKK/Immunophotonics, DFG Grant (Deutsche Forschungsgemeinschaft), Philogen, and Mundipharma; consulting fees from Philogen, Sanofi, Novartis, and BMS; participation on the Data Safety Board, University of Basel; and stocks or stock options from Hookipa Pharma, outside the submitted work. Teresa Amaral reports personal honoraria from BMS, CeCaVa, Novartis, and Pierre Fabre; institutional financial support from iFIT, NeraCare, Novartis, Sanofi, and SkylineDx, and an institutional research grant from Novartis, outside the submitted work. Eftychia Chatziioannou, Ulrike Keim, Olivia Seeber, Andreas Meiwes, Isabell Boessenecker, Stephanie Sanchez Gonzalez, and Francisco Merraz Torres have no relationships to disclose.

Figures

Fig. 1
Fig. 1
a Patient FUP using the reverse Kaplan–Meier method of those who achieved a CR under ICI. Time is calculated since CR. The mFUP time after CR was 56 months (95% CI 52–58). b Patient FUP using the reverse Kaplan–Meier method after treatment discontinuation. mFUP time after treatment discontinuation was 47 months (95% CI 38–51). c Five-year PFS analysis of patients (n = 40) who achieved a CR under ICI and subsequently discontinued therapy. The Kaplan–Meier curve is displayed, and time is calculated since achieving CR. The 5-year PFS was 79% (95% CI 62–89%). d Five-year PFS analysis of patients (n = 40) who achieved a CR under ICI and subsequently discontinued therapy. The Kaplan–Meier curve is displayed, and time is calculated since treatment discontinuation. ICI immune checkpoint inhibition, CR complete response, FUP follow-up, mFUP median follow-up, CI confidence interval, PFS progression-free survival
Fig. 2
Fig. 2
a The 5-year OS analysis of patients according to the response. The Kaplan–Meier curve is displayed, and time is calculated since therapy initiation. b The 5-year PFS analysis of patients according to the response. The Kaplan–Meier curve is displayed, and time is calculated since treatment initiation. OS overall survival, PFS progression-free survival, RECIST Response Evaluation Criteria in Solid Tumors, CR complete response, PR partial response, SD stable disease, PD progressive disease
Fig. 3
Fig. 3
a–g Dot plots showing the variation of blood biomarkers (LDH, S100, PLR, NLR, and relative lymphocyte count) in patients who achieved a CR from baseline value at the time of therapy start (T0) to the time of complete response (T1) and time of progression (T2). Each line represents one patient, and the plots show only patients whose values were reported at both time points. LDH lactate dehydrogenase, PLR platelet-to-lymphocyte ratio, NLR neutrophil-to-lymphocyte ratio, CR complete response
Fig. 4
Fig. 4
a Patient swimmer plot showing the time patients achieved a CR under first-line immunotherapy. The type of ICI, therapy duration, off-treatment duration, response to rechallenge with second-line immunotherapy, disease progression, and death as events are also depicted. Type of treatment includes PD-1 inhibitor monotherapy (PD-1 inhibitor), CTLA-4 inhibitor monotherapy (CTLA-4 inhibitor), and combined CTLA-4 and PD-1 inhibitor (CombiIT). b Patient swimmer plot showing the late-onset irAEs related to first-line immunotherapy. The time of onset and late-occurring immune-related toxicities are depicted. Type of treatment includes PD-1 inhibitor monotherapy (PD-1 inhibitor), CTLA-4 inhibitor monotherapy (CTLA-4 inhibitor), and combined CTLA-4 and PD-1 inhibitor (CombiIT). CR complete response, PR partial response, SD stable disease, PD progressive disease, CombiIT combination immunotherapy, irAEs immune-related adverse events, ICI immune checkpoint inhibition, PD-1 programmed death-1, CTLA-4 cytotoxic T-lymphocyte-associated protein 4
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