Real‐world effectiveness of chemotherapy regimens after immunotherapy in patients with advanced melanoma in Spain: Results from the GEM1801 study

Miguel‐Ángel Berciano‐Guerrero; Elisabeth Pérez‐Ruiz; Ainara Soria; Javier Medina Martínez; Pablo Ayala de Miguel; Eva Muñoz‐Couselo; Lorena Bellido; Rafael López Castro; Enrique Espinosa; Lourdes Gutiérrez Sanz; Pablo Cerezuela‐Fuentes; Almudena García Castaño; Guillermo Crespo; Teresa Puértolas; Carlos Aguado de la Rosa; Mónica Corral Subias; Begoña Campos Balea; Aida Bujosa Rodríguez; Victor Navarro Pérez; María José Lecumberri; Francisco Ramón García Arroyo; Alberto Jacobo Cunquero Tomás; Karmele Mujika; Luis Antonio Fernández; José Carlos Villa Guzmán; Berta Hernández; Joaquín Fra Rodríguez; José Luis Manzano; Salvador Martín Algarra; Iván Márquez‐Rodas

doi:10.1002/cncr.70497

. 2026 Jul 7;132(14):e70497. doi: 10.1002/cncr.70497

Real‐world effectiveness of chemotherapy regimens after immunotherapy in patients with advanced melanoma in Spain: Results from the GEM1801 study

Miguel‐Ángel Berciano‐Guerrero ^1,^2,^3,^4,^✉, Elisabeth Pérez‐Ruiz ^1,², Ainara Soria ⁵, Javier Medina Martínez ⁶, Pablo Ayala de Miguel ⁷, Eva Muñoz‐Couselo ⁸, Lorena Bellido ⁹, Rafael López Castro ¹⁰, Enrique Espinosa ¹¹, Lourdes Gutiérrez Sanz ¹², Pablo Cerezuela‐Fuentes ¹³, Almudena García Castaño ^14,^{^†}, Guillermo Crespo ¹⁵, Teresa Puértolas ¹⁶, Carlos Aguado de la Rosa ¹⁷, Mónica Corral Subias ¹⁸, Begoña Campos Balea ¹⁹, Aida Bujosa Rodríguez ²⁰, Victor Navarro Pérez ²¹, María José Lecumberri ²², Francisco Ramón García Arroyo ²³, Alberto Jacobo Cunquero Tomás ²⁴, Karmele Mujika ²⁵, Luis Antonio Fernández ²⁶, José Carlos Villa Guzmán ²⁷, Berta Hernández ²⁸, Joaquín Fra Rodríguez ²⁹, José Luis Manzano ³⁰, Salvador Martín Algarra ³¹, Iván Márquez‐Rodas ³²

^¹Medical Oncology Department, Hospital Regional Universitario, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Málaga, Spain

^²Medical Oncology Intercenter Unit, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain

^³Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA‐BIONAND), Málaga, Spain

^⁴University of Málaga, Málaga, Spain

^⁵Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain

^⁶Medical Oncology Department, Hospital Universitario de Toledo, Toledo, Spain

^⁷Medical Oncology Department, Hospital Universitario San Pedro de Alcántara, Cáceres, Spain

^⁸Medical Oncology Department, Hospital Universitari Vall d’Hebron and Vall d'Hebron Institute of Oncology, Barcelona, Spain

^⁹Medical Oncology Department, Hospital Universitario Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

^¹⁰Medical Oncology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain

^¹¹Universidad Autónoma de Madrid, School of Medicine, Hospital Universitario La Paz, CIBERONC, Madrid, Spain

^¹²Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain

^¹³Medical Oncology Department, Instituto Murciano de Investigación Sanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Ciudad de Murcia, Spain

^¹⁴Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain

^¹⁵Medical Oncology Department, Hospital Universitario de Burgos, Burgos, Spain

^¹⁶Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain

^¹⁷Medical Oncology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain

^¹⁸Medical Oncology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

^¹⁹Medical Oncology Department, Hospital Lucus Augusti, Lugo, Spain

^²⁰Medical Oncology Department, Hospital Son Llàtzer, Palma de Mallorca, Spain

^²¹Medical Oncology Department, Hospital Universitario Costa del Sol, Marbella, Spain

^²²Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain

^²³Medical Oncology Department, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain

^²⁴Medical Oncology, Consorcio Hospital General Universitario de Valencia, Valencia, Spain

^²⁵Medical Oncology Department, Onkologikoa Fundazioa, Donosti, Spain

^²⁶Medical Oncology Department, Hospital Universitari Parc Taulí de Sabadell, Sabadell, Spain

^²⁷Medical Oncology Department, Hospital General de Ciudad Real, Ciudad Real, Spain

^²⁸Medical Oncology Department, Hospital Universitario de la Princesa, Madrid, Spain

^²⁹Medical Oncology Department, Hospital Universitario Río Hortega, Valladolid, Spain

^³⁰Medical Oncology Department, Institut Català d’Oncologia, ICO‐Badalona, H. Germans Trias i Pujol, Badalona, Spain

^³¹Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain

^³²Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Correspondence , Miguel‐Ángel Berciano‐Guerrero, Medical Oncology Department, Hospital Regional Universitario, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Málaga 29011, Spain. Email: mangel.berciano.sspa@juntadeandalucia.es

^{^†}

Died December 27, 2025.

^✉

Corresponding author.

PMCID: PMC13339129 PMID: 42411543

ABSTRACT

Background

Chemotherapy schemes have historically shown low efficacy in patients with metastatic melanoma and have been replaced by immunotherapy and targeted therapy. This work aimed to study whether chemotherapy remains an option after progression to immunotherapy in specific contexts.

Methods

The GEM1801 registry includes patients with advanced melanoma in Spain. For this substudy, patients with metastatic melanoma who received chemotherapy after immunotherapy were selected. Baseline characteristics and treatment outcomes were analyzed.

Results

Of the 1316 patients included, with a median time of 4.8 months (range, 0.0–35.8) from the first immunotherapy, 92 received chemotherapy: 12 after adjuvant immunotherapy (cohort A), 45 subsequently to immunotherapy (cohort B), and 35 after receiving bridge therapies (cohort C). The median age was 66 years (range, 35–94), and 55.4% of the patients were male. Most patients had an Eastern Cooperative Oncology Group (ECOG) status of ≤1 (65.2%), whereas only 21.7% had ECOG 2. Among the patients, 54.3% had elevated lactate dehydrogenase levels. Chemotherapy regimens received were taxane/platinum‐based therapies (47.8%), dimethyl triazeno imidazol carboxamide (DTIC) (26.1%), fotemustine (17.4%), and other alkylating agents such as temozolomide (8.7%). With a median follow‐up of 31.9 months, the objective response rate was 12%, the median progression‐free survival was 3.5 months (95% CI, 2.9–4.8), and the median overall survival was 6.1 months (95% CI, 5.3–9.2).

Conclusions

As in previous studies, patients treated with chemotherapy after immunotherapy failure had poor outcomes, similar to those from pre‐immunotherapy era, and should be used when no other options are available.

Keywords: chemotherapy, immune checkpoint inhibitors, metastatic melanoma, real‐world

Short abstract

Immunotherapy does not enhance the efficacy of subsequent chemotherapy and should be used when no other options are available.

INTRODUCTION

Melanoma is the deadliest form of cutaneous cancer. With large variations across world regions, the incidence rates observed were 19/100,000 person‐years (males and females) in Western Europe, 18/100,000 person‐years for men and 14/100,000 person‐years for women in North America, and less than 1/100,000 person‐years in African and Asian countries. ¹ In Spain, the Sociedad Española de Oncología Médica (SEOM) estimates 9408 new cases of melanoma in 2025, 20% higher than in 2024. ² Despite efforts in prevention, early detection, and the introduction of new therapeutic regimens, patients with metastatic melanoma have a 10‐year overall survival (OS) below 50%, ³ , ⁴ underscoring the need to explore and optimize therapeutic options.

Historically, chemotherapy regimens have shown modest efficacy and significant toxicity, with only a small proportion of patients obtaining benefit. ⁵ The introduction of targeted therapies, such as BRAF/MEK inhibitors ⁶ , ⁷ , ⁸ and immune checkpoint inhibitors (ICIs), such as anti–PD‐1 with or without anti‐CTLA4, ³ , ⁴ have revolutionized the therapeutic landscape in melanoma and have become the standard of care. First‐line targeted therapies in BRAF‐mutated patients showed an improved objective response rate (ORR) and longer progression‐free survival (PFS) than those obtained with dimethyl triazeno imidazol carboxamide (DTIC) in phase 3 clinical trials. ⁹ , ¹⁰ ICIs have also demonstrated superior efficacy in phase 3 clinical trials compared to investigator‐chosen chemotherapy. ¹¹ , ¹² The benefits of ICI for the treatment of patients with advanced melanoma have been consolidated in recent years and are recommended by current guidelines. ¹³ Therefore, chemotherapy is relegated as a latter‐line therapy, being recommended by these clinical guidelines after failure of standard first‐line therapies (targeted therapy or immunotherapy), contraindication to immunotherapy, or in palliative settings where disease control is required when clinical trials are not available. ¹³ , ¹⁴

The rapid substitution of chemotherapy as the standard of care by ICI and targeted therapies has resulted in the current lack of available efficacy data for chemotherapy in the post‐modern therapy setting. Chemotherapy regimens such as fotemustine, DTIC, or temozolomide reported a PFS lower than 2 months, an OS of less than 8 months, and an ORR of less than 14%. ⁵ , ¹⁵ Moreover, in several tumor types, there is growing evidence of a synergistic effect between immunotherapy and chemotherapy, and both therapies are used concurrently. ¹⁶ , ¹⁷ , ¹⁸ Chemotherapy may enhance or restore ICI efficacy through mechanisms such as T‐cell response activation, ¹⁹ natural killer cell activation, ²⁰ or reduction of myeloid‐derived suppressor cells. ²¹ However, whether this synergistic effect is reciprocal and whether ICI can enhance the efficacy of subsequent chemotherapy remains unclear. Data on chemotherapy efficacy after ICI treatment in melanoma are limited to date. In clinical trials, after progression to ipilimumab, the median PFS was 4.2 months, and the ORR was 11%. ¹² In a retrospective study of Polish patients, chemotherapy after ICI showed a median PFS and OS of 2.8 and 6 months, respectively, and a response rate of 17%. ²²

The Spanish Multidisciplinary Melanoma Group (GEM) analyzed data obtained from the GEM1801 Spanish registry to describe the current role of chemotherapy and its efficacy following progression to ICIs in a real‐world setting.

MATERIALS AND METHODS

Study design and population

The GEM1801 Spanish Registry (ClinicalTrials.gov: NCT03605771) is a prospective observational study conducted in 37 centers in Spain that obtained data from patient medical history records. The patients included were adults diagnosed with resectable stage III, unresectable stage III, or stage IV melanoma (American Joint Committee on Cancer 8th edition) after January 8, 2018. The decision regarding patient treatment was made following local standard clinical practice and independently from study inclusion. Informed consent was obtained before the inclusion in the study. For this substudy, patients with unresectable stage III or IV treated with chemotherapy regimens after ICI therapy were selected. Patients can subsequently receive chemotherapy after ICI or after bridge therapies, such as targeted therapy. The GEM1801 study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, 1964, local laws, SAS order 3470/2009, and Organic Law 3/2018 of December 5 on the Protection of Personal Data and guarantee of digital rights. The study was reviewed and approved by the ethics committee of the Hospital Gregorio Marañón de Madrid (ref: 06/2018).

Objectives and endpoints

The main objective of this analysis was to describe the population of patients receiving chemotherapy after ICIs (with or without bridge therapy between) and to calculate the efficacy of chemotherapy after ICI. The efficacy end points analyzed for chemotherapy were PFS, defined as the time from chemotherapy initiation to progression or death in the absence of progression, and OS, defined as the time from chemotherapy initiation to death.

A univariable analysis was performed for PFS and OS, considering the following variables at the start of chemotherapy: age (<65 vs. ≥65 years), sex, Eastern Cooperative Oncology Group performance status (ECOG PS) (0, 1, or 2), number of organs affected (0–1, 2, or ≥3), presence of brain or liver metastasis, BRAF status, lactate dehydrogenase (LDH) levels (normal vs. elevated, above the upper limit of normal), type of ICI treatment, type of chemotherapy, and time from the end of the last ICI treatment. For the multivariable analysis, given the sample size, the following variables were selected based on the literature: age (<65 vs. ≥65 years), ECOG PS (0, 1, or 2), presence of liver metastasis, LDH levels (normal vs. elevated), and time from the end of the last ICI treatment. Additionally, for the univariable and multivariable analyses, patients were grouped into three cohorts according to the relationship between the first ICI treatment and the subsequent chemotherapy as follows: patients receiving chemotherapy after ICI adjuvant treatment (cohort A), patients receiving chemotherapy subsequently to ICI treatment in the advanced/metastatic setting (cohort B), and patients receiving chemotherapy after ICI and other bridge therapies in the advanced/metastatic setting (cohort C).

Statistical analyses

The statistical analyses consisted of descriptive statistics. For categorical variables, percentages and confidence intervals (CI) were calculated using Clopper‐Pearson, and for quantitative variables, the median and corresponding CIs were calculated. The Kaplan–Meier method was used for the analysis of time‐to‐event outcomes and survival analyses, such as PFS and OS, reporting medians and their 95% CI, and univariable Cox proportional hazards models for the risk factor analyses. For the multivariable Cox regression models, missing data were handled using a complete‐case analysis. Statistical tests were performed using the log‐rank and Wald test. All statistical analyses were conducted using R. ²³

RESULTS

Patient characteristics

Between August 2018 and January 2025, the Spanish Multidisciplinary Melanoma Group registry included 1316 patients. Of these, 92 patients from 28 hospitals received chemotherapy regimens after ICI treatment (Figure 1A). At chemotherapy treatment initiation, the median age was 66 years (range, 35–94), 55.4% of patients were male, had an ECOG status of 0 (17.4%), 1 (47.8%), or 2 (21.7%), and had elevated LDH levels (54.3%). At the start of chemotherapy, four patients (4.3%) had unresectable stage III disease. The other patients had stage IV disease, with metastasis present in one (17.4%), two (20.7%), or three or more (57.6%) organs, predominantly lymph nodes (57.6% of patients), lungs (51.1%), liver (32.6%), skin (28.3%), and soft tissues (27.2%). The primary origin was cutaneous in 48 patients (52.2%), acral in 16 (17.4%), mucosal in 11 (12.0%), uveal in eight (8.7%), and unknown in seven (7.6%). According to the timing of chemotherapy, 12 (13.0%) patients received the first ICI treatment in the adjuvant setting (cohort A) (Figure S1). Of these, two received chemotherapy as a first‐line treatment (16.7%), and 10 received one or more bridge therapies with ICIs (83.3%), targeted therapies (40.0%), or clinical trials (10.0%). The first ICI treatment was received by 80 (87.0%) of the patients in the metastatic setting: 45 (56.25%) were treated with chemotherapy subsequently to ICI (cohort B), and 35 (43.75%) received bridge therapies with ICIs (74.3%), targeted therapies (37.1%), clinical trials (14.3%), or tebentafusp (2.9%) (cohort C). The sequence of treatments between the first ICI and chemotherapy is shown in Figure 1B. The most frequent first ICI treatments received by the selected patients were anti–PD‐1 (71.7%) and anti–PD‐1 plus anti–CTLA‐4 (25.0%), and after a median time of 4.8 months (95% CI, 3.2–6.0) from the end of the first ICI. The chemotherapy regimens administered were mainly paclitaxel plus carboplatin (38.0%), DTIC (26.1%), and fotemustine (17.4%). A detailed description of the baseline characteristics of each cohort and their treatments is presented in Table 1 and Table S1.

(A) CONSORT diagram of patient selection for analysis. (B) River plot showing the treatment sequence in the population of patients treated with chemotherapy after ICI. CONSORT indicates Consolidated Standards of Reporting Trials; ICI, immune checkpoint inhibitors.

TABLE 1.

Baseline characteristics of patients treated with chemotherapy after ICI.

Characteristics	Cohort A	Cohort B	Cohort C	Total	p
Characteristics	n = 12	n = 45	n = 35	n = 92	p
Median age; years (range)	68 (44–82)	64 (43–94)	67 (35–86)	66 (35–94)
Gender, No. (%)
Male	6 (50.0)	26 (57.8)	19 (54.3)	51 (55.4)
Female	6 (50.0)	19 (42.2)	16 (45.7)	41 (44.6)
Origin, No. (%)					.332
Cutaneous	7 (58.3)	24 (53.3)	17 (48.6)	48 (52.2)
Acral	4 (33.3)	7 (15.6)	5 (14.3)	16 (17.4)
Mucosal	1 (8.3)	7 (15.6)	3 (8.6)	11 (12.0)
Uveal	0 (0.0)	5 (11.1)	3 (8.6)	8 (8.7)
Unknown	0 (0.0)	2 (4.4)	5 (14.3)	7 (7.6)
Not available	0 (0.0)	0 (0.0)	2 (5.7)	2 (2.2)
ECOG, No. (%)					.323
0	4 (33.3)	9 (20.0)	3 (8.6)	16 (17.4)
1	6 (50.0)	21 (46.7)	17 (48.6)	44 (47.8)
2	2 (16.7)	10 (22.2)	8 (22.9)	20 (21.7)
Missing	0 (0.0)	5 (11.1)	7 (20.0)	12 (13.0)
BRAF status, No. (%)					.0015
BRAF native	6 (50.0)	38 (84.4)	20 (57.1)	64 (69.6)
BRAF mutated	5 (41.7)	3 (6.7)	13 (37.1)	21 (22.8)
Unknown	1 (8.3)	4 (8.9)	2 (5.7)	7 (7.6)
LDH; No. (%)					.9811
Normal	3 (25.0)	11 (24.4)	10 (28.6)	24 (26.1)
Elevated	7 (58.3)	23 (51.1)	20 (57.1)	50 (54.3)
Missing	2 (16.7)	11 (24.4)	5 (14.3)	18 (19.6)
Organs affected, No. (%)					.0018
0	1 (8.3)	3 (6.7)	0 (0.0)	4 (4.3)
1	2 (16.7)	11 (24.4)	3 (8.6)	16 (17.4)
2	6 (50.0)	9 (20.0)	4 (11.4)	19 (20.7)
≥3	3 (25.0)	22 (48.9)	28 (80.0)	53 (57.6)
Metastasis location, No. (%) ^a
Lymph nodes	7 (58.3)	23 (51.1)	23 (65.7)	53 (57.6)	.423
Lung	6 (50.0)	21 (46.7)	20 (57.1)	47 (51.1)	.647
Liver	4 (33.3)	17 (37.8)	9 (25.7)	30 (32.6)	.520
Bone	3 (25.0)	9 (20.0)	11 (31.4)	23 (25.0)	.504
Brain	3 (25.0)	7 (15.6)	8 (22.9)	18 (19.6)	.629
Skin	0 (0.0)	15 (33.3)	11 (31.4)	26 (28.3)	.065
Soft tissues	2 (16.7)	7 (15.6)	16 (45.7)	25 (27.2)	.007
Peritoneum	2 (16.7)	5 (11.1)	6 (17.1)	13 (14.1)	.541
Adrenal	1 (8.3)	1 (2.2)	8 (22.9)	10 (10.9)	.178
Pleura	2 (16.7)	1 (2.2)	4 (11.4)	7 (7.6)	.136
Splenic	2 (16.7)	0 (0.0)	3 (8.6)	5 (5.4)	.140
No. of bridge therapies, No. (%)					—
0	2 (16.7)	—	—	47 (51.1)
1	5 (41.7)	—	24 (68.6)	29 (31.5)
≥2	5 (41.7)	—	11 (31.4)	16 (17.4)
Type of bridge therapies, No. (%) ^b
ICI	8 (66.7)	—	21 (60.0)	29 (31.5)
Targeted therapy	4 (33.3)	—	13 (37.1)	17 (37.8)
Clinical trial	1 (8.3)	—	9 (25.7)	10 (10.9)
Tebentafusp	0 (0.0)	—	1 (2.9)	1 (1.1)

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Note: Patients were grouped in three cohorts: patients receiving chemotherapy after ICI adjuvant treatment (cohort A), patients receiving chemotherapy subsequently to ICI treatment in the advanced/metastatic setting (cohort B), and patients receiving chemotherapy after ICI and other bridge therapies in the advanced/metastatic setting (cohort C).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase.

^{^a}

Patients could have more than one location.

^{^b}

Patients may receive more than one bridge therapy.

According to treatment timing, patients with BRAF mutations received chemotherapy with bridge therapies from ICI treatment more frequently (37.1% vs. 6.7% after systemic ICI treatment) (Table S2). Excluding ICIs, the most frequent bridge therapy was targeted therapy (17 patients, 37.8%).

According to the chemotherapy treatments, alkylating agents such as temozolomide were used to treat older patients, with a median age of 76 years (95% CI, 65–83) (p = .0354) (Table S3). Fotemustine was the preferred treatment for patients with BRAF mutations (50%, p = .0281). Patients treated with fotemustine received more bridge therapies other than ICI (62.5%) and were mainly treated with targeted therapies (61.5%). Patients treated with DTIC and fotemustine had more brain metastases (33.3 and 37.5%, p = .0120). The other baseline characteristics were balanced between the subgroups.

Chemotherapy compliance

With a median treatment duration of 2.2 months (range, 0.0–19.6), the reasons for chemotherapy treatment discontinuation were disease progression in 57 patients (62.0%), death in 11 patients (12.0%), toxicity in six patients (6.5%), investigator’s decision in five (5.4%), patient’s decision in two (2.2%), and maximum benefit in two (2.2%). The reasons for discontinuation were similar for all the chemotherapy regimens.

After chemotherapy treatment discontinuation, 32 patients (34.8%) received subsequent systemic treatment, seven of whom (21.9%) received ICI, three (9.4%) received targeted therapies, 18 (19.6%) received another chemotherapy treatment, and four (12.5%) were recruited in a clinical trial.

PFS

At a median follow‐up of 31.9 months (95% CI, 17–Not Reached [NR]), the median PFS with chemotherapy was 3.5 months (95% CI, 2.9–4.8), and the 12‐month PFS rate was 12.2% (95% CI, 6.9–21.8) (Figure 2A). At the data cutoff, eight patients (8.8%) were alive and without disease progression. As shown in Figure 3, the time to progression to chemotherapy did not seem to be related to that of the first ICI treatment (Figure 3).

(A) Kaplan–Meier curve of PFS for the overall population. (B) Kaplan–Meier curve of PFS for patients grouped by chemotherapy treatment. (C) Multivariate Cox regression analysis for PFS. ChT indicates chemotherapy; CI, confidence interval; DTIC, dimethyl triazeno imidazol carboxamide; ECOG, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ICI, immune checkpoint inhibitors; LDH, lactate dehydrogenase; PFS, progression‐free survival; TPBT, taxane/platinum‐based therapy.

Tornado plot. PFS time for the first ICI treatment (left) and PFS time for chemotherapy treatment after ICI (right). ChT indicates chemotherapy; ICI, immune checkpoint inhibitor; PFS, progression‐free survival.

The median PFS was similar among the different chemotherapy treatments (p = .686), with a median PFS of 3.3 months (95% CI, 1.9–5.5) for patients treated with DTIC, 2.6 months (95% CI, 1.2–9.5) for fotemustine, 4.1 months (95% CI, 3.1–5.5) for taxane‐platinum‐based therapy, and 3.4 months (95% CI, 2.7–NR) for other alkylating agents (Figure 2B). Multivariable analysis showed a worse prognosis for patients with ECOG performance status 2 vs. 0 (hazard ratio [HR], 4.58; 95% CI, 1.84–11.4; p = .001), patients with elevated LDH versus normal (HR, 3.04; 95% CI, 1.56–5.92; p = .001), and those who received chemotherapy after adjuvant ICI (HR, 3.11; 95% CI, 1.16–8.34; p = .024) (Figure 2C). Given the low number of patients receiving chemotherapy after adjuvant ICI, these results should be interpreted cautiously because of the wide confidence interval. Brain or liver metastasis, BRAF status, and sex were not associated with shorter PFS in the univariable analysis (Figure S2A).

PFS was also calculated for the poor‐prognosis subpopulation of patients with acral and mucosal melanomas. The median PFS was 3.3 months (95% CI, 2.5–6.5) for acral melanoma and 4.8 months (95% CI, 2.4–NR) for mucosal melanoma.

OS

For the overall population, the median OS since chemotherapy started was 6.1 months (95% CI, 5.3–9.2), and the 12‐month OS rate was 27.5% (95% CI, 19.5–38.9) (Figure 4A). At the data cutoff, eight patients (8.8%) were receiving treatment, 77 (84.6%) had died, two (2.2%) were alive without receiving any treatment, and four (4.4%) were lost to follow‐up. No toxicity‐related death was reported. Similar to PFS, the survival was not influenced by the type of chemotherapy received (p = .293), with a median OS of 5.9 months (95% CI, 4.8–15.1) for patients treated with DTIC, 5.2 months (95% CI, 2.0–NR) with fotemustine, 8.8 months (95% CI, 5.5–11.7) with taxane‐platinum‐based therapy, and 5.5 months (95% CI, 3.9–NR) with other alkylating agents (Figure 4B). Multivariable analysis showed that patients with liver metastasis (HR, 2.58; 95% CI, 1.27–5.21; p = .009), elevated LDH levels (HR, 1.99; 95% CI, 1.04–3.81; p = .039), and those who received bridge therapies (HR, 2.91; 95% CI, 1.28–6.58, p = .011) had worse survival prognosis (Figure 4C). Moreover, similar to PFS, brain metastasis and sex were not associated with shorter OS in the univariable (Figure S3). Nevertheless, BRAF‐mutated patients had worse survival prognosis at the univariable level (HR, 1.97; 95% CI, 1.15–3.35; p = .013). For patients with acral and mucosal melanoma, the median OS was 7.6 (95% CI, 5.0–NR) and 9.7 months (95% CI, 4.8–NR), respectively.

(A) Kaplan–Meier curve of OS for the overall population. (B) Kaplan–Meier curve of OS for patients grouped by chemotherapy treatment. (C) Multivariate Cox regression analysis for OS. ChT, chemotherapy; ECOG, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitors; OS, overall survival; TPBT, taxane/platinum‐based therapy.

Response rates

The best overall response to chemotherapy according to investigator evaluation was a partial response (PR) in 11 (12.0%) patients. No responses were obtained with chemotherapy after adjuvant ICI. Among patients who received chemotherapy subsequent to systemic ICI, seven (15.6%) achieved PR. Four (11.4%) PR were reported in patients from cohort C. No complete responses were reported, and 16 patients (17.4%) had stable disease as their best response. Using a univariate logistic regression model, odds ratios (ORs) were estimated for different baseline characteristics. Patients with normal LDH levels had a higher probability of response than those with elevated LDH levels (OR, 0.13; 95% CI, 0.02–0.63; p = .019).

DISCUSSION

Here, we report real‐world data on the use of chemotherapy in the immunotherapy era for the treatment of patients with metastatic melanoma after ICI treatment. Chemotherapy schemes, one of the scarce treatment options for patients with advanced‐stage melanoma before the introduction of immunotherapy and targeted therapies, have historically been associated with poor outcomes. In our study, chemotherapy showed a similar efficacy after ICI treatment to those obtained in the pre‐immunotherapy era. ¹⁵ , ²⁴ , ²⁵

Despite the improved survival outcomes obtained with ICI and targeted therapies compared to those obtained with chemotherapy regimens, chemotherapy is still the selected option for some patients. An observational study of patients with cutaneous melanoma who progressed to ICI or targeted therapies and had characteristics similar to our population (55.2% of patients with elevated LDH and a median of three organs affected) showed a median PFS and OS of 2.8 and 6.0 months with chemotherapy, respectively. ²² These results are consistent with previous real‐world studies. ²⁶

The antitumor activity of chemotherapy could be explained beyond its direct antitumoral activity through an additional immunomodulatory response, ²⁷ with a potential role in enhancing tumor immunogenicity proposed for DTIC, temozolomide, and cisplatin. ²⁸ This enhancing activity through immunomodulation is supposed to be reciprocal, and chemotherapy efficacy could be enhanced through a long‐term ICI effect, ²⁹ the mechanism of which is not yet defined. Previous reports have shown that no additional benefit is obtained with chemotherapy regimens after ICI failure, ³⁰ as supported by our results, which are in the range of historic first‐line treatments with DTIC (5.9 vs. 5.6–7.7 months ⁵ , ¹⁵ ), fotemustine (5.2 vs. 7.3 months ¹⁵ ), or taxane/platinum‐based therapies (8.8 vs. 11.3 months ³¹ ). More recently, with immunotherapy treatments available, the efficacy of paclitaxel plus carboplatin was explored prospectively in a small cohort of 17 Chinese patients with nonacral melanoma, reporting a median OS of 14.0 months. ³² Our results cannot suggest an immunomodulatory effect of ICI. In our study, patients who were treated with chemotherapy subsequently to ICI failure showed better outcomes. However, the possibility of this effect being due to the higher pretreatment of the population not subsequently treated should be considered as a potential bias.

Another potential role of chemotherapy is to restore the efficacy of ICI through immune response activation. ³³ A retrospective study reported a lower efficacy in patients who received bridge therapies between ICI treatments ³⁴ ; however, the low number of patients who received chemotherapy as a bridge required larger data sets to address this issue.

A third role proposed for chemotherapy is its concurrent use with ICI, which is currently recommended as a first‐line treatment for different cancer types, ³⁵ , ³⁶ and several clinical trials have been conducted to evaluate the combination of ICI plus chemotherapy in the frontline setting for the treatment of different carcinomas. Nevertheless, the available data on melanoma are limited to combinations with early immunotherapies or ipilimumab plus DTIC, obtaining a survival comparable to ipilimumab alone. ³⁷ Given the poor prognosis of patients treated with conventional chemotherapy, recent drug developments have focused on antibody–drug conjugates, such as pembrolizumab plus enfortumab–vedotin in advanced melanoma patients, which are currently being studied in the PlugIN clinical trial sponsored by GEM (NCT06906822).

Additionally, current research aims to revitalize the utility of chemotherapy through strategies such as nanotherapy (drug encapsulation to reduce toxicity) and synergy with immunomodulators. These studies suggest that metronomic chemotherapy (low and continuous doses) can modulate the tumor microenvironment, enhancing the efficacy of immunotherapy. ³⁸ , ³⁹ , ⁴⁰ , ⁴¹

The population in our study was enriched with rare melanoma subtypes, such as acral, mucosal, and uveal melanoma, which accounted for 38.1% of the patients. Chemotherapy is considered more probable for these patients, possibly due to the low efficacy of ICI. These patients have a poor prognosis, even in the immunotherapy era. For patients with acral or mucosal melanoma, we have recently described in our GEM1801 study poor results of immunotherapy in the first line setting. ⁴² , ⁴³ In a nonrandomized phase 2 clinical trial involving patients with acral melanoma in the Asian population, the combination of camrelizumab, apatinib, and temozolomide showed an encouraging preliminary median FPS of 18.4 months. ⁴⁴ In patients with mucosal melanoma, a retrospective analysis of ICI reported a median PFS of 4.0 months and a median OS of 19.0 months, whereas chemotherapy and interferon in the pre‐immunotherapy era reported a median PFS of 3.0–10.0 months and median OS of 10.0–22.0 months, depending on the location of the mucosal melanoma. ⁴⁵ , ⁴⁶ Chemotherapy treatments showed similar PFS in our study but a shorter overall survival. Considering the poor prognosis of patients with acral and mucosal melanoma, chemotherapy regimens, either alone or in combination, could be an option after progression to ICI, if no clinical trials with innovative therapies are available.

Our study population was enriched with patients with elevated LDH levels (54.3%) or three or more affected organs (57.6%). Our results show that frail patients have a worse prognosis with chemotherapy. The benefit‐risk of chemotherapy, which is frequently associated with higher toxicity, should be carefully evaluated. However, with no toxicity‐related treatment discontinuations reported, chemotherapy treatment in clinical practice showed better tolerability than in benchmark studies from pre‐ICI era. ⁵ , ¹⁵ , ⁴⁷

Contrary to previous reports from clinical trials, ⁵ , ⁴⁸ our results did not show differences between different chemotherapy treatments in terms of PFS and OS, possibly due to the limited number of patients in each treatment group and for receiving it in the second line and beyond. For example, despite the median OS obtained with taxane/platinum‐based schemes seeming to be higher than that obtained with fotemustine, the HR at univariable level was 1.8 (95% CI, 0.96–3.37, p = .068). Temozolomide, a treatment associated with greater improvement in patients’ quality of life, ⁴⁹ was the preferred chemotherapy for older patients. As expected, fotemustine was selected for patients with brain metastases, but DTIC was the other preferred treatment over temozolomide.

Our analysis showed that some subsets of patients, such as those with normal LDH levels, have a higher probability of response to treatment and can use it to achieve tumor burden reduction. Patients with BRAF mutations showed lower survival rates than those with BRAF native (HR, 1.97), suggesting that in the case of progression to targeted therapies, rechallenge with targeted therapies may still be a better option. ⁵⁰

The limitations of this study are consistent with those usually found in observational studies, such as patient selection bias and incomplete data collection. The latter is minimized through exhaustive remote monitoring. Another limitation is the lack of a comparative arm with patients receiving chemotherapy without previous ICI treatment, which is currently not acceptable, or a group of patients without chemotherapy after progression to ICI and/or BRAF inhibitors. Finally, the statistical power of subgroup analyses was limited due to the low number of patients.

In conclusion, the results of chemotherapy after ICI failure are still poor. Whenever it is possible, chemotherapy should be reserved only for patients who have no other options, such as clinical trials with innovative treatments.

AUTHOR CONTRIBUTIONS

Miguel‐Ángel Berciano‐Guerrero: Conceptualization; investigation; funding acquisition; writing—original draft; writing—review and editing; methodology; validation; visualization; project administration; resources; and supervision. Elisabeth Pérez‐Ruiz: Conceptualization; investigation; funding acquisition; writing—original draft; writing—review and editing; visualization; validation; methodology; project administration; resources; and supervision. Ainara Soria: Investigation; funding acquisition; writing—original draft; writing—review and editing; project administration; resources; supervision; visualization; and validation. Javier Medina Martínez: Investigation; funding acquisition; writing—original draft; writing—review and editing; visualization; validation; project administration; resources; and supervision. Pablo Ayala de Miguel: Funding acquisition; investigation; writing—original draft; writing—review and editing; visualization; validation; project administration; resources; and supervision. Eva Muñoz‐Couselo: Funding acquisition; writing—original draft; investigation; validation; writing—review and editing; visualization; project administration; resources; and supervision. Lorena Bellido: Supervision; resources; project administration; validation; writing—review and editing; visualization; writing—original draft; funding acquisition; and investigation. Rafael López Castro: Investigation; funding acquisition; writing—original draft; writing—review and editing; visualization; validation; project administration; resources; and supervision. Enrique Espinosa: Supervision; resources; project administration; validation; visualization; writing—review and editing; writing—original draft; funding acquisition; and investigation. Lourdes Gutiérrez Sanz: Investigation; funding acquisition; writing—original draft; writing—review and editing; visualization; validation; project administration; supervision; and resources. Pablo Cerezuela‐Fuentes: Investigation; funding acquisition; writing—original draft; writing—review and editing; visualization; validation; project administration; resources; and supervision. Almudena García Castaño: Supervision; resources; writing—original draft; writing—review and editing; visualization; validation; project administration; investigation; and funding acquisition. Guillermo Crespo: Funding acquisition; investigation; writing—original draft; writing—review and editing; visualization; validation; project administration; resources; and supervision. Teresa Puértolas: Resources; project administration; visualization; validation; writing—original draft; writing—review and editing; funding acquisition; supervision; and investigation. Carlos Aguado de la Rosa: Funding acquisition; investigation; validation; visualization; writing—original draft; writing—review and editing; project administration; resources; and supervision. Mónica Corral Subias: Visualization; investigation; validation; funding acquisition; writing—original draft; writing—review and editing; supervision; resources; and project administration. Begoña Campos Balea: Visualization; investigation; validation; funding acquisition; writing—original draft; writing—review and editing; project administration; resources; and supervision. Aida Bujosa Rodríguez: Visualization; investigation; validation; funding acquisition; writing—original draft; writing—review and editing; supervision; resources; and project administration. Victor Navarro Pérez: Visualization; investigation; validation; writing—original draft; writing—review and editing; funding acquisition; project administration; resources; and supervision. María José Lecumberri: Visualization; validation; investigation; writing—original draft; writing—review and editing; supervision; resources; project administration; and funding acquisition. Francisco Ramón Garcia Arroyo: Visualization; validation; investigation; writing—original draft; writing—review and editing; funding acquisition; project administration; resources; and supervision. Alberto Jacobo Cunquero Tomás: Visualization; validation; investigation; funding acquisition; writing—original draft; writing—review and editing; supervision; resources; and project administration. Karmele Mujika: Visualization; validation; investigation; writing—original draft; writing—review and editing; funding acquisition; project administration; resources; and supervision. Luis Antonio Fernández: Visualization; validation; investigation; writing—original draft; writing—review and editing; funding acquisition; supervision; resources; and project administration. José Carlos Villa Guzmán: Visualization; validation; investigation; writing—original draft; writing—review and editing; funding acquisition; project administration; resources; and supervision. Berta Hernández: Visualization; validation; investigation; funding acquisition; writing—original draft; writing—review and editing; supervision; resources; and project administration. Joaquín Fra Rodríguez: Visualization; validation; investigation; funding acquisition; writing—original draft; writing—review and editing; project administration; resources; and supervision. José Luis Manzano: Visualization; validation; investigation; funding acquisition; writing—original draft; writing—review and editing; supervision; resources; project administration. Salvador Martín Algarra: Conceptualization; validation; methodology; visualization; investigation; funding acquisition; writing—original draft; writing—review and editing; resources; project administration; and supervision. Iván Márquez‐Rodas: Conceptualization; visualization; validation; methodology; investigation; writing—original draft; writing—review and editing; supervision; resources; project administration; and funding acquisition.

CONFLICT OF INTEREST STATEMENT

Alberto Jacobo Cunquero Tomás reports fees for professional activities from Merck Sharp & Dohme and Pierre Fabre Pharmaceuticals. Begoña Campos Balea reports honoraria from BMS, Roche, MSD, Novartis, Pierre‐Fabre, Sun Pharma, Inmunocore and Regeneron; travel fees from Pierre‐Fabre, Roche, BMS and Novartis; and participation on a data safety monitoring board or advisory board from Roche and Astra Zeneca. Berta Hernández reports consulting fees from Bristol‐Myers Squibb, Merck Sharp & Dohme, and Regeneron; and travel fees from Pierre Fabre Pharmaceuticals. Carlos Aguado de la Rosa reports consulting fees from AstraZeneca and Bristol‐Myers Squibb; fees for other professional activities from Amgen Inc, AstraZeneca, BeiGene USA, Inc, Bristol‐Myers Squibb, EMD Serono, F. Hoffmann‐La Roche, Pierre Fabre Pharmaceuticals, Inc, and Regeneron Pharmaceuticals, Inc; grant and/or contract funding from EMD Serono, Instituto Científico, Pfizer, Pierre Fabre Pharmaceuticals, Inc, and Takeda Oncology; and travel fees from AstraZeneca, F. Hoffmann‐La Roche, and Pierre Fabre Pharmaceuticals, Inc. Elisabeth Pérez‐Ruiz has received honoraria and/or served on advisory boards for BMS, MSD, Novartis, and Pierre‐Fabre. Enrique Espinosa reports fees for professional activities from Immunocore. Eva Muñoz‐Couselo reports consulting fees from Bristol‐Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, and Regeneron; grant and/or contract funding from MSD, Sanofi and, BMS; and speaking fees from Amgen, Bristol‐Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Regeneron. Guillermo Crespo reports consulting fees from Bristol‐Myers Squibb, F. Hoffmann‐La Roche, and Pierre Fabre Pharmaceuticals; and travel fees from Bristol‐Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre Pharmaceuticals. Iván Márquez‐Rodas reports honoraria from Amgen, Astra Zeneca, BiolineRx, BMS, Celegene, GSK, Highlight Therapeutics, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, and Sun Pharma; and travel and accommodation fees from Amgen, Astra Zeneca, BiolineRx, BMS, Celegene, GSK, Highlight Therapeutics, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, and Sun Pharma. Javier Medina Martínez reports consulting fees from Bristol‐Myers Squibb and Pierre Fabre Pharmaceuticals. Joaquín Fra Rodríguez reports fees for professional activities from Amgen, AstraZeneca, BeiGene, Ltd, Merck, and Roche; and travel fees from Deciphera Pharmaceuticals and Pierre Fabre Pharmaceuticals. José Carlos Villa Guzmán reports fees for professional activities from ASCO Post. Karmele Mujika reports participation as a fiduciary officer for Hospital Universitario Donostia. Lorena Bellido reports fees for professional activities from Amgen, AstraZeneca, F. Hoffmann‐La Roche, Janssen Pharmaceuticals, and Pierre Fabre Pharmaceuticals; support for attending meetings from MSD, Novartis, Sanofi, Astra Zeneca, Roche, Pierre Fabre, and Pfizer; and travel fees from Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Miguel‐Ángel Berciano‐Guerrero has received honoraria and/or served on advisory boards for BMS, MSD, Eisai, Novartis, PharmaMar, Pierre‐Fabre and Regeneron. Pablo Ayala de Miguel reports consulting fees from Regeneron and Sun Pharmaceutical Industries Inc; and grant and/or contract funding from Bristol‐Myers Squibb, Merck Sharp & Dohme, Pierre Fabre Pharmaceuticals, and Regeneron. Teresa Puértolas reports consulting fees from Bristol‐Myers Squibb, Immunocore, Novartis, Pierre Fabre Pharmaceuticals, Seagen, and Sun Pharmaceuticals; and travel fees from Pierre Fabre Pharmaceuticals. Victor Navarro Pérez reports consulting fees from SAS. Pablo Cerezuela‐Fuentes reports honoraria from BMS, MSD, Novartis, Pierre‐Fabre and Regeneron; and travel fees from Pierre‐Fabre, MSD, and Novartis. Rafael López Castro reports honoraria from Pierre‐Fabre, Novartis, and BMS; travel fees from Pierre‐Fabre; and participation on an advisory board for Pierre‐Fabre, Novartis, and BMS. The other authors declare no conflicts of interest.

Supporting information

Supplementary Material

CNCR-132-e70497-s001.docx^{(1.2MB, docx)}

ACKNOWLEDGMENTS

The authors thank all patients and families, investigators and study staff involved in the GEM1801 study; the MFAR Clinical Research team for regulatory, monitoring, and quality assurance activities; Guillem Marco, PhD, for manuscript and language editing; and Eva Maicas, MSc, for statistical analysis. We deeply miss our dear friend and coauthor, Dra. Almudena García Castaño, who passed away before this article was published. We honor her vital scientific contributions; above all, we remember her warmth, joy, and smiles, which she brought to our team. Her dedication to the values and vision of the GEM will never be forgotten. GEM1801 is funded by Spanish Multidisciplinary Melanoma Group (GEM), through grants from Novartis, Pierre Fabre, Incyte, MSD, Roche, BMS, Mural Oncology and Sun Pharma. This analysis of chemotherapy after immune checkpoint inhibitors was supported by a grant from Iovance. This work was also supported by Universidad de Málaga/CBUA: Funding for open access charge. This work has not been published elsewhere.

Berciano‐Guerrero M‐Á, Pérez‐Ruiz E, Soria A, et al. Real‐world effectiveness of chemotherapy regimens after immunotherapy in patients with advanced melanoma in Spain: results from the GEM1801 study. Cancer. 2026;e70497. doi: 10.1002/cncr.70497

The clinical trial identification is ClinicalTrials.gov: NCT03605771.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material

CNCR-132-e70497-s001.docx^{(1.2MB, docx)}

Data Availability Statement

The data that support the findings of this study are available from the corresponding author on reasonable request.

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PERMALINK

Real‐world effectiveness of chemotherapy regimens after immunotherapy in patients with advanced melanoma in Spain: Results from the GEM1801 study

Miguel‐Ángel Berciano‐Guerrero, MD, PhD

Elisabeth Pérez‐Ruiz, MD, PhD

Ainara Soria, MD

Javier Medina Martínez, MD, PhD

Pablo Ayala de Miguel, MD, PhD

Eva Muñoz‐Couselo, MD, PhD

Lorena Bellido, MD, PhD

Rafael López Castro, MD

Enrique Espinosa, MD, PhD

Lourdes Gutiérrez Sanz, MD, PhD

Pablo Cerezuela‐Fuentes, MD, PhD

Almudena García Castaño, MD

Guillermo Crespo, MD, PhD

Teresa Puértolas, MD, PhD

Carlos Aguado de la Rosa, MD

Mónica Corral Subias, MD

Begoña Campos Balea, MD

Aida Bujosa Rodríguez, MD

Victor Navarro Pérez, MD, PhD

María José Lecumberri, MD

Francisco Ramón García Arroyo, MD

Alberto Jacobo Cunquero Tomás, MD

Karmele Mujika, MD

Luis Antonio Fernández, MD, PhD

José Carlos Villa Guzmán, MD

Berta Hernández, MD

Joaquín Fra Rodríguez, MD

José Luis Manzano, MD, PhD

Salvador Martín Algarra, MD, PhD

Iván Márquez‐Rodas, MD, PhD

ABSTRACT

Background

Methods

Results

Conclusions

Short abstract

INTRODUCTION

MATERIALS AND METHODS

Study design and population

Objectives and endpoints

Statistical analyses

RESULTS

Patient characteristics

FIGURE 1.

TABLE 1.

Chemotherapy compliance

PFS

FIGURE 2.

FIGURE 3.

OS

FIGURE 4.

Response rates

DISCUSSION

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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