Abstract
Background
Ipilimumab+nivolumab (IPINIVO) can induce durable responses in advanced melanoma, but many patients experience progression at some point. It is currently unknown to what extent these patients benefit from IPINIVO rechallenge. This study describes efficacy and safety of IPINIVO rechallenge.
Methods
Data from advanced melanoma patients rechallenged with IPINIVO after previous ipilimumab-containing treatment were retrieved from the nationwide Dutch Melanoma Treatment Registry. Patient characteristics, responses, survival, and safety were analyzed.
Results
Among 3.759 patients receiving ipilimumab-containing treatment, 73 received rechallenge IPINIVO. 41 received IPINIVO, 32 ipilimumab monotherapy (IPI) as initial therapy. Objective response to rechallenge IPINIVO was seen in 36.1% (initial IPINIVO) and 40.0% (initial IPI) of patients. Median progression-free survival after rechallenge was 2.8 months (initial IPINIVO) and 5.6 months (initial IPI), but reached 18.4 months for responders to rechallenge therapy. Grade ≥3 immune-related adverse events occurred in 40.5% (initial IPINIVO) and 38.7% (initial IPI) of patients. Objective responses to initial and rechallenge treatment were discordant in 48.6% (initial IPINIVO) and 53.3% (initial IPI) of patients. Fifteen patients (20.5%) responded to rechallenge therapy but not to initial treatment.
Conclusions
Rechallenge IPINIVO after previous ipilimumab-based therapy had a considerable response rate, acceptable safety profile, and potential for a durable response.
Subject terms: Melanoma, Cancer immunotherapy
Background
Immune checkpoint inhibition (ICI) has been the cornerstone of therapy for advanced melanoma for several years, significantly improving patient survival. In first-line ICI, the combination of ipilimumab and nivolumab has shown the highest response rates (58%) with durable responses, translating into a melanoma-specific survival rate of 52% after 10 years in the CHECKMATE 067 trial [1]. The DREAMseq and SECOMBIT trials have endorsed ICI as the preferred first-line treatment for BRAFV600-mutant metastatic melanoma [2, 3]. However, many patients still do not achieve a (durable) response to ICI.
As a general rule in oncology, patients are not rechallenged to systemic therapies on which they have shown progressive disease. However, studies have suggested that rechallenge of a previous therapy could again result in tumor response [4–7]. For advanced BRAFV600-mutant melanoma patients, treatment with BRAF/MEK inhibition and even rechallenge treatment with BRAF/MEK inhibition can induce tumor response after progression on ICI [7]. However, responses to BRAF/MEK inhibition are mostly not long-lasting, and for BRAFV600-wildtype melanoma patients treatment options are limited. Moreover, observational studies in miscellaneous tumor populations indicate that ICI therapy can in selected cases be safely resumed after cessation due to irAEs, including rechallenge with ipilimumab + nivolumab [8, 9][7]. This brings up questions about the possibility of rechallenging patients to ICI after disease progression. Tumor response to combination ipilimumab + nivolumab has been observed in patients resistant to anti-PD-1 therapy, as demonstrated by Pires da Silva [10] and in the SWOG S1616 trial [11]. Hepner described reinduction therapy with ipilimumab, with or without anti-PD-1, in a cohort of 47 patients that had achieved response to initial therapy with ipilimumab and nivolumab followed by secondary progression. A modest response was seen to the reinduction therapy (objective response in 12/47 patients) [12]. However, responses to rechallenge ICI after initial absence of response have not been investigated.
In this study, we assessed response rates, toxicity, and survival outcomes of all patients with advanced melanoma in the Netherlands who received a rechallenge with ipilimumab + nivolumab after ipilimumab-containing treatment.
Methods
Patients
The Dutch Melanoma Treatment Registry (DMTR) has prospectively registered demographic and clinical data from all patients with advanced melanoma in the Netherlands since 2013 [13]. In this study, we included all patients who received a rechallenge of ipilimumab + nivolumab after previous ipilimumab monotherapy or ipilimumab + nivolumab for advanced melanoma between 2012 and 2022. Treatment was considered as rechallenge therapy if the second treatment episode was started at least 90 days after the stop date of the initial treatment episode. Response to the first treatment episode was not an inclusion criterion, intercurrent treatment (such as BRAF/MEK inhibition) was allowed.
Toxicities were graded according to the Common Terminology Criteria of Adverse Events (CTCAE) versions 4.03 or 5.0. Only severe immune-related adverse events (irAEs) of grade 3 or higher are registered in the DMTR. In compliance with Dutch regulations, research with DMTR data was approved by the medical ethical committee not to be subject to the Medical Research Involving Human Subjects Act.
In the DMTR database, which contains real-world data, response evaluations are based on the judgment of the treating physician in accordance with the RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria [14]. Best overall response (BOR) was the best response evaluation a patient had after initiation of treatment until the start of a new melanoma therapy or the last follow-up visit. Objective response rate (ORR) was defined as the percentage of patients deriving a complete response (CR) or partial response (PR) out of all patients. Disease control rate (DCR) was defined as the percentage of patients having CR, PR, or stable disease (SD).
Statistical analysis
Descriptive analyses were performed to describe patient and disease characteristics. Categorical characteristics were presented as frequencies or percentages. Continuous variables were displayed as medians with interquartile ranges or as means with standard deviations, depending on their distribution.
Cross tables were used to compare the response to initial and rechallenge therapy.
As patient numbers are small, no extensive comparative statistics could be performed. To compare the basic characteristics of responders and non-responders to rechallenge therapy Pearson’s Chi-squared tests or Fisher’s Exact tests were performed for categorical variables, and Welch T-tests or Wilcoxon Rank Sum tests were performed for continuous variables.
Overall survival (OS) was defined as the time from the start of ICI to the date of last follow-up visit (censored observation) or date of death. Progression free survival (PFS) was defined as the time from the start date of ICI to the date of first progression or death, or to the date of last follow-up visit (censored). OS and PFS were assessed using the Kaplan-Meier method.
All analyses were conducted using R version 4.3.2.
Results
Patient characteristics
The DMTR database included 3.759 patients who received at least one treatment episode of ipilimumab monotherapy and/or ipilimumab + nivolumab. Of these, 73 patients received ipilimumab-containing treatment for unresectable stage IIIC or stage IV melanoma and later had a rechallenge with combination ipilimumab + nivolumab. Additionally, three patients received ipilimumab and nivolumab in a neoadjuvant setting for resectable stage IIIC melanoma and received retreatment with ipilimumab and nivolumab for later progression to stage IV disease. These patients were analyzed separately.
Of the 73 patients who received initial treatment for unresectable/metastatic disease, 32 (43.8%) were initially treated with ipilimumab monotherapy and 41 patients (56.2%) received combination ipilimumab + nivolumab. Patient characteristics for both the initial and rechallenge treatments are presented in Table 1.
Table 1.
Characteristics at time of initial and rechallenge treatments.
| Initial treatment (n = 73) | Rechallenge treatment (n = 73) | |||
|---|---|---|---|---|
| Ipilimumab monotherapy (n = 32) | Ipilimumab + nivolumab (n = 41) | After initial ipilimumab monotherapy (n = 32) | After initial ipilimumab + nivolumab (n = 41) | |
| Age | ||||
| Mean (SD) | 56.9 (12.7) | 57.3 (14.6) | 61.3 (13.3) | 58.9 (14.6) |
| Gender | ||||
| Male | 20 (62.5%) | 24 (58.5%) | 20 (62.5%) | 24 (58.5%) |
| Female | 12 (37.5%) | 17 (41.5%) | 12 (37.5%) | 17 (41.5%) |
| ECOG PS | ||||
| 0 | 26 (86.7%) | 26 (70.3%) | 10 (37.0%) | 17 (51.5%) |
| 1 | 4 (13.3%) | 10 (27.0%) | 15 (55.6%) | 16 (48.5%) |
| 2 | – | 1 (2.7%) | 2 (7.4%) | – |
| No. missings | 2 | 4 | 5 | 8 |
| LDH level | ||||
| Normal | 28 (90.3%) | 21 (51.2%) | 16 (53.3%) | 24 (61.5%) |
| 1-2x elevated | 3 (9.7%) | 15 (36.6%) | 13 (43.3%) | 12 (30.8%) |
| >2x elevated | – | 5 (12.2%) | 1 (3.3%) | 3 (7.9%) |
| No. missings | 1 | – | 2 | 2 |
| Brain metastases | ||||
| No | 22 (75.9%) | 26 (63.4%) | 14 (53.8%) | 16 (42.1%) |
| Yes | 7 (24.1%) | 15 (36.6%) | 12 (46.2%) | 22 (57.9%) |
| Symptomatic | 1 (3.4%) | 5 (12.2%) | 5 (19.2%) | 8 (21.1%) |
| Asymptomatic | 4 (13.8%) | 10 (24.4%) | 4 (15.4%) | 13 (34.2%) |
| Unknown if symptomatic | 2 (6.9%) | – | 3 (11.5%) | 1 (2.6%) |
| No. missings | 3 | – | 6 | 3 |
| Liver metastases | ||||
| No | 23 (76.79%) | 25 (62.5%) | 24 (88.9%) | 30 (73.2%) |
| Yes | 7 (23.3%) | 15 (37.5%) | 3 (11.1%) | 11 (26.8%) |
| No. missings | 2 | 1 | 5 | - |
| BRAF V600 mutation | ||||
| No | 11 (40.7%) | 10 (25.0%) | 10 (37.0%) | 10 (24.4%) |
| Yes | 16 (59.3%) | 30 (75.0%) | 17 (63.0%) | 31 (75.6%) |
| No. missings | 5 | 1 | 5 | – |
| Intercurrent therapy | ||||
| BRAF/MEK inhibition | – | – | 14 (82.4%*) | 27 (87.1%*) |
| Anti-PD-1 | – | – | 15 (46.9%) | 10 (24.4%) |
| Other** | – | – | 6 (18.8%) | 3 (7.3%) |
| Best overall response | ||||
| CR | 5 (15.6%) | 3 (7.5%) | 5 (16.7%) | 6 (16.7%) |
| PR | 8 (25.0%) | 15 (37.5%) | 7 (23.3%) | 7 (19.4%) |
| SD | 9 (28.1%) | 8 (20.0%) | 2 (6.7%) | 2 (5.6%) |
| PD | 10 (31.3%) | 14 (35.0%) | 16 (53.3%) | 21 (58.3%) |
| No. missings | – | 1 | 2 | 5 |
| Toxicity grade ≥ 3 | ||||
| No | 24 (75.0%) | 22 (55.0%) | 19 (61.3%) | 22 (59.5%) |
| Yes | 8 (25.0%) | 18 (45.0%) | 12 (38.7%) | 15 (40.5%) |
| No. missings | – | 1 | 1 | 4 |
| Reason for stopping therapy | ||||
| Planned/completed | 24 (77.4%) | 4 (10.0%) | 3 (10.7%) | 2 (6.3%) |
| Progression | 4 (12.9%) | 13 (32.5%) | 7 (25.0%) | 19 (59.4%) |
| Toxicity | 3 (9.7%) | 21 (52.5%) | 11 (39.3%) | 8 (25.0%) |
| Patient condition | – | 1 (2.5%) | 6 (21.4%) | 2 (6.3%) |
| Death | – | – | – | 1 (3.1%) |
| Other | – | 1 (2.5%) | 1 (3.6%) | – |
| No. missings | 1 | 1 | 4 | 9 |
* Percentage calculated for patients with a known BRAFV600 mutation (n = 17 for initial ipilimumab monotherapy, n = 31 for initial ipilimumab + nivolumab)
** Other intercurrent therapies included nivolumab + anti-LAG-3 (n = 2), chemotherapy (n = 2), nivolumab + T-cells (n = 1), and high-dose IL2 (n = 1) after initial ipilimumab monotherapy, and nivolumab + anti-LAG-3 (n = 2) and TIL (n = 1) after initial ipilimumab+nivolumab.
For the 41 patients who initially received ipilimumab + nivolumab combination therapy, the mean age at the start of initial treatment was 57.3 years, with the majority of patients having a good performance status (70.3% ECOG PS 0) and normal LDH levels (51.2%). Brain metastases were present in 36.6% of patients. Rechallenge therapy occurred at a median of 13.1 months (range 3.1–43.9) after the stop date of the initial treatment. At the start of the rechallenge therapy, the mean age had become 58.9 years. Compared to the initial treatment, the performance status of patients at rechallenge was worse (51.5% ECOG PS 0) and more patients had brain metastases (57.9% of patients). The initial treatment was discontinued prematurely in 90.0% of cases, including 52.5% for toxicity and 32.5% for progressive disease. For the rechallenge episode, the rate of premature treatment discontinuation was 93.7%, including 59.4% discontinuation due to progression and 25.0% due to toxicity. Time between the stop of initial and the start of rechallenge treatment was shorter if patients had progression after the first treatment episode (median 7.2 months, range 3.1–22.8) when compared to patients that discontinued initial treatment due to toxicity (median 19.8 months, range 3.4–43.9). At the start of rechallenge therapy, 27 patients had undergone intercurrent treatment with BRAF/MEK inhibitors (65.9% of patients, 87.1% of patients with a BRAFV600 mutation). During the initial treatment episode, a median number of 2 cycles (range 1–4) ipilimumab + nivolumab was administered. The majority of patients (80.5%) did not receive any nivolumab maintenance cycles, with the number of nivolumab cycles ranging from 0 to 47. During the rechallenge episode, a median of 3 cycles (range 1–4) ipilimumab + nivolumab was administered, with 78.0% of patients not receiving any nivolumab maintenance cycles (range 0–19).
For the 32 patients who initially received ipilimumab monotherapy, the mean age at start of initial treatment was 56.9 years. The vast majority of patients had a good performance status (86.7% ECOG PS 0) and normal LDH levels (90.3%), brain metastases were present in 24.1% of patients. Rechallenge therapy was started median 53.9 months after the stop date of initial therapy (range 3.4–92.1 months). At the start of rechallenge therapy with ipilimumab and nivolumab, the mean age was 61.3 years. Compared to the initial treatment, patients had a worse ECOG performance status (37.0% had an ECOG PS 0), LDH levels were higher (normal in 53.3%) and brain metastases were more frequent (46.2% of patients). For the initial ipilimumab monotherapy, the main reason for stopping therapy was a completed treatment episode of four cycles (77.4%). For the rechallenge episode, 89.3% of patients prematurely discontinued treatment, of whom 39.3% for toxicity, 25.0% for progression, and 21.4% because of poor patient condition. At the start of rechallenge therapy, 14 patients had received intercurrent BRAF/MEK inhibition therapy (43.8% of patients, 82.4% of patients with a known BRAFV600 mutation). The median number of cycles administered during initial ipilimumab monotherapy was 4 (range 1–4), the median number of ipilimumab + nivolumab cycles during rechallenge therapy was 3 (range 1–4). Most patients (75.0%) did not receive any nivolumab maintenance cycles, with the number of cycles ranging from 0 to 22.
Efficacy
Treatment response
After initial treatment with ipilimumab + nivolumab, the objective response rate (ORR) was 45.0%, and the disease control rate (DCR) was 65.0%. After rechallenge treatment, the response rates to ipilimumab + nivolumab were lower, with an ORR of 36.1% and a DCR of 41.7%. An overview of individual patient responses to initial and rechallenge treatment is displayed in Fig. 1. For patients with complete response data (to both initial and rechallenge treatment), cross tables of response rates are presented in Table 2.
Fig. 1. Sankey diagram showing responses of individual patients to initial and rechallenge treatment.
Patients are grouped based on the best response to initial treatment (left) and rechallenge treatment (right). CR Complete response, PR Partial response, SD Stable disease, PD Progressive disease.
Table 2.
Cross tables of responders vs. non-responders to initial and rechallenge treatments.
| a) ORR after initial ipilimumab/nivolumab treatment and rechallenge | ||||
|---|---|---|---|---|
| Response to rechallenge treatment | ||||
| No | Yes | Total | ||
| Response to initial treatment | No | 12 (34.4%) | 7 (20.0%) | 19 (54.3%) |
| Yes | 10 (28.6%) | 6 (17.1%) | 16 (45.7%) | |
| Total | 22 (62.9%) | 13 (37.1%) | 35 (100.0%) | |
| b) DCR after initial ipilimumab/nivolumab treatment and rechallenge | ||||
| Disease control after rechallenge treatment | ||||
| No | Yes | Total | ||
| Disease control after initial treatment | No | 9 (25.7%) | 5 (14.3%) | 14 (40.0%) |
| Yes | 11 (31.4%) | 10 (28.6%) | 21 (60.0%) | |
| Total | 20 (57.1%) | 15 (42.9%) | 35 (100.0%) | |
| c) ORR after initial ipilimumab monotherapy and rechallenge ipilimumab/nivolumab | ||||
| Response to rechallenge treatment | ||||
| No | Yes | Total | ||
| Response to initial treatment | No | 10 (33.0%) | 8 (26.7%) | 18 (60.0%) |
| Yes | 8 (26.7%) | 4 (13.3%) | 12 (40.0%) | |
| Total | 18 (60.0%) | 12 (40.0%) | 30 (100.0%) | |
| d) DCR after initial ipilimumab monotherapy and rechallenge ipilimumab/nivolumab | ||||
| Disease control after rechallenge treatment | ||||
| No | Yes | Total | ||
| Disease control after initial treatment | No | 6 (20.0%) | 3 (10.0%) | 9 (30.0%) |
| Yes | 10 (3.3%) | 11 (36.7%) | 21 (70.0%) | |
| Total | 16 (53.3%) | 14 (46.7%) | 30 (100.0%) | |
Of the 41 patients treated with initial ipilimumab + nivolumab, no response data were available for six patients. Of the remaining 35 patients, six patients (17.1%) had objective response to both the initial and the rechallenge treatments. Twelve patients did not gain objective response from either treatment episode (34.3%). This translates into about half of the patients (n = 18, 51.4%) showing a concordant response when comparing the initial and rechallenge treatments. The other 17 patients (48.6%) had different responses to the initial and rechallenge treatments. Among these, ten patients (28.6%) achieved objective response to the initial treatment but not to the rechallenge. Seven patients (20.0%) did not respond to the initial treatment but did respond to the rechallenge.
Regarding the DCR, ten patients (28.6%) had disease control after both the initial and rechallenge treatments, while nine patients did not achieve disease control after either treatment (25.7%). This translates to a consistent treatment effect for both treatment episodes in 19 patients (54.3%). For the remaining 16 patients (45.7%), the DCR to the initial and rechallenge treatments was discordant. Among these, 11 patients (31.4%) had disease control after the initial treatment but not after the rechallenge, and five patients (14.3%) had no disease control after the initial treatment but did achieve disease control after the rechallenge therapy.
For the patients initially treated with ipilimumab monotherapy, the ORR to initial treatment was 40.6% and the DCR 68.8%. The ORR to rechallenge therapy with ipilimumab + nivolumab for these patients was 40.0% and the DCR 46.7%. Similar to the responses seen for patients who were initially treated with combination ipilimumab + nivolumab, the response to initial ipilimumab monotherapy was often not concordant with the response to rechallenge therapy (concordant in 46.7% of patients). The responses to rechallenge therapy were not evidently better in patients with initial ipilimumab monotherapy when compared to patients with initial ipilimumab + nivolumab (Table 2, Fig. 1).
Responders versus non-responders to rechallenge therapy
The characteristics of patients at start of rechallenge therapy, categorized by their objective response to the rechallenge treatment, are shown in Table 3. When comparing patients that responded to rechallenge therapy to patients that did not, the mean age was 65.1 vs. 55.8 years, the frequency of brain metastases was 42.1% vs. 57.9%, the prevalence of liver metastases was 13.6% vs. 25.6% and the amount of patients with BRAF V600 mutations was 62.5% vs. 81.1%. An ECOG PS 0 was seen in 55.6% vs. 40.5%, respectively. Objective response rates to initial treatment were comparable between responders vs. non-responders to rechallenge therapy (40.0% vs. 45.0%). The best response to the initial treatment was stable disease in 32.0% vs. 15.0% and progressive disease in 28.0% vs. 40.0% for patients who responded to rechallenge therapy vs. patients who did not. The reason for discontinuing initial treatment was the planned end of treatment in 44.0% of responders vs. 35.9% of non-responders. For patients who responded to rechallenge therapy, the median time between initial and rechallenge treatment was 26.6 months vs. 22.8 months for patients who did not respond to rechallenge therapy. The median number of intercurrent systemic treatment lines was 1 vs. 2, respectively. Comparative statistics assessing age, gender, ECOG PS (categorized), LDH levels (categorized), brain metastases, liver metastases, BRAF V600 mutation, objective response to initial treatment, type of initial treatment, and the rate of toxicity to initial treatment showed no significant differences between responders and non-responders to rechallenge therapy, except for responders being older (Supplementary Table 1). However, patient numbers are small.
Table 3.
Characteristics of responders vs. non-responders to rechallenge therapy at time of start of rechallenge therapy.
| No response to rechallenge therapy (n = 41) | Response to rechallenge therapy (n = 25) | |
|---|---|---|
| Age | ||
| Mean (SD) | 55.8 (14.5) | 65.1 (11.4) |
| Gender | ||
| Male | 23 (56.1%) | 16 (64.0%) |
| Female | 18 (43.9%) | 9 (36.0%) |
| ECOG PS | ||
| 0 | 15 (40.5%) | 10 (55.6%) |
| 1 | 20 (54.1%) | 8 (44.4%) |
| 2 | 2 (5.4%) | – |
| No. missings | 4 | 7 |
| LDH level | ||
| Normal | 21 (53.8%) | 14 (58.3%) |
| 1-2x elevated | 14 (35.9%) | 10 (41.7%) |
| >2x elevated | 4 (10.3%) | – |
| No. missings | 2 | 1 |
| Brain metastases | ||
| No | 16 (42.1%) | 11 (57.9%) |
| Yes | 22 (57.9%) | 8 (42.1%) |
| Symptomatic | 9 (23.7%) | 2 (10.5%) |
| Asymptomatic | 10 (26.3%) | 5 (26.3%) |
| Unknown if symptomatic | 3 (7.9%) | 1 (5.3%) |
| No. missings | 3 | 6 |
| Liver metastases | ||
| No | 29 (74.4%) | 19 (86.4%) |
| Yes | 10 (25.6%) | 3 (13.6%) |
| No. missings | 2 | 3 |
| BRAF V600 mutation | ||
| No | 7 (18.9%) | 9 (37.5%) |
| Yes | 30 (81.1%) | 15 (62.5%) |
| No. missings | 4 | 1 |
| Best response to initial treatment | ||
| CR | 4 (10.0%) | 3 (12.0%) |
| PR | 14 (35.0%) | 7 (28.0%) |
| SD | 6 (15.0%) | 8 (32.0%) |
| PD | 16 (40.0%) | 7 (28.0%) |
| No. missings | 1 | – |
| Initial treatment | ||
| Ipilimumab monotherapy | 18 (43.9%) | 12 (48.0%) |
| Ipilimumab + nivolumab | 23 (56.1%) | 13 (52.0%) |
| Toxicity grade ≥3 to initial therapy | ||
| No | 25 (62.5%) | 17 (68.0%) |
| Yes | 15 (37.5%) | 8 (32.0%) |
| No. missings | 1 | – |
| Reason for stopping initial therapy | ||
| Planned | 14 (35.9%) | 11 (44.0%) |
| Progression | 10 (25.6%) | 6 (24.0%) |
| Toxicity | 13 (33.3%) | 8 (32.0%) |
| Patient condition | 1 (2.6%) | – |
| Other | 1 (2.6%) | – |
| No. missings | 2 | – |
| Time between initial and rechallenge treatment | ||
| Median in months [Q1-Q3] | 22.8 [12.9–39.9] | 26.4 [11.6–58.8] |
| No. of therapy lines between treatments | ||
| Median [Q1-Q3] | 2 [1,2] | 1 [0-2] |
Survival
Median progression free survival (PFS) of patients from the start of initial treatment was 6.9 months (95% confidence interval (CI): 3.6–11.3) for patients treated with initial ipilimumab monotherapy, and 6.6 months (95% CI 2.5–10.1) for patients treated with initial ipilimumab + nivolumab. From the start of rechallenge treatment, the median PFS was 5.6 months (95% CI 2.8–18.4) for patients who received initial ipilimumab monotherapy and 2.8 months (95% CI 2.4–8.0) for patients who received ipilimumab + nivolumab as initial therapy. For patients with objective response to initial treatment, median PFS was 2.8 months (95% CI 2.7–8.4) from the start of rechallenge therapy, compared to 3.8 months (95% CI 2.8–18.4) for patients with no objective response to initial treatment. Patients with objective response to the rechallenge therapy had a median PFS of 18.4 months (95% CI 14.6–NR) compared to 2.5 months (95% CI 2.1–2.8) for the non-responders.
Median overall survival (OS) of patients from the start of initial treatment was 78.6 months (95% CI 60.5 – NR) for patients with initial ipilimumab monotherapy and 37.7 months (95% CI 28.8 – NR) for the patients treated with initial ipilimumab + nivolumab. From the start of rechallenge therapy, the median OS was 19.3 months (95% CI 12.4–NR) and 11.2 months (95% CI 10.1–NR) for patients with initial ipilimumab monotherapy and for patients with initial ipilimumab + nivolumab respectively. Patients with objective response to their initial treatment had a median OS of 12.9 months (95%CI 10.1–NR), patients with no response to initial treatment had a median OS of 19.3 months (95% CI 10.6–NR), when measured from the start of the rechallenge therapy. Non-responders to the rechallenge therapy had a median OS of 6.8 months (95% CI 4.6–12.4), median OS for responders was not reached. For patients that had received intercurrent BRAF/MEK inhibition prior to rechallenge therapy, the median OS from the start of rechallenge therapy was 11.2 months (95% CI 10.1–NA) compared to median 18.4 months (95% CI 12.4–NA) for patients that had not intercurrently been treated with BRAF/MEK inhibitors (75.0% of whom were BRAFV600 wildtype).
A total of 15 patients received subsequent BRAF/MEK inhibition therapy after progression on rechallenge ipilimumab + nivolumab. These were 13 patients who had no objective response to rechallenge therapy and 2 patients who did achieve response to rechallenge therapy. One patient with response to rechallenge ipilimumab + nivolumab resumed anti-PD-1 after secondary progression; this was a patient who stopped ipilimumab + nivolumab due to toxicity. No other subsequent therapies after rechallenge ipilimumab + nivolumab were given in this study population.
Survival curves for OS and PFS are displayed in Supplementary Figs. 1, 2.
Safety
Among the patients who received initial treatment with monotherapy ipilimumab, 25.0% developed grade 3 or higher toxicity during that episode (Table 1). Initial treatment with combination ipilimumab + nivolumab resulted in grade 3 or higher toxicity in 45.0% of patients. Following rechallenge therapy, grade 3 or higher toxicity occurred in 39.7% of all patients. For patients who received ipilimumab + nivolumab both at initial therapy and at rechallenge therapy, the rate of grade ≥3 toxicity to rechallenge therapy was 40.5%. For patients who received initial ipilimumab monotherapy, the rate of toxicity to rechallenge ipilimumab + nivolumab therapy was 38.7%.
Five out of eight patients (62.5%) who experienced severe irAEs after initial ipilimumab monotherapy developed severe irAEs after rechallenge therapy. Among the 18 patients who developed severe irAEs following initial ipilimumab + nivolumab, toxicity information after rechallenge treatment was missing for three patients. Of the remaining patients, eight out of 15 (53.3%) again experienced severe irAEs.
The occurrence of gastrointestinal irAEs after rechallenge treatment was 21.6% and 25.8% for patients who had received initial combination ICI and ipilimumab monotherapy respectively. After initial treatment, gastrointestinal irAEs occurred in 15.6% and 14.6% of patients respectively.
Severe endocrine irAEs did not occur after rechallenge treatment. After initial treatment, 6.3% of patients with ipilimumab monotherapy and 12.2% of patients with initial ipilimumab + nivolumab developed severe endocrine irAEs. Hepatitis was seen in 20.0% of patients after initial combination ipilimumab + nivolumab and in 8.1% of patients after rechallenge therapy. Frequencies of irAEs after initial treatments and rechallenge treatment are detailed in Supplementary Table 2.
Individual case studies
Patients with response to rechallenge therapy but no response to initial therapy
A total of 15 out of 73 patients (20.5%) did not respond to the initial therapy but did respond to the rechallenge therapy. These patients were studied on an individual scale. Seven out of 15 patients were initially treated with ipilimumab + nivolumab, the other eight patients received ipilimumab monotherapy initially. Details on the initial and rechallenge therapy episodes of these patients are described in Supplementary Table 3. Two patients discontinued initial treatment after two cycles due to toxicity, both patients were also discontinued from rechallenge treatment due to toxicity but did achieve response to the rechallenge. Five patients were discontinued from initial ipilimumab + nivolumab therapy early due to fast progressive disease, these patients received intercurrent BRAF/MEK inhibition and were later successfully rechallenged to ICI. One patient had stable disease after initial ipilimumab + nivolumab therapy (4 cycles) and nivolumab maintenance therapy up to two years treatment. This patient was rechallenged at time of disease progression 25 months after the last nivolumab cycle, resulting in a partial response. The other patients initially did not respond to ipilimumab monotherapy but did respond to rechallenge therapy with combination ipilimumab + nivolumab.
Outcomes in patients with initial neoadjuvant treatment
The DMTR database contained three patients who initially received ipilimumab + nivolumab for resectable stage IIIC melanoma and who received retreatment with ipilimumab + nivolumab after later progression to stage IV disease. These patients received initial treatment with two cycles of ipilimumab 1 mg/kg + nivolumab 3 mg/kg followed by resection. Disease progression to stage IV disease occurred 20, 24, and 33 months after the start of neoadjuvant treatment, after which patients received ipilimumab 3 mg/kg + nivolumab 1 mg/kg. The radiological response to neoadjuvant ICI was not recorded, all three patients had no evidence of disease after resection. Two patients experienced severe irAEs after the neoadjuvant treatment (colitis and hepatitis); both patients had recurrence of their irAE after rechallenge therapy. The patient with colitis received prednisone and a TNF-alpha inhibitor in both episodes, the patient experiencing hepatitis received only corticosteroids. The patients experiencing colitis and hepatitis had a complete response and a partial response to the rechallenge therapy respectively, the third patient had progressive disease as best response.
Discussion
Despite vast progress in the treatment and survival of advanced melanoma patients in the past decade, the number of therapy lines remains limited, especially for patients without a BRAF mutation. In this retrospective study of prospectively collected data, we present the largest cohort of melanoma patients who were rechallenged with combination ipilimumab + nivolumab after prior treatment with ipilimumab monotherapy or ipilimumab + nivolumab. We show that rechallenging with ipilimumab + nivolumab resulted in an ORR of 36.1% for patients who received initial ipilimumab + nivolumab therapy and an ORR of 40.0% for patients who were initially treated with ipilimumab monotherapy. While the median PFS after rechallenge therapy was low (2.8 months and 5.6 months for patients that received initial combination therapy and ipilimumab monotherapy respectively), responders to rechallenge therapy had a substantial duration of response, with a median PFS of 18.4 months.
Previous observational studies showed moderate response rates on rechallenge anti-PD-1 monotherapy following a prior treatment course of anti-PD-1 monotherapy, with an ORR ranging from 14 to 55% and a DCR ranging from 50% - 81% in advanced/metastatic melanoma patients [15–26]. Response to rechallenge ipilimumab therapy after prior ipilimumab therapy has been described by several observational studies with an ORR ranging from 13 to 38% and a DCR ranging from 48 to 75% [27–30]. However, comparative data on rechallenge combination anti-CTLA-4 + anti-PD-1 therapy after prior anti-CTLA-4 exposure is limited with only small patient numbers (n = 12 and n = 3) in observational studies [31, 32]. We observed a slightly higher response than published by Hepner et al. who showed an ORR of 26% and a DCR of 45% in a combined retrospective cohort of 47 patients rechallenged with combination anti-CTLA-4 + anti-PD-1 (n = 41) or anti-CTLA-4 monotherapy (n = 6) after previous anti-PD-1 + anti-CTLA-4 treatment [12]. This is notable since their study included only patients who reached initial response and secondary progression to ICI, while in our study patients were also included if they did not have a response to their initial ipilimumab-containing treatment episode.
We observed an acceptable safety profile of rechallenge therapy, with grade ≥3 toxicity in 40.5% of patients who had initially received combination ipilimumab + nivolumab therapy and 38.7% of patients initially receiving ipilimumab monotherapy. This is in line with previous observational data [8, 9]. The rate of toxicity after rechallenge therapy in this population was even lower than the rate of toxicity to initial combination ipilimumab + nivolumab (45.0%). However, the toxicity rate to rechallenge therapy was higher for patients who had severe irAEs after initial treatment (62.5% for those initially treated with ipilimumab monotherapy and 58.8% for those initially treated with combination therapy). There is a potential selection bias in these retrospective analyses on toxicity, as patients who previously experienced severe toxicity are less likely to receive rechallenge therapy.
A unique aspect of this study is that patients were included who did not have an objective response to initial ipilimumab-containing treatment (41 out of 73 patients, 56.2%), in contrast to the abovementioned studies that included only patients who experienced response to initial therapy. Fifteen of these 41 patients (36.6%) did have an objective response to rechallenge therapy. This suggests that rechallenge ipilimumab + nivolumab therapy could be considered even in patients without objective response to previous treatment. Inversely, our data demonstrated that response to initial treatment is not a predictor of the response to rechallenge treatment. In our study, 51.4% of patients exhibited a concordant response to both initial and rechallenge ipilimumab + nivolumab treatment, and 46.7% of patients with initial ipilimumab monotherapy and rechallenge ipilimumab + nivolumab therapy exhibited a concordant response. However, these analyses should be interpreted in the light of possible survivorship bias. The patients in this study population received rechallenge ipilimumab + nivolumab in a real-world setting by decision of their treating physicians. As a result, patients with favorable characteristics and longer survival after initial ICI treatment could have been more likely to receive rechallenge therapy, potentially leading to more favorable outcomes.
As neoadjuvant treatment with ipilimumab + nivolumab as investigated in the NADINA trial is emerging as standard of care for patients with resectable stage III melanoma [33], information on rechallenge treatment with ipilimumab + nivolumab is becoming increasingly important. Future research on response to rechallenge therapy with ipilimumab + nivolumab after prior neoadjuvant treatment remains of clinical importance.
In this study, patients treated with ipilimumab + nivolumab as well as patients treated with ipilimumab monotherapy as initial treatment episode were included. These patient groups should be regarded as different patient categories. Ipilimumab monotherapy since 2016 is no longer a commonly given treatment in the Netherlands [34]. Patients with ipilimumab monotherapy thus received their initial treatment earlier in time, possibly explaining why a longer time was seen between initial and rechallenge therapy in this patient group. This might explain the more favorable survival of patients who initially were treated with ipilimumab monotherapy, since these were likely patients with a more indolent disease course. Patients who developed progressive disease after initial ipilimumab monotherapy early in time, will not have received a rechallenge ipilimumab + nivolumab since this combination was not yet a registered treatment in the Netherlands. This survivorship bias is likely also reflected in the much more favorable survival and response outcomes of the patients initially treated with ipilimumab monotherapy in our study population when compared to for example those obtained in CHECKMATE 067 (ORR 19%, median OS 19.9months) [1]. Analyses in this study were therefore performed separately for patients with initial ipilimumab monotherapy and patients with initial ipilimumab + nivolumab.
Due to the small number of patients, statistical comparative analyses were not contributory. Nonetheless, patients who had a tumor response to rechallenge ipilimumab + nivolumab appeared to have more favorable characteristics in terms of performance status, LDH, and brain metastases and tended to more often have achieved disease control after the initial treatment.
Our study should be interpreted in the light of several limitations. First, the small number of patients precluded conclusive comparative statistical analysis. Additionally, the retrospective selection of patients introduces potential bias. The patients that were described in this study were given rechallenge ICI therapy by decision of their treating physicians, based on the judgment that rechallenge therapy might be beneficial for them. This could lead to favorable response and toxicity rates. While the results of this study are likely valid for patients who survive and remain in good clinical condition long enough to receive rechallenge therapy with ipilimumab + nivolumab, the results will not be valid for all patients. The decision of rechallenge therapy with ipilimumab and nivolumab should be made only after careful consideration.
In conclusion, we demonstrate that in selected patients rechallenge with ipilimumab + nivolumab in advanced melanoma has a considerable response rate, an acceptable safety profile, and the potential for a durable response, regardless of the response to initial treatment. Further studies are warranted to identify predictive factors for treatment response to better select patients who are most likely to benefit from rechallenge with ipilimumab + nivolumab combination therapy.
Supplementary information
Acknowledgements
We thank all physicians and data managers who registered patient data in the Dutch Melanoma Treatment Registry.
Author contributions
EJD: conceptualization, methodology, formal analysis, data interpretation, writing original draft, review and editing, data collection, project administration. HHN: conceptualization, data interpretation, writing original draft, review and editing, data collection, project administration. AJME: data interpretation, review and editing, data collection, project administration. MJB: data interpretation, review and editing, data collection, project administration. MB: data interpretation, review and editing, data collection, project administration. AMK: data interpretation, review and editing, data collection. MMR: data interpretation, review and editing, data collection. CB: data interpretation, review and editing. MJBA: data interpretation, review and editing, data collection, project administration. FWPJB: data interpretation, review and editing, data collection, project administration. CUB: data interpretation, review and editing, data collection, project administration. WAMB: data interpretation, review and editing, data collection, project administration. JWBG: data interpretation, review and editing, data collection, project administration. GAPH: data interpretation, review and editing, data collection, project administration. DP: data interpretation, review and editing, data collection, project administration. RSR: data interpretation, review and editing, data collection, project administration. AMS: data interpretation, review and editing, data collection, project administration. GV: data interpretation, review and editing, data collection, project administration. MWJMW: data interpretation, review and editing, data collection, project administration. EK: data interpretation, review and editing, data collection, project administration. JBH: data interpretation, review and editing, data collection, project administration. AAMV: data interpretation, review and editing, data collection, project administration. KPMS: conceptualization, data interpretation, review and editing, data collection, project administration, supervision.
Funding
The Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002) for the Dutch Melanoma Treatment Registry (DMTR). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis and Roche Pharma. Roche Pharma stopped funding in 2019 and Pierre Fabre started funding in 2019. For this work no funding was granted.
Data availability
The datasets generated during and/or analyzed during this study are not publicly available due to privacy regulations in the Netherlands. Requests for data sharing can be addressed to the corresponding author.
Competing interests
HHN has advisory/consultancy relations with Bayer, Roche, Johnson&Johnson, and Illumina. AJME has advisory/consultancy relations with Amgen, Bristol Myers Squibb, Ipsen Biopharmaceuticals, Janssen-Cilag BV, Merck, Merck Sharp & Dohme, Novartis, Pfizer Canada and Pierre Fabre Pharmaceuticals. He received a research grant from Bristol-Myers Squibb, paid to institution. CB received research grants from Philips, Bracco, Sensius, all paid to institution. CUB has advisory/consultancy relations with Bristol Myers Squibb, Roche, Merck and Third Rock Ventures. He received research grants from 4SC, Bristol Myers Squibb, Roche, Merck, NanoString Technologies, all paid to institution. He received an individual research grant from Third Rock Ventures. He is co-founder of Signature Oncology and Imagene BV, and has a pending patent (Patent number WO 2021/177822 A1). GAPH received research grants from Bristol-Myers Squibb and Seerave, all paid to institution. DP has advisory/consultancy relations with Novartis and Pierre Fabre Pharmaceuticals. She received a travel grant from Pierre Fabre Pharmaceuticals. EK has advisory/consultancy relations with Delcath, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis, and Pierre-Fabre. Not related to current work and paid to institute. JBH has advisory/consultancy relations with AZ, BioNTech, CureVac, Eisai, Ipsen, Instil Bio, Iovance Bio, MSD, Novartis, Neogene Therapeutics, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures, and T-Knife. He received research grants from Amgen, BioNTech, Bristol Myers Squibb, Novartis, Sastra Cell Therapy. He is editor-in-Chief of ESMO Immmuno-Oncology & Technology (IOTECH). AAMV has advisory/consultancy relations with Bristol-Myers Squibb, MSD, Sanofi, Merck, Pierre Fabre, Novartis, Pfizer, Roche, Eisai and Ipsen. KPMS has advisory/consultancy relations with AbbVie, and Sairopa. She received research grants from Bristol-Myers Squibb, Genmab, Philips, Pierre Fabre, and Tigatx, all paid to institution. She does data and safety monitoring for Sairopa. No other competing interests were reported.
Ethics approval and consent to participate
This study was performed in accordance with the Declaration of Helsinki. In compliance with Dutch regulations, research with DMTR data was approved by the medical ethical committee (METC Leiden University Medical Center, 2013) not to be subject to the Medical Research Involving Human Subjects Act, thereby waiving the requirement for informed consent.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-025-03027-z.
References
- 1.Wolchok JD, Chiarion-Sileni V, Rutkowski P, Cowey CL, Schadendorf D, Wagstaff J, et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2025;392:11–22. [DOI] [PMC free article] [PubMed]
- 2.Atkins MB, Lee SJ, Chmielowski B, Tarhini AA, Cohen GI, Truong TG, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq trial-ECOG-ACRIN EA6134. J Clin Oncol. 2022;41:186–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ascierto PA, Mandaì M, Ferrucci PF, Guidoboni M, Rutkowski P, Ferraresi V, et al. Sequencing of ipilimumab plus nivolumab and encorafenib plus binimetinib for untreated BRAF-mutated metastatic melanoma (SECOMBIT): a randomized, three-arm, open-label phase II trial. J Clin Oncol. 2022;41:212–21. [DOI] [PubMed] [Google Scholar]
- 4.Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017;18:464–72. [DOI] [PubMed] [Google Scholar]
- 5.Cremolini C, Rossini D, Dell’Aquila E, Lonardi S, Conca E, Del Re M, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol. 2019;5:343–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): A randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14:1175–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Van Not OJ, van den Eertwegh AJM, Haanen JB, van Rijn RS, Aarts MJB, van den Berkmortel FWPJ, et al. BRAF/MEK inhibitor rechallenge in advanced melanoma patients. Cancer. 2024;130:1673–83. [DOI] [PubMed] [Google Scholar]
- 8.Dolladille C, Ederhy S, Sassier M, Cautela J, Thuny F, Cohen AA, et al. Immune Checkpoint Inhibitor Rechallenge after Immune-Related Adverse Events in Patients with Cancer. JAMA Oncol. 2020;6:865–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhao Q, Zhang J, Xu L, Yang H, Liang N, Zhang L, et al. Safety and efficacy of the rechallenge of immune checkpoint inhibitors after immune-related adverse events in patients with cancer: a systemic review and meta-analysis. Vol. 12, Frontiers in Immunology. Frontiers Media S.A.; 2021. p. 730320. [DOI] [PMC free article] [PubMed]
- 10.Pires da Silva I, Ahmed T, Reijers ILM, Weppler AM, Betof Warner A, Patrinely JR, et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Lancet Oncol. 2021;22:836–47. [DOI] [PubMed] [Google Scholar]
- 11.VanderWalde A, Bellasea SL, Kendra KL, Khushalani NI, Campbell KM, Scumpia PO, et al. Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. Nat Med. 2023;29:2278–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hepner A, Atkinson VG, Larkin J, Burrell RA, Carlino MS, Johnson DB, et al. Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti–PD-1 therapy. Eur J Cancer. 2021;153:213–22. [DOI] [PubMed] [Google Scholar]
- 13.Jochems A, Schouwenburg MG, Leeneman B, Franken MG, Van Den Eertwegh AJM, Haanen JBAG, et al. Dutch melanoma treatment registry: quality assurance in the care of patients with metastatic melanoma in the Netherlands. Eur J Cancer. 2017;72:156–65. [DOI] [PubMed] [Google Scholar]
- 14.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;45:228–47. [DOI] [PubMed] [Google Scholar]
- 15.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;13:3074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Blasig H, Bender C, Hassel JC, Eigentler TK, Sachse MM, Hiernickel J, et al. Reinduction of PD1-inhibitor therapy: first experience in eight patients with metastatic melanoma. Melanoma Res. 2017;27:321–5. [DOI] [PubMed] [Google Scholar]
- 17.Jansen YJL, Rozeman EA, Mason R, Goldinger SM, Geukes Foppen 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;30:1154–61. [DOI] [PubMed] [Google Scholar]
- 18.Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol. 2019;30:582–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20:1239–51. [DOI] [PubMed] [Google Scholar]
- 20.Nardin C, Hennemann A, Diallo K, Funck-Brentano E, Puzenat E, Heidelberger V, et al. Efficacy of immune checkpoint inhibitor (ICI) rechallenge in advanced melanoma patients’ responders to a first course of ICI: a multicenter national retrospective study of the french group of skin cancers (Groupe de Cancérologie Cutanée, GCC). Cancers. 2023;15:3564. [DOI] [PMC free article] [PubMed]
- 21.Nomura M, Otsuka A, Kondo T, Nagai H, Nonomura Y, Kaku Y, et al. Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Cancer Chemother Pharm. 2017;80:999–1004. [DOI] [PubMed] [Google Scholar]
- 22.Pokorny R, McPherson JP, Haaland B, Grossmann KF, Luckett C, Voorhies BN, et al. Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma. J Immunother Cancer. 2021;9:e001781. [DOI] [PMC free article] [PubMed]
- 23.Sadrolashrafi K, Samlowski W. Retreatment of patients with metastatic cutaneous melanoma who relapse after elective checkpoint inhibitor discontinuation after a complete remission. Oncologist. 2023;28:E270–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.van Zeijl MCT, van den Eertwegh AJM, Wouters MWJM, de Wreede LC, Aarts MJB, van den Berkmortel FWPJ, et al. Discontinuation of anti-PD-1 monotherapy in advanced melanoma—Outcomes of daily clinical practice. Int J Cancer. 2022;150:317–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Warner AB, 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;38:1655–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Whitman ED, Scherrer E, Ou W, Krepler C. Outcomes of retreatment with anti-PD-1 monotherapy after response to first course in patients with cutaneous melanoma. Future Oncol. 2020;16:1441–53. [DOI] [PubMed] [Google Scholar]
- 27.Chiarion-Sileni V, Pigozzo J, Ascierto PA, Simeone E, Maio M, Calabrò L, et al. Ipilimumab retreatment in patients with pretreated advanced melanoma: The expanded access programme in Italy. Br J Cancer. 2014;110:1721–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Formozo AA, Gomes JR, Schmerling RA, Buzaid AC. Retrospective analysis of rechallenge with ipilimumab in patients with metastatic melanoma. J Ski Cancer. 2021;2021:5531864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Lebbé C, Weber JS, Maio M, Neyns B, Harmankaya K, Hamid O, et al. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann Oncol. 2014;25:2277–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Robert C, Schadendorf D, Messina M, Hodi FS, O’Day S. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013;19:2232–9. [DOI] [PubMed] [Google Scholar]
- 31.Shah P, Punekar SR, Pavlick AC. Response to immune checkpoint inhibitor rechallenge after high-grade immune related adverse events in patients with advanced melanoma. Melanoma Res. 2021;31:242–8. [DOI] [PubMed] [Google Scholar]
- 32.Spain L, Walls G, Messiou C, Turajlic S, Gore M, Larkin J. Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series. Cancer Immunol, Immunother. 2017;66:113–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. 2024;391:1696-1708. [DOI] [PubMed]
- 34.Van Not OJ, Van Den Eertwegh AJM, Haanen JB, Blank CU, Aarts MJB, Van Breeschoten J, et al. Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021. EClinicalMedicine. 2024;69:102485. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during this study are not publicly available due to privacy regulations in the Netherlands. Requests for data sharing can be addressed to the corresponding author.