Abstract
Background
Immune checkpoint inhibitors (ICIs) are increasingly used in adolescents and young adults (AYAs) with cancer; however, data on treatment response, the frequency and pattern of immune-related adverse events (irAEs), and the feasibility of ICI rechallenge after irAEs are limited.
Methods
This retrospective study included 136 AYAs (80 males and 56 females) who received ICI therapy for melanoma at our institution from 2013 to 2023. We documented the initial ICI treatment and ICI rechallenge, along with associated irAEs and treatment responses. Kaplan-Meier plots were used to analyze overall survival (OS) and progression-free survival.
Results
At ICI initiation, the median age was 33 (range, 15–39) years, and most patients had stage III or IV disease (93%) and BRAF mutations (63%). Treatment settings included adjuvant (n=70), palliative (n=50), and neoadjuvant (n=16). Compared with those receiving ICI monotherapy (n=77), patients receiving ICI combination therapy (n=59) had significantly higher rates of irAEs of any grade (53% vs 75%, p=0.011) and grade three or four irAEs (12% vs 32%, p=0.003) and higher rates of treatment delay (26% vs 51%, p=0.044), and hospitalization (8% vs 20%, p=0.032). ICI rechallenge was common (n=71), even after prior irAEs (n=48). Colitis and hepatitis were the most common irAEs following initial ICI therapy (26% and 23%, respectively) and ICI rechallenge (31% and 29%, respectively). The adjuvant, palliative, and neoadjuvant ICI therapy groups had 5-year OS rates of 86%, 77%, and 88%, respectively. In the palliative therapy group, the overall response rate and disease control rate were 38% and 42% during initial ICI therapy and 35% and 44% during ICI rechallenge. Elevated baseline lactate dehydrogenase levels were associated with worse OS (adjusted HR, 21.04, 95% CI, 1.35 to 328.29, p=0.030), and colitis and/or hepatitis were strongly associated with better OS (adjusted HR, 0.10, 95% CI 0.01 to 0.83, p=0.033).
Conclusions
AYA patients receiving ICI therapy for melanoma had high incidence of colitis and hepatitis and favorable survival. Initial and rechallenge ICI therapy had similar patterns of irAE severity and efficacy. Colitis and hepatitis were associated with improved OS.
Keywords: Immune Checkpoint Inhibitors, Melanoma, Immune related adverse event - irAE, Survivorship
WHAT IS ALREADY KNOWN ON THIS TOPIC
Melanoma has a relatively high incidence in the adolescent and young adult (AYA) population, and immune checkpoint inhibitors (ICIs) have been shown to be effective in this group. AYA patients with melanoma treated with ICIs exhibit unique characteristics, including a higher incidence of hepatitis.
WHAT THIS STUDY ADDS
Our findings suggest that ICI rechallenge can be performed safely and cautiously in AYA patients with melanoma, even in those with prior immune-related adverse events (irAEs), with comparable efficacy. Notably, hepatitis and colitis had a high incidence in this population and were associated with improved overall survival.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study lays the groundwork for further exploration of ICI rechallenge in AYA patients with melanoma, highlighting the need for more dedicated research on irAE management and optimal rechallenge strategies in this population.
Introduction
One of the most common solid tumors among adolescents and young adults (AYAs; age 15–39 years at diagnosis) is melanoma, whose annual incidence in this population is around 6 per 100,000 and mortality rate is around 0.3 per 100,000.1 Survival rates overall for late-stage melanoma have significantly improved due to the use of immune checkpoint inhibitors (ICIs); however, immune-related adverse events (irAEs) have emerged as a significant challenge.1,4 Notably, the patients enrolled in the registrational trials that led to the approval of ICIs had an average age of 55–60 years.4,8 Some studies have suggested AYA patients with melanoma have tumor and host biology that are distinct from those of older patients, including more frequent BRAF mutations and PTEN alterations, as well as distinct stroma-infiltrating lymphocytes.19,11 However, data on ICI toxicity and response in AYA patients with melanoma are limited.
The role of age in ICI response and toxicity is not well understood. Some studies suggest that AYAs and older patients with melanoma have similar response rates to ICI therapy, with the largest reported AYA cohort consisting of 210 patients from the study by van der Kooij et al.12,14 AYA patients treated with ICIs may exhibit different patterns of irAEs.12,14 For instance, hepatitis was reported to be more prevalent in AYA patients than in older patients with melanoma13 14; however, this difference might be due to the fact that AYA patients with melanoma are more likely to receive more aggressive combination ICI regimens. Some data also suggest that younger patients may experience shorter progression-free survival (PFS) with ICI treatment compared with older patients.15 In addition, data suggest that patients who experience irAEs have better response to ICI therapy given both response and toxicity result from immune activation, but these data have not been assessed in AYA patients with melanoma specifically.16,18
Severe irAEs can lead to treatment delay, treatment cessation, and/or hospitalization,18 all of which can adversely affect survival. ICI rechallenge after irAEs has been reported in older adults with melanoma; however, few studies have assessed the safety and efficacy of ICI rechallenge in AYA patients with melanoma.17 18 Therefore, it is crucial to investigate how irAEs affect the course of ICI therapy in AYA patients and determine whether AYA patients can safely receive ICI rechallenge.
In this study, we examined survival and toxicity outcomes in a large cohort of AYA patients who received ICI therapy for melanoma, including patients who received ICI rechallenge after experiencing irAEs.
Methods
Study design and patient population
In this retrospective study, we searched our department database to identify AYA patients who received ICI therapy for melanoma at a tertiary cancer center from 2013 to 2023. Eligible patients were age 15–39 years old at the time of ICI initiation. Data collected from the patients’ electronic medical records included demographic data; baseline melanoma characteristics, including disease stage and mutation status; baseline laboratory test values, including lactate dehydrogenase (LDH) values; information about ICI therapy, including initial and rechallenge ICI therapy data and treatment delay, treatment cessation, and hospitalization data; treatment-related irAEs; treatment response; and PFS and overall survival (OS). We classified the ICI treatment into three categories: (1) adjuvant therapy, administered after complete surgical resection; (2) neoadjuvant therapy, given prior to surgical resection; and (3) palliative therapy, used for surgically unresectable disease. irAEs were assessed and graded based on the updated American Society of Clinical Oncology guidelines.19 Treatment response was determined using the Response Evaluation Criteria In Solid Tumors 1.1).20 The overall response rate (ORR) was the percentage of patients who had a complete or partial response in the neoadjuvant therapy or palliative therapy groups. The disease control rate (DCR) was the percentage of patients who had a complete response, partial response, or stable disease after treatment. PFS was calculated from the date of ICI initiation to the date of disease progression or death. For the adjuvant group, recurrence-free survival was calculated. OS was calculated from the date of ICI initiation to the date of death or last follow-up. Treatment delay was defined as an interruption of less than 3 months. Treatment cessation was defined as a switch to new therapy or a pause of the original treatment for over 3 months. ICI rechallenge was defined as the resumption of immunotherapy after treatment cessation with either the same or a different ICI.
Statistical analysis
For the extracted data, categorical variables were presented as frequency, while numerical variables were reported as median. Categorical variables between different groups were compared using the χ² test or Fisher’s exact test, as appropriate. For numerical variables, an unpaired, two-tailed t-test or Mann-Whitney U test was used for comparisons between two groups, while one-way analysis of variance or the Kruskal-Wallis test was applied for comparisons among three or more groups, as appropriate. Kaplan-Meier plots were used to analyze survival with corresponding 95% CIs, and the p values were reported using the log-rank test. Adjusted HRs were estimated using Cox proportional hazards models to investigate the association between OS and risk factors, including age, sex, LDH level, initial ICI therapy type (combination therapy vs monotherapy), type of melanoma, BRAF mutation status, and a history of colitis or hepatitis with initial ICI.
Results
Baseline patient characteristics
The baseline characteristics of the 136 patients included in the study are given in table 1. The median ages at initial diagnosis and ICI initiation were 31 years (range, 13–39 years) and 33 years (range, 15–39 years), respectively. Of the 136 patients, 107 (79%) had non-acral cutaneous melanoma, and 86 (63%) had a BRAF V600E/R/K mutation. At ICI therapy initiation, 73 (54%) had stage III melanoma, 10 (7%) had stage IV M1A/B melanoma, and 44 (32%) had stage IV M1C/D melanoma. 20 patients (15%) received targeted therapy before starting ICI therapy. Of the 81 patients for whom baseline LDH levels were available, 14 (17%) had levels above the upper limit of normal.
Table 1. Patients’ baseline characteristics.
| Characteristic | No. of patients (%), N=136 |
|---|---|
| Age, median (range), years | 33 (15–39) |
| Sex | |
| Female | 56 (41) |
| Male | 80 (59) |
| Melanoma subtype | |
| Cutaneous | 107 (79) |
| Acral | 4 (3) |
| Mucosal | 3 (2) |
| N/A | 22 (16) |
| Disease stage | |
| IIB | 6 (4) |
| IIC | 1 (1) |
| I/II* | 2 (2) |
| IIIA | 11 (8) |
| IIIB | 19 (14) |
| IIIC | 32 (24) |
| IIID | 11 (8) |
| IVM1a | 4 (3) |
| IVM1b | 6 (4) |
| IVM1C | 28 (21) |
| IVM1D | 16 (12) |
| BRAF mutation | |
| Present | 86 (63) |
| Absent | 41 (30) |
| N/A | 9 (7) |
| Targeted therapy | |
| Previous | 20 (15) |
| Concurrent | 16 (12) |
| LDH level | |
| Above ULN | 14 (10) |
| WLN | 67 (49) |
| N/A | 55 (41) |
All data are no. of patients (%) unless otherwise indicated.
For these two patients, they had localized melanoma initially but specific staging at ICI initiation was unavailable.
ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; N/A, not available; ULN, upper limit of normal; WLN, within normal limits.
Initial ICI therapy
The characteristics of the patients at time of initial ICI therapy organized by intent of therapy are shown in table 2. The median time from primary diagnosis to ICI initiation was 3.5 months (IQR 2.0–22.3 months), and the median duration of initial ICI therapy was 8 months (IQR 2–11 months). Seventy patients (51%) received adjuvant ICI therapy, 50 (37%) received palliative ICI therapy, and 16 (12%) received neoadjuvant ICI therapy. The median durations of initial adjuvant, palliative, and neoadjuvant ICI therapy were 10 months (IQR, 4–11 months), 5 months (IQR, 2–13 months), and 1.5 months (IQR, 0–9 months), respectively. 77 patients (57%) received ICI monotherapy with anti-PD1, anti-PDL1, or anti-CTLA4 agents, whereas 59 (43%) received ICI combination therapy comprising anti-PD1 with either anti-CTLA4 or anti-LAG3. The majority of patients who received monotherapy were treated with anti-PD-1 agents (92%, 71 of 77 patients), and most patients in the combination therapy group received anti-PD-1 plus anti-CTLA-4 (97%, 57 of 59 patients).
Table 2. Patients’ characteristics by intent of immune checkpoint inhibitor (ICI) therapy.
| No. of patients (No. of patients (%) | ||||
|---|---|---|---|---|
| Characteristic |
Adjuvant ICI,
N=70 |
Palliative ICI,
N=50 |
Neoadjuvant ICI,
N=16 |
P value |
| Disease stage at ICI initiation | <0.001 | |||
| II | 7 (10) | 1 (2)* | 1 (6) | |
| III | 58 (83) | 1 (2)† | 14 (88) | |
| IV | 5 (7) | 48 (96) | 1 (6) | |
| Initial ICI therapy | 70 (100) | 50 (100) | 16 (100) | |
| Combination therapy | <0.001 | |||
| Yes | 7 (10) | 39 (78) | 13 (81) | |
| No | 63 (90) | 11 (22) | 3 (19) | |
| Duration, median (IQR), months | 10 (4–11) | 5 (2–13) | 1.5 (0–9) | 0.068 |
| Reason for stopping | 0.002 | |||
| irAEs | 13 (19) | 12 (24) | 2 (12) | |
| Progression | 20 (29) | 26 (52) | 1 (6) | |
| Other‡ | 4 (6) | 1 (2) | 1 (6) | |
| irAEs | ||||
| Any | 34 (49) | 39 (78) | 12 (75) | 0.002 |
| Grade 3 or 4 | 5 (7) | 18 (36) | 5 (31) | <0.001 |
| Time to onset, median (IQR), months | 2 (0–4) | 1 (0–2) | 1 (0–2) | |
| Treatment delay | 17 (24) | 28 (56) | 5 (31) | 0.002 |
| Treatment cessation | 14 (20) | 17 (34) | 3 (19) | 0.180 |
| Hospitalization | 3 (4) | 12 (24) | 3 (19) | 0.006 |
| ORR, ORR, % | – | 38 | 75 | – |
| DCR, DCR, % | 67 | 42 | 81 | 0.004 |
| Rechallenge ICI therapy | 28 (40) | 34 (68) | 9 (56) | 0.010 |
| irAEs | ||||
| Previous | 12/28 (43) | 30/34 (88) | 6/9 (67) | 0.001 |
| Any | 19/28 (68) | 21/34 (62) | 6/9 (67) | 0.876 |
| Grade 3 or 4 | 8/28 (29) | 6/34 (18) | 3/9 (33) | 0.471 |
| ORR, ORR, % | – | 35 | 56 | – |
| DCR, DCR, % | 25 | 44 | 56 | – |
All data are no. of patients (%) unless otherwise indicated.
p-values less than 0.05 are shown in bold italics.
This patient initially received palliative ICI therapy at an outside hospital and was reported to have localized disease at the time.
This patient initially received palliative ICI therapy for mucosal melanoma and presumed unresectable pelvic lymph node involvement at an outside hospital.
ICIs were stopped due to non-medical factors including insurance interruption.
DCR, disease control rate; irAE, immune-related adverse event; ORR, objective response rate; PFS, progression-free survival.
56 patients (41%) were able to complete the planned ICI therapy course, while the remaining 80 patients (59%) had their treatment interrupted for various reasons. For the 80 patients who were unable to complete initial ICI therapy, the two most common reasons for stopping therapy were disease progression and irAEs. Of the 70 patients receiving adjuvant ICI therapy, 13 (19%) stopped therapy because of irAEs, and 20 (29%) stopped because of disease recurrence. Of the 50 patients receiving palliative ICI therapy, 12 (24%) stopped therapy because of irAEs, and 26 (52%) stopped because of disease progression.
At the end of initial ICI therapy, the ORR and DCR for patients receiving neoadjuvant ICI therapy were 75% and 81%, respectively, and those for the patients receiving palliative ICI therapy were 38% and 42%, respectively.
irAEs occurring during initial ICI therapy are shown in table 3. Of the 136 patients who started initial ICI therapy, 85 (63%) had irAEs of any grade, and 28 (21%) had grade 3 or 4 irAEs. The median time from the initiation of ICI combination therapy to first irAE onset (41 days, IQR, 24–73.5 days) was significantly shorter than that from the initiation of ICI monotherapy to first irAE onset (64 days, IQR, 42–165 days, p=0.024). The most common irAEs of any grade were endocrine irAEs (26%), colitis (26%), and hepatitis (23%). 35 (26%) patients were reported to have endocrine-related toxicities, including hypothyroidism, adrenal insufficiency, hypophysitis, immune-related diabetes, and multiple organ endocrine toxicities, etc. Hypothyroidism was the most common, occurring in 14 out of 35 patients. Among those with multiple endocrine organ involvement (6/35), the majority also had thyroid involvement. Adrenal insufficiency was reported in 5 out of 35 patients. All cases of hypothyroidism were grade 1 or 2. Grade 3 or 4 toxicities were reported in two patients with immune-related diabetes, one patient with multiple endocrine involvement, one with hypophysitis, and one with adrenal insufficiency. Regarding skin toxicities, 21 out of 26 cases were grade 1, and the remaining 5 were grade 2. No grade 3 or higher skin toxicities were observed. The most common grade 3 or 4 irAEs were hepatitis (9%) and colitis (8%). As expected, patients receiving combination therapy were significantly more likely than those receiving monotherapy to experience irAEs of any grade (75% vs 53%; p=0.011) and grade 3 or 4 irAEs (32% vs 12%; p=0.003). Patients receiving combination therapy also had higher rates of colitis of any grade (39% vs 16%; p=0.002), grade 3 or 4 colitis (12% vs 5%; p=0.157), hepatitis of any grade (34% vs 14%; p=0.007), and grade 3 or 4 hepatitis (17% vs 3%; p=0.003). 48 patients (35%) had multisystem irAEs of any grade, and 23 (17%) had multi-system grade 3 or 4 irAEs.
Table 3. Immune-related adverse events (irAEs) during initial immune checkpoint inhibitor (ICI) therapy and rechallenge ICI therapy.
| Initial ICI therapy | Rechallenge ICI therapy | ||||||
|---|---|---|---|---|---|---|---|
| irAEs | Any ICI, N=136 |
ICI combination, N=59 |
ICI monotherapy, N=77 |
P value* | Any ICI, N=48 |
ICI combination, N=19 |
ICI monotherapy, N=29 |
| Total | |||||||
| Any | 85 (63) | 44 (75) | 41 (53) | 0.011 | 33 (69) | 13 (68) | 20 (69) |
| Grade 3 or 4 | 28 (21) | 19 (32) | 9 (12) | 0.003 | 12 (25) | 5 (26) | 7 (24) |
| Cutaneous | |||||||
| Any | 26 (19) | 15 (25) | 11 (14) | 0.101 | 6 (13) | 3 (16) | 3 (10) |
| Grade 3 or 4 | 0 (0) | 0 (0) | 0 (0) | NA | 0 (0) | 0 (0) | 0 (0) |
| GI/Colitis | |||||||
| Any | 35 (26) | 23 (39) | 12 (16) | 0.002 | 15 (31) | 2 (11) | 13 (45) |
| Grade 3 or 4 | 11 (8) | 7 (12) | 4 (5) | 0.159 | 8 (17) | 1 (5) | 7 (24) |
| Liver/hepatitis | |||||||
| Any | 31 (23) | 20 (34) | 11 (14) | 0.007 | 14 (29) | 6 (32) | 8 (28) |
| Grade 3 or 4 | 12 (9) | 10 (17) | 2 (3) | 0.004 | 4 (8) | 3 (16) | 1 (3) |
| Lung | |||||||
| Any | 2 (2) | 0 (0) | 2 (3) | 0.211 | 2 (4) | 2 (11) | 0 (0) |
| Grade 3 or 4 | 1 (1) | 0 (0) | 1 (1) | 0.379 | 1 (2) | 1 (5) | 0 (0) |
| Endocrine† | |||||||
| Any | 35 (26) | 18 (31) | 17 (22) | 0.267 | 7 (15) | 4 (8) | 3 (10) |
| Grade 3 or 4 | 5 (4) | 3 (5) | 2 (3) | 0.447 | 1 (2) | 0 (0) | 1 (3) |
| Multi-system | |||||||
| Any | 48 (35) | 28 (47) | 20 (26) | 0.009 | 19 (40) | 8 (42) | 11 (40) |
| Grade 3 or 4 | 23 (17) | 17 (29) | 6 (8) | 0.001 | 8 (17) | 3 (16) | 5 (17) |
| Treatment delay | 50 (37) | 30 (51) | 20 (26) | 0.044 | 22 (46) | 8 (42) | 14 (48) |
| Treatment cessation | 34 (25) | 19 (32) | 15 (19) | 0.089 | 17 (35) | 5 (26) | 12 (41) |
| Hospitalization | 18 (13) | 12 (20) | 6 (8) | 0.032 | 9 (19) | 2 (11) | 7 (24) |
(1) All data are no. of patients (%) unless otherwise indicated. (2) In our cohort, we also observed rare irAEs with varying degrees of severity, including ocular toxicity (grade 1–3), musculoskeletal toxicity (grade 2–3), hematologic toxicity (grade 1–2), renal toxicity (grade 1–3), and nervous system toxicity (grade 1).
(3) p-values less than 0.05 are shown in bold italics.
ICI combination therapy vs ICI monotherapy.
Endocrine toxicity included hypothyroidism, adrenal insufficiency, hypophysitis, immune-related diabetes, and multiple organ endocrine toxicities etc.
GI, gastrointestinal.NA, not available.
50 patients (37%) had irAEs that led to treatment delay, and 34 (25%) had irAEs that led to treatment cessation. Treatment delays were significantly more common among patients receiving combination therapy than among those receiving monotherapy (51% vs 26%; p=0.044); however, the groups’ rates of treatment cessation were not significantly different (32% vs 19%; p=0.089). Compared with the monotherapy group, the combination therapy group had a significantly higher rate of hospitalization due to irAEs (20% vs 8%; p=0.032). Patients receiving palliative ICI therapy had a higher treatment delay rate than those receiving neoadjuvant or adjuvant ICI therapy. Specifically, among the 50 patients who received palliative ICI therapy, 28 (56%) experienced treatment delays, 17 (34%) had treatment cessation, and 12 (24%) required hospitalization because of irAEs (table 2).
The time to any irAEs was significantly shorter in patients with grade 3 or 4 irAEs compared with those without (p=0.026). However, no significant differences were observed between the groups in terms of age, sex, or baseline laboratory values, including LDH (table 4).
Table 4. Characteristics of patients with grade 3 or 4 irAEs during initial ICI therapy and on rechallenge.
| No. (%) | ||||
|---|---|---|---|---|
| Variables | Total | With Grade 3 or 4 irAEs | Without Grade 3 or 4 irAEs | P value |
| Initial ICI therapy | N=136 | N=28 | N=108 | |
| Age, median (range), years | 33 (15–39) | 33 (15–38) | 33 (19–39) | 0.63 |
| Sex | ||||
| Male | 80 (59) | 19 (68) | 61 (56.5) | 0.28 |
| Female | 56 (41) | 9 (32) | 47 (43.5) | |
| Baseline laboratory values, median | ||||
| LDH | ||||
| WNL | 67 (49.3) | 17 (61) | 50 (46) | 0.39 |
| ULN | 14 (10.3) | 2 (7) | 12 (11) | |
| N/A | 55 (40.4) | 9 (32) | 46 (43) | |
| Lymphocytes, /µL | 1800 | 1700 | 1810 | >0.05 |
| Neutrophils, /µL | 4200 | 4240 | 4220 | |
| Lymphocytes 3 months post-ICI therapy, /µL | 1720 | 1760 | 1790 | |
| Stage of the Melanoma | ||||
| II | 7 (5) | 0 (0) | 7 (7) | 0.001 |
| III | 73 (54) | 8 (29) | 65 (60) | |
| IV | 56 (41) | 20 (71) | 36 (33) | |
| Combination ICI therapy | ||||
| Yes | 59 (43) | 19 (68) | 40 (37) | 0.003 |
| No | 77 (57) | 9 (32) | 68 (63) | |
| Time to irAE, median (range), m | 1 (0–12) | 1 (0–5) | 2 (0–12) | 0.006 |
| Rechallenge ICI therapy | 71 | 17 | 54 | |
| Initial combination ICI therapy | ||||
| Yes | 39 (55) | 8 (47) | 31 (57) | 0.46 |
| No | 32 (45) | 9 (53) | 23 (43) | |
| Grade 3 or 4 irAEs with initial ICI therapy | ||||
| Yes | 19 (27) | 8 (47) | 11 (20) | 0.030 |
| No | 52 (73) | 9 (53) | 43 (80) | |
| Rechallenged with combination ICI therapy | ||||
| Yes | 40 (56) | 9 (53) | 31 (57) | 0.75 |
| No | 31 (44) | 8 (47) | 23 (43) | |
p-values less than 0.05 are shown in bold italics.
ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; LDH, lactate dehydrogenase; N/A, not available; ULN, upper limit of normal; WLN, within normal limit.
Rechallenge ICI therapy
The characteristics of the patients who received rechallenge ICI therapy organized by intent of therapy are shown in table 2. Of the entire 136-patient cohort, 71 patients (52%) received rechallenge ICI therapy; 48 patients (35%) received rechallenge ICI therapy after developing irAEs during initial ICI therapy. The decision to rechallenge with ICI is typically made by the primary physician after a holistic assessment that considers multiple factors. Except for patients with immune-related endocrinopathy, all the patients’ prior irAEs had resolved to grade 1 or lower on rechallenge. The primary reasons for ICI rechallenge included three categories: 43 of the 71 patients were rechallenged due to disease progression; 14 patients received ICI rechallenge as consolidation therapy to potentially prolong therapeutic benefit; and the remaining 14 patients were rechallenged on ICI because their irAEs had resolved. In our cohort, patients with baseline stage IV disease (70%) were more likely to undergo rechallenge, likely due to disease progression, compared with those with stage III (41%) or stage II (33%) disease (p=0.002). We did not observe a statistically significant association between the presence of initial irAEs of any grade (p=0.20) or grade 3 or 4 irAEs (p=0.06) and the likelihood of being rechallenged.
irAEs occurring during rechallenge ICI therapy are shown in table 3. Among the 48 patients who experienced irAEs during initial ICI therapy, 33 (69%) had recurrent irAEs of any grade and 12 (25%) had grade 3 or 4 recurrent irAEs during rechallenge ICI therapy. Rates of irAEs of any grade and of grade 3 or 4 irAEs between patients who received rechallenge ICI combination therapy and those who received rechallenge ICI monotherapy did not differ significantly (p=0.97 and p=0.87, respectively). Colitis and hepatitis were the most common irAEs during rechallenge ICI therapy. The rates of colitis and hepatitis during rechallenge therapy (31% and 29%, respectively) were slightly higher than those during initial ICI therapy (26% and 23%, respectively), but these differences were not significant (p=0.46 and p=0.38, respectively). Similarly, the rates of irAE-related treatment delay, treatment cessation, and hospitalization after rechallenge therapy (46%, 35%, and 19%, respectively) were also slightly higher than those after initial ICI therapy (37%, 25%, and 13%, respectively), but these differences were not significant (p=0.27, p=0.16, and p=0.35, respectively). Of the 33 patients who experienced irAEs again during rechallenge ICI therapy, 15 developed the same irAEs (see online supplemental Table 1).
Among the 71 patients who received rechallenge ICI therapy, 17 experienced grade 3 or 4 irAEs. A significantly higher percentage of these patients had a history of grade 3 or 4 irAEs during initial ICI therapy compared with those who did not develop severe irAEs during rechallenge (p=0.030). However, no significant differences were observed between the groups regarding prior combination ICI therapy (p=0.46) or rechallenge combination therapy (p=0.75). On evaluating the characteristics of irAEs in relation to changes in treatment regimen from initial therapy to rechallenge, the overall pattern of irAEs remained largely consistent across groups. Notably, patients who received initial ICI monotherapy followed by ICI combination therapy on rechallenge, presumably due to disease progression, exhibited a comparatively lower incidence of irAEs and treatment-related interruptions post rechallenge. However, the small sample sizes within each subgroup and the heterogeneity in indications for rechallenge limit the ability to draw definitive conclusions from these observations (see online supplemental Table 2).
PFS and OS
The 5-year OS rates for the adjuvant, palliative, and neoadjuvant ICI therapy groups were 86% (95% CI 73% to 100%), 77% (95% CI 66% to 91%), and 88% (95% CI 67% to 100%), respectively. Patients who received palliative ICI therapy had 1-year, 3-year, and 5-year PFS rates of 42% (95% CI 30% to 58%), 27% (95% CI 17% to 44%), and 20% (95% CI 10% to 38%), respectively (see online supplemental Table 3).
In the palliative ICI therapy group, high LDH levels at baseline were significantly associated with worse OS (adjusted HR, 21.04, 95% CI 1.35 to 328.29; p=0.030). Conversely, the occurrence of colitis or hepatitis was associated with improved OS (adjusted HR, 0.10, 95% CI 0.01 to 0.83; p=0.033) (online supplemental Table 4).
In the palliative ICI therapy group, the occurrence of colitis or hepatitis during initial ICI therapy was associated with superior OS (log-rank test p=0.023) (figure 1A). Furthermore, among patients in the palliative ICI therapy group who received rechallenge ICI therapy, those who had colitis or hepatitis on rechallenge had better OS than those who did not have these irAEs, but the difference was not significant (log-rank test p=0.15) (figure 1B).
Figure 1. Overall survival of the patients in the palliative immune checkpoint inhibitor (ICI) therapy group based on the presence of colitis or hepatitis during initial ICI therapy (A) and rechallenge ICI therapy (B).
Discussion
Our study is one of the largest retrospective studies of AYA patients receiving ICI therapy for melanoma to date. We found that patients receiving initial ICI therapy and those receiving rechallenge ICI therapy had similar patterns of irAEs. Although irAEs were a major cause of treatment delay, they did not negatively impact OS. In fact, the presence of colitis or hepatitis was positively associated with improved OS.
AYA patients with melanoma benefit from ICI therapy but may also be impacted by irAEs.1 2 14 21 Understanding the unique efficacy and irAE profiles associated with both initial and rechallenge ICI therapy in this population is critical. A few retrospective studies showed that rechallenge ICI therapy is relatively safe when done carefully22,24 and may offer benefits for disease control,25 but these studies were not specific to AYAs.22,25 With detailed data on ICI therapy and irAEs in one of the largest AYA cohorts with melanoma, our study strengthens evidence of ICI efficacy and safety in this group.
Our findings support the notion that the characteristics of AYA patients with melanoma are distinct from those of older patients with the disease. The percentages of patients in the present study who were female or had BRAF mutations are consistent with those in a recent multicenter retrospective study comparing AYA patients with older patients with melanoma, which supports that the AYA population has higher rates of these factors compared with older patients.14 Most patients also had advanced-stage melanoma at ICI initiation. However, nearly two-thirds of the patients in the present study underwent complete tumor resection and received either adjuvant or neoadjuvant ICI therapy, while the remaining one-third received palliative ICI therapy. The patients receiving palliative ICI therapy had a relatively low 5-year PFS rate of 20% but a high 5-year OS rate of 77%. This suggests that AYA patients with melanoma had a high chance of multiple progression, and rechallenge ICI therapy was often critically needed. Previous studies suggested that the superior survival of younger patients may be attributable to the more frequent utilization of combination ICI therapy in this population.26 In our study, more than 40% of patients initially received ICI combination therapy, and among those in the palliative group, this proportion was 78%, consistent with findings from previous studies.26
We also found that patients receiving initial ICI therapy and those receiving rechallenge ICI therapy had similar patterns of irAEs, with no significant difference in irAE rates. Colitis and hepatitis were the most common severe irAEs. Several other retrospective studies have shown that rechallenge ICI therapy after irAEs, even grade 3 or 4 irAEs, is safe with careful monitoring; however, most of these studies were not specific to AYAs.22,2427 Our study supports the notion that AYA patients with melanoma can safely receive rechallenge ICI therapy with careful monitoring. More importantly, the rates of irAE-related treatment delay, treatment cessation, and hospitalization did not differ significantly between patients receiving initial ICI therapy and those receiving rechallenge ICI therapy. However, different factors were associated with the irAEs in the initial ICI therapy group and those in the rechallenge therapy group. In the initial ICI therapy group, patients received combination therapy were more likely to develop grade 3 or 4 irAEs, which is consistent with clinical trial observations.4 6 In the rechallenge therapy group, combination therapy received as either initial ICI therapy or rechallenge ICI therapy was not associated with grade 3 or 4 irAEs; instead, patients who had a history of grade 3 or 4 irAEs during initial ICI therapy had higher rates of developing grade 3 or 4 irAEs again.
We also found that the efficacy of rechallenge ICI therapy was similar to that of initial ICI therapy, especially among patients receiving palliative ICI therapy, which is consistent with several other retrospective studies.23,2527 30 31 In our study, in the palliative therapy group, both the ORR and DCR following rechallenge ICI therapy were similar to those following initial ICI therapy.
In addition to assessing traditional metrics, such as ORR, DCR, and PFS, we aimed to identify clinically relevant biomarkers that could predict OS in AYA patients with melanoma. We focused on the palliative cohort to explore this relationship, as this group includes patients with unresectable disease, showed poorest OS, and represents the most clinically relevant population in which rechallenge is often required. We found that a higher LDH level at baseline was associated with worse outcomes, consistent with previous studies.32,34 Other factors, including age, sex, combination ICI therapy, and treatment delay, were not significantly associated with OS. While irAEs overall were not associated with improved survival, we observed a significant correlation between colitis or hepatitis and better OS. Notably, both colitis and hepatitis were also the most common irAEs in our cohort. Several trials and retrospective studies seem to suggest that irAEs are associated with improved outcomes.35,38 Future investigations, such as analyses of the gut microbiome in this population, may yield valuable insights.
The main limitations of our study include its retrospective, single-institution design and relatively small sample size. In addition, because of the retrospective nature of the study and the fact that some patients were initially treated at outside institutions, lower-grade irAEs may have been missed or underreported. Our study focused on higher-grade irAEs, which typically require higher levels of medical attention and thus are more likely to be documented and reported accurately. This is confirmed by the fact that the irAE rates in the present study are similar to those in several other retrospective studies but lower than those reported in clinical trials.4,813 14 Since the occurrence of immune-related colitis or hepatitis was not known at baseline, there is a potential risk of guarantee-time bias. However, the 1-year OS in the palliative group was 94%, and most irAEs occurred early in the treatment course (median time 1 month, IQR 0–2). Because these events typically arose soon after treatment initiation and before death, the amount of added “guarantee time” was minimal, and the potential distortion is reduced. Based on these considerations, we believe our results remain reliable. Finally, a proportion of patients in the present study initially received treatment at outside hospitals, which may have led to missing information on irAEs.
Conclusions
This study, which included one of the largest cohorts of AYA patients receiving ICI therapy for melanoma, provides a detailed analysis of their treatment courses and irAE profiles. Our findings show that initial ICI therapy and rechallenge ICI therapy had similar irAEs and efficacy. The occurrence of colitis or hepatitis might be a biomarker of better outcomes.
Supplementary material
Acknowledgements
We thank Joe Munch in MD Anderson’s Research Medical Library for editing the manuscript. Biorender was used to make the graphic abstract.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Presented at: Data were partially presented at the 2024 ASCO Annual Meeting (He J. et al., J Clin Oncol 42(16_suppl): 12117).
Ethics approval: The study was approved by an Institutional Review Board and the use of an informed consent process for patients was waived, as no identifiable information was included.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data relevant to the study are included in the article or uploaded as supplementary information.