
==== Front
J Immunother Cancer
J Immunother Cancer
jitc
jitc
Journal for Immunotherapy of Cancer
2051-1426
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39209453
10.1136/jitc-2024-009061
jitc-2024-009061
Original Research
Clinical/Translational Cancer Immunotherapy
2435
1506
Nivolumab maintenance improves overall survival of patients with advanced melanoma who experience severe immune-related adverse events on nivolumab plus ipilimumab
Maloney Anna K 12Anna.Maloney@quinnipiac.edu

Giobbie-Hurder Anita 3agiohur@ds.dfci.harvard.edu

Katukota Nikita 2nikitaclassof2023@berkeley.edu

Fogarasi Miklos C 1miklos.fogarasi@quinnipiac.edu

http://orcid.org/0000-0002-4253-943X
Ott Patrick A 245Patrick_Ott@dfci.harvard.edu

Hodi F Stephen 245stephen_hodi@dfci.harvard.edu

https://twitter.com/ta_sussman
http://orcid.org/0000-0003-3429-4468
Sussman Tamara A 245tsussmanmd@gmail.com

http://orcid.org/0000-0003-3877-3984
Silk Ann W 245ann_silk@dfci.harvard.edu

https://twitter.com/rhaq1
Haq Rizwan 245Rizwan_Haq@dfci.harvard.edu

Liu David 245David_Liu@dfci.harvard.edu

Insco Megan 25Megan_Insco@DFCI.HARVARD.EDU

http://orcid.org/0000-0002-7979-8953
Buchbinder Elizabeth I 25elizabeth_buchbinder@dfci.harvard.edu

1 Quinnipiac University Frank H Netter MD School of Medicine, North Haven, Connecticut, USA
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
3 Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
4 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
5 Harvard Medical School, Boston, Massachusetts, USA
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Supplement: Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1136/jitc-2024-009061).

EB consults as an advisory board member for Werewolf pharma, Merck, Iovance, Sanofi, Xilio, Novartis and Instilbio, receives clinical trial support from Lilly, Novartis, Partners therapeutics, Genentech and BVD. FSH reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from 7 Hills Pharma, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Catalym, personal fees from Immunocore, personal fees from Kairos, personal fees from Rheos, personal fees from Zumutor, personal fees from Corner Therapeutics, personal fees from Puretech, personal fees from Curis, personal fees from AstraZeneca, personal fees from Solu Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent THERAPEUTIC PEPTIDES Therapeutic Peptides- Patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, a patent ÚNTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES Deduplication number: 20170343552 pending, and a patent Antibodies against EDIL3 and methods of use thereof pending.

DrElizabeth IBuchbinder; elizabeth_buchbinder@dfci.harvard.edu
2024
28 8 2024
12 8 e00906106 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
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Abstract

Background

The combination of ipilimumab and nivolumab is a highly effective treatment for metastatic cutaneous melanoma. However, immune-related adverse events (irAEs) are common, often necessitating treatment interruption and the use of immunosuppressive agents. There is no data on the impact of resuming nivolumab on survival following recovery from the irAE and completion of immunosuppressive treatment.

Patients and methods

In this retrospective analysis, we examined a cohort of patients treated with ipilimumab/nivolumab who developed irAEs requiring treatment interruption and immunosuppressive therapy. The differences in physician practice patterns at our institution allowed us to examine the survival effect of restarting single-agent nivolumab. A multivariate analysis of clinical factors associated with improved survival was performed.

Results

We identified 165 patients who were treated with ipilimumab/nivolumab and developed irAEs requiring treatment interruption and immunosuppressive therapy. Patients with the best overall response of progressive disease were excluded. Of the remaining 122 patients, 46 resumed single-agent nivolumab. When stratified by age and adjusted for sex, M-stage, lactate dehydrogenase (LDH), therapy duration, and irAE type, the effect of resumption of nivolumab on survival was highly significant (p=0.02). Patients who resumed nivolumab had a 68% reduction in the hazard of death compared with patients who had not yet or never resumed nivolumab (HR: 0.32, 95% CI: 0.12 to 0.84). Of the patients who resumed nivolumab, 12 (26%) patients had subsequent irAEs, with five patients having grade 3 irAEs. No grade 4 or 5 irAEs were noted.

Conclusions

Resuming single-agent nivolumab following a treatment interruption for ipilimumab/nivolumab-associated irAE and completion of immunosuppressive therapy increased overall survival compared with discontinuing nivolumab permanently in patients with metastatic melanoma. Toxicity observed post-resumption of single-agent nivolumab was manageable with no severe irAEs observed.

Nivolumab
Immunotherapy
Blitzer Family Fund n/a
==== Body
pmcWHAT IS ALREADY KNOWN ON THIS TOPIC

Combination ipilimumab/nivolumab therapy is very effective in advanced melanoma with a high rate of discontinuation of therapy due to toxicity.

WHAT THIS STUDY ADDS

This study evaluates the role of resuming nivolumab alone after completion of treatment for toxicity.

An overall survival benefit was demonstrated with the resumption of nivolumab.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

This study has the potential to improve the survival of patients with advanced melanoma by making the resumption of nivolumab standard practice.

Background

The combination of the anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) directed monoclonal antibodies ipilimumab and nivolumab is widely considered the most active therapy for patients with unresectable metastatic melanoma. The results of a phase 3 trial (CheckMate 067) showed that nivolumab in combination with ipilimumab leads to response rates around 55–60%, longer progression-free survival, and longer overall survival than is achieved with ipilimumab alone in treatment-naïve patients with advanced melanoma.1 2 However, immune-related toxicities can be severe and lead to cessation of treatment and prolonged immunosuppressive therapy in over half of patients treated with combination immunotherapy.

Recent studies demonstrated that in patients with BRAF-mutated metastatic melanoma, a front-line combination ipilimumab and nivolumab improved survival over targeted therapy,3 4 establishing anti-PD-1-based immunotherapy as the preferred first-line therapy for these patients. Combined treatment with nivolumab and the anti-lymphocyte-activation gene 3 (LAG-3) antibody relatlimab also demonstrated improved efficacy compared with single-agent PD-1 and is an option for front-line patients with metastatic melanoma.5 Of note, a higher rate of grade 3 and 4 immune-related toxicities is observed in patients treated with a combination of anti-PD-1 and anti-CTLA-4 (53%) compared with anti-PD-1 and anti-LAG-3 (18.9%).5

In clinical trials evaluating the combination of ipilimumab and nivolumab, patients were discontinued from immunotherapy if they developed a grade 3 toxicity requiring steroid taper. However, in clinical practice some patients who were not on a clinical trial were placed back on nivolumab after steroid taper to continue treatment of melanoma, particularly if the patient had severe disease initially, there were residual lesions seen on the scan and it was felt that this could be given safely. The assumption in these cases was that nivolumab would be safe since many of the more severe autoimmune toxicities, including colitis and hepatitis, are more commonly associated with combination treatment, and with ipilimumab in particular.6

There is currently no guidance concerning treatment resumption after immune-related toxicity on nivolumab/ipilimumab therapy. The impact of continuing or discontinuing single-agent nivolumab on disease progression and overall survival in patients with metastatic melanoma has not been determined. The practice variability within our institution provided a unique opportunity to examine the effect on survival of resuming single-agent nivolumab post nivolumab/ipilimumab immune toxicity for patients with advanced melanoma.

Methods

Database identification

Patients with unresectable metastatic cutaneous melanoma who provided informed consent were identified via the Dana-Farber Cancer Institute Melanoma Research Electronic Data Capture (REDCap) database. This study was approved by the Dana-Farber Harvard Cancer Center Institutional Review Board (IRB), protocol 24–103, and consent was determined to be not applicable due to the retrospective nature of the study. Key eligibility criteria were patients with metastatic/unresectable disease, treatment with a combination of nivolumab and ipilimumab, and development of immune-related adverse events (irAE) that required interruption of treatment and administration of steroids.

Statistical analysis

In this retrospective cohort analysis, we examined a cohort of patients who developed irAEs on a combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg, which led to treatment interruption and steroid therapy. Within this cohort, we compared patients who permanently discontinued treatment to those who resumed single-agent nivolumab after steroid taper and other immunosuppressive therapy was complete. The primary endpoint was overall survival (OS), defined as the time from the start of the treatment hold until death from any cause. Follow-up of patients who did not die is censored at the date of last contact.

For these analyses, the resumption of nivolumab is a time-dependent covariate. To accommodate this time-dependent switch, an extended Cox model is employed in which patients can change their status from “did not resume nivo” to “resumed nivo” at the appropriate time. The interpretation of the HR is slightly different when a time-dependent covariate is used: The HR is interpreted as the effect of resuming nivolumab compared with those who have not yet or never resumed nivolumab. The change in wording reflects the time-dependent nature of the predictor. The distribution of OS in the aggregated sample is summarized using the method of Kaplan-Meier (KM). The graphical presentations of OS according to the resumption of nivolumab use the Simon-Makuch representation which looks similar to a K-M curve but allows for the time-dependent covariate.

The model of OS is stratified by age (divided into quartiles) to allow for differences in the underlying baseline hazard of death, and controls for sex, M-stage, lactate dehydrogenase (LDH) (normal, abnormal, and unknown), duration of therapy, and type of irAE.

Results

Study cohort

The initial data set consisted of 165 patients with cutaneous melanoma treated with ipilimumab and nivolumab for whom treatment was held due to an irAE (figure 1). The median follow-up time from initiation of ipilimumab and nivolumab therapy was 43 months (inverted K-M estimate). The median time to treatment hold was 1.9 months (range 0.03–31.4 months) and the median duration of hold was 2.5 months (range 0.25–28.8 months). Of the 165 patients, the median OS was 44.5 months (95% CI: 24 months to ∞). At 1 and 2 years, survival was 79% (95% CI: 72% to 85%) and 59% (95% CI: 51% to 67%), respectively (figure 2). 43 of these 165 patients had the best overall response (BOR) of progressive disease (PD). Since the majority of patients with PD would not resume nivolumab because they progressed on combination therapy and would be unlikely to benefit from nivolumab alone, these patients were removed from the data set, resulting in a study cohort of 122 patients (table 1). Within this group, median survival was not reached. At 1 and 2 years, survival was 89% (95% CI: 82% to 94%) and 69% (95% CI: 59% to 77%) (figure 2).

Table 1 Patient characteristics (n=122)

	N	%	
Sex	46	37.7	
 Female	
 Male	76	62.3	
M-stage			
 M0	18	14.8	
 M1b	26	21.3	
 M1c	56	45.9	
 M1d	22	18.0	
LDH	46	37.7	
 >ULN	
 Missing	9	7.4	
 <ULN	67	54.9	
irAE	49	40.2	
 Colitis	
 Dermatitis	3	2.5	
 Endocrinopathy	7	5.7	
 Hepatitis	20	16.4	
 Nephritis	4	3.3	
 Pancreatitis	4	3.3	
 Pneumonitis	12	9.8	
 Uveitis	3	2.5	
 Other (observed in ≤2 pts)*	20	16.4	
* Other irAEs include: Tthrombocytopenia, Nneuropathy, Aaltered Mmental status, systemic inflammatory response syndrome (), Ffatigue, Ddyspnea, Mmyocarditis, Mmusculoskeletal, and Ppapillitis.

irAEimmune-related adverse event LDHlactate dehydrogenaseULNupper limit of normal

Figure 1 Flow sheet of patient selection.

Figure 2 Overall survival of all patients included in the study. (A) 165 patients who discontinued due to toxicity, (B) 122 patients who did not have the best overall response of progressive disease.

The median age in the 122 patient study cohort was 63 years (range: 31–85) and 62% of patients were men. The largest proportion of patients had stage M1c disease (46%) followed by M1b (21%) disease. Approximately 41% of patients had ipilimumab/nivolumab held due to colitis and an additional 21% due to hepatitis. All patients received steroids and 18 of the 122 patients received non-steroid immunosuppressive regimens in addition to steroids including infliximab (11 patients), mycophenolate mofetil (2), tacrolimus (2), vedolizumab (2) and rituximab (1). Treatment with non-steroid immunosuppressive agents did not influence the resumption of nivolumab, 37.5% (39 of 104) patients who did not receive non-steroidal immunosuppressive agents resumed nivolumab and 38.9% (7 of 18) patients who received non-steroidal immunosuppressive agents resumed nivolumab (p=0.91 by Fisher’s exact test).

Patients who resume nivolumab monotherapy after irAE have prolonged overall survival

Of 122 patients, 46 resumed single-agent maintenance nivolumab following resolution of toxicity and completion of steroid taper, whereas 76 patients did not resume treatment. When stratified by age and adjusted for sex, M-stage, LDH, duration of therapy, and type of irAE causing the treatment pause, patients who resumed treatment had prolonged OS (p=0.02). Patients who resumed nivolumab had a 68% reduction in the hazard of death compared with patients who had not yet or never resumed nivolumab (HR: 0.32, 95% CI: 0.12 to 0.84) (figure 3). None of the 122 patients in the cohort died from irAEs. 79 of 122 patients (64.8%) had at least one grade 3 or higher irAE: 4 (5.1%) had the subsequent outcome of complete response (CR), 32 (40.5%) had partial response (PR), 17 (21.5%) had stable disease (SD), 7 (8.9%) had subsequent PD, and 19 (24.1%) were unknown.

Figure 3 Simon and Makuch’s representation of overall survival in 122 patients who did not have the best overall response of progressive disease, comparing patients who resumed nivolumab with those who did not.

To assess whether confounding variables could account for observed prolonged OS in patients who resumed nivolumab versus those who did not, we compared covariates such as irAE type, LDH level, sex, M-stage, duration of treatment interruption, age, irAE grade, and year ipilimumab/nivolumab therapy started. The only characteristic with a suggested difference between the two groups was the type of irAE leading to discontinuation of ipilimumab plus nivolumab therapy (p=0.08). More patients with gastrointestinal or pulmonary irAEs did not resume nivolumab (table 2 and online supplemental table 1). Common Terminology Criteria for Adverse Events (CTCAE) grading by irAE subtype is included in table 3.

Table 2 Comparison of potential confounding characteristics of 122 patients who did not have the best overall response of progressive disease, between patients who resumed nivolumab and those who did not

	All	Resumed nivolumab	
No	Yes	
N	%	N	%	N	%	
irAE type leading to discontinuation (p=0.08)							
 Endocrine	7	5.7	4	5.3	3	6.5	
 Gastrointestinal	49	40.2	33	43.4	16	34.8	
 Hepatic	20	16.4	11	14.5	9	19.6	
 Other*	30	24.6	18	23.7	12	26.1	
 Pulmonary	12	9.8	10	13.2	2	4.3	
 Renal	4	3.3	–	–	4	8.7	
LDH (p=0.19)							
 >ULN	51	41.8	27	35.5	24	52.2	
 Missing	9	7.4	6	7.9	3	6.5	
 <ULN	62	50.8	43	56.6	19	41.3	
Sex (p=0.57)							
 F	46	37.7	27	35.5	19	41.3	
 M	76	62.3	49	64.5	27	58.7	
M-stage (p=0.59)							
 M0	18	14.8	11	14.5	7	15.2	
 M1b	26	21.3	19	25.0	7	15.2	
 M1c	56	45.9	34	44.7	22	47.8	
 M1d	22	18.0	12	15.8	10	21.7	
Duration ipi/nivo before interruption (p=0.69)							
 ≤1 month	29	23.8	18	23.7	11	23.9	
 1–2 months	28	23.0	16	21.1	12	26.1	
 2–3 months	23	18.9	13	17.1	10	21.7	
 >3 months	42	34.4	29	38.2	13	28.2	
Age (years) (p=0.10)							
 ≤55	31	25.4	19	25.0	12	26.1	
 56–62	28	23.0	14	18.4	14	30.4	
 63–71	33	27.0	19	25.0	14	30.4	
 72+	30	24.6	24	31.6	6	13.0	
irAE grade (p=0.27)							
 1	10	8.2	8	10.5	2	4.3	
 2	23	18.9	11	14.5	12	26.1	
 3	76	62.3	46	60.5	30	65.2	
 4	3	2.5	2	2.6	1	2.2	
 Unknown	10	8.2	9	11.8	1	2.2	
Year ipi/nivo started (p=0.31)							
 2013–15	36	29.5	25	32.9	11	23.9	
 2016–22	86	70.5	51	67.1	35	76.1	
* Other irAEs include: Ddermatitis, Uuveitis, Tthrombocytopenia, Nneuropathy, Aaltered Mmental status, (SIRS), Ffatigue, Mmyocarditis, and Ppapillitis.

irAEimmune-related adverse eventLDHlactate dehydrogenaseSIRSsystemic inflammatory response syndromeULNupper limit of normal

Table 3 CTCAE grading of irAE by group percentages calculated with irAE classification (n=122)

	CTCAE grade	
1	2	3	4	Missing	
N	%	N	%	N	%	N	%	N	%	
irAE classification											
 Endocrine	–	–	3	42.9	2	28.6	–	–	2	28.6	
 Gastrointestinal	–	–	5	10.2	38	77.6	2	4.1	4	8.2	
 Hepatic	1	5.0	4	20.0	13	65.0	1	5.0	1	5.0	
 Other	7	23.3	9	30.0	13	43.3	–	–	1	3.3	
 Pulmonary	2	16.7	2	16.7	7	58.3	–	–	1	8.3	
 Renal	–	–	–	–	3	75.0	–	–	1	25.0	
CTCAECommon Terminology Criteria for Adverse EventsirAEimmune-related adverse event

We then probed whether covariates had an impact on OS in a multivariate setting using an extended Cox model. OS was influenced most strongly by the resumption of nivolumab, LDH, and patient sex (table 4). Eastern Coooperative Oncology Group (ECOG) status, BRAF mutation status, comorbidities and number of cycles of ipilimumab and nivolumab were compared between the two groups and there were no clear trends between those patients that resumed or did not resume nivolumab (online supplemental table 1). There were only three patients with an ECOG status of 2 or higher and those patients did not resume nivolumab. The number of patients with specific comorbidities in each group was low (online supplemental table 2).

Table 4 Multivariate analysis

Characteristic	P value	
irAE type	0.65	
LDH	0.11	
Sex	0.29	
M-stage	0.93	
Resumption of nivo*	0.02	
Duration ipi-nivo	0.37	
* Time-dependent covariate.

irAEimmune-related adverse eventLDHlactate dehydrogenase

To evaluate whether the type of response (CR vs PR vs SD) at the initial scan was influencing who resumed nivolumab, the Response Evaluation Criteria in Solid Tumors (RECIST) response (based on investigator or radiologists assessment) at the first scan was analyzed. Scans were obtained at different time points in the treatment course for patients depending on individual factors, such as clinical symptoms of progression or onset of toxicity. Some patients did not have scans at that time and were marked as unknown response. No differences in nivolumab resumption rates were found among RECIST response categories at the first scan (Fisher’s exact p=0.13). Higher proportions of patients with PR or PD resumed nivolumab, compared with those with CR or SD. There was no difference between patients classified as responder/non-responder at the first scan (Fisher’s exact p=0.19). Among responders, 44% resumed nivolumab compared with 31% of non-responders (table 5).

Table 5 RECIST response at the first scan compared between patients who resumed nivolumab and those who did not (n=122)

	All	Resumed nivolumab	
No	Yes	
N	%	N	%	N	%	
RECIST response first scan	
 CR	7	5.7	6	7.9	1	2	
 PR	57	46.7	30	39.5	27	58.6	
 SD	40	32.8	30	39.5	10	21.7	
 PD	11	9.0	6	7.9	5	10.9	
 UNK	7	5.7	4	5.3	3	2.9	
Responder first scan	
 N	58	47.5	40	52.6	18	39.1	
 Y	64	52.5	36	47.4	28	60.9	
CRcomplete responsePDprogressive diseasePRpartial responseRECISTResponse Evaluation Criteria in Solid TumorsSDstable diseaseUNKunknown response

We also examined the BOR in patients with initial SD or PD to determine if resuming nivolumab leads to subsequent response. There were 58 patients with RECIST response of SD, PD, or unknown (not rated by RECIST) at the first scan. Subsequent BOR for these patients included nine patients (15.5%) who ultimately responded to therapy. A higher proportion of patients who eventually had a BOR of CR or PR resumed nivolumab compared with those with non-response or unknown response (55.6% vs 26.5%, Fisher’s exact p value=0.11) (table 6). Of the 46 patients who resumed single-agent nivolumab, 10 remained on therapy at the time of data collection. Of the 36 patients who stopped single-agent nivolumab, the median duration of nivolumab therapy was 14.8 months.

Table 6 Analysis of 58 patients with RECIST response at first scan of SD, PD or unknown and their subsequent BOR by resuming nivolumab or not resuming nivolumab

	All	Resumed nivolumab	
No	Yes	
N	%	N	%	N	%	
BOR overall							
 Non-response	35	60.3	25	71.4	10	28.6	
 Unknown	14	24.1	11	78.6	3	21.4	
 Responder	9	15.5	4	44.4	5	55.6	
BORbest overall responsePDprogressive diseaseRECISTResponse Evaluation Criteria in Solid TumorsSDStable disease

Of the 46 patients who resumed nivolumab, 12 (26%) patients had subsequent irAEs while on single-agent nivolumab. Of these 12, 10 patients had irAEs on single agent nivolumab that were different from the irAEs on dual therapy ipilimumab/nivolumab. 5 of the 12 patients had grade 3 irAEs (only 1 of whom had a recurrence of the prior ipilimumab/nivolumab-associated toxicity), and no grade 4 or 5 irAEs were noted. The irAEs noted on subsequent single-agent nivolumab were enterocolitis (three patients; grades 1, 2, and 3), hepatitis (one patient; grade 3), pneumonitis (one patient; grade 3), pancreatitis (two patients; grades 1 and 3), endocrinopathy (five patients; grades 1 and 2), and dermatitis (one patient; grade 1). Enterocolitis grade 2 was treated with a prednisone taper, and grade 3 was treated with infliximab. Hepatitis was treated with a prednisone taper. Pneumonitis was treated with hydrocortisone taper. Pancreatitis grade 3 was treated with prednisone taper. Dermatitis was treated with prednisone.

Discussion

Combination immunotherapy with ipilimumab and nivolumab, is a standard front-line treatment for patients with metastatic melanoma. Nivolumab and relatlimab were established as another front-line option after it was demonstrated to improve outcomes over nivolumab alone in the treatment of metastatic melanoma.5 Immune-related toxicities grade 3 or higher occur in 55–60% of patients treated with ipilimumab and nivolumab and 19% with nivolumab and relatlimab.7 This creates a need to understand how to manage additional therapy after toxicity and the risk of toxicity recurrence. This analysis focused on ipilimumab and nivolumab but future studies should be done looking at nivolumab and relatlimab.

In this analysis, an improvement in OS was noted when nivolumab was resumed after the completion of immunosuppressive therapy for irAEs. Patients with the BOR of progressive disease after ipilimumab and nivolumab were excluded from the analysis. Patients with initial PD at the time of toxicity who received additional nivolumab were included since some of these patients had subsequent response during maintenance nivolumab. There have been some studies demonstrating improved responses in patients who have irAEs to immunotherapy but long-term data on this has been mixed.79 Since all patients in this study experienced an irAE this benefit would extend across both groups.

Nine patients who did not achieve a response to treatment initially were converted to responders while on nivolumab. Prior studies have demonstrated that patients with early response to ipilimumab and nivolumab generally do better long-term and that the efficacy of this therapy is likely driven by the first two doses.10 11 However, in these studies, nivolumab was continued even in patients with a good response and likely helped play a role in patients doing well long-term. There have been studies suggesting that patients with a complete response might not need further therapy since they are expected to do so well.12 This is becoming a common practice in the neoadjuvant setting.13 In our study, only one patient with a CR received further therapy, while the other six did not. This aligns with current practice and suggests that patients who did not resume therapy might have improved OS.

One of the largest concerns with resuming immunotherapy after severe toxicity is a possible recurrence of autoimmune toxicity. A prior analysis of 80 patients who had severe irAEs from ipilimumab and nivolumab demonstrated an 18% rate of recurrent irAEs.14 The rates of toxicity in patients who resumed nivolumab were similar at 26% and were manageable.

Limitations of our study include its retrospective nature and potential confounders influencing treating physicians’ choice to resume therapy which was likely influenced by the patient’s overall status and toxicity. Of note, stratification of the data demonstrated no clear differences between the treatment populations aside from the irAE type. Factors such as LDH sex, M-stage, duration of ipilimumab/nivolumab, age, irAE type, and irAE grade were controlled for in the analysis since these might influence the physicians’ desire to resume nivolumab and how patients did long-term.

There is a need for clear guidance on whether to resume single-agent nivolumab post combination ipilimumab/nivolumab toxicity. The resumption of single-agent PD-1 inhibition should also be examined after other combination regimens such as nivolumab and relatlimab. Further research is needed in a clinical trial setting to explore the implications of resuming single-agent nivolumab on OS in patients with metastatic melanoma to avoid confounders common with retrospective studies such as those noted in this study. As new tools such as circulating tumor DNA enter into research and clinical practice these assays may help inform decisions in this space. It will be important to incorporate circulating tumor DNA assays into clinical trials testing the benefit of nivolumab maintenance.

A randomized, clinical trial comparing patients who resume single-agent nivolumab after irAEs to those who do not would better describe the relationship between resuming nivolumab after irAEs and increased OS. In addition, a trial would allow for research samples to identify cytokines and other mediators potentially involved in influencing more, or higher-graded, irAEs. Zhao et al examined cytokines on immune checkpoint inhibitor therapy in patients with lung cancer found that baseline levels of interleukin (IL)-1β and IL-2, as well as on-treatment levels of IL-5, interferon (IFN)-α and IFN-γ were associated with irAEs.10 They also found that on-treatment levels of IL-6, IL-8, IL-10 and IL-17 were related to the clinical response.10 A clinical trial where cytokines and other markers are described in patients with melanoma could help predict which patients are likely to develop irAEs on ICI therapy, and which patients are likely to respond to continuation of nivolumab.

In the interim, in-depth discussions should be had with patients to determine their treatment plan in the setting of combination toxicity. Patients should be educated on the observational benefits of resuming nivolumab such as the potential for increased OS, along with the risks such as irAE recurrence or developing new irAEs. Shared decision-making should be used between the physician and patient to determine if resuming nivolumab would maintain or improve their quality of life.

supplementary material

10.1136/jitc-2024-009061 online supplemental file 1

Data availability statement

Data are available upon reasonable request.

Funding: This study was funded by the Blitzer Family Foundation.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Data availability free text: All data relevant to the study are included in the article or uploaded as online supplemental information. The data generated and/or analyzed during this study are available from the corresponding author on reasonable request.

Presented at: Study presented as poster discussion at ASCO Annual meeting 2023.
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