The Miller Lab -

Should Ipilimumab Be the New “Standard” for Refractory MCC?

David M. Miller MD, PhD
MassGeneral Cancer Center
Harvard Medical School

Disclosures

I have received honoraria for participation on advisory boards for Merck, EMD Serono, Regeneron, Sanofi Genzyme, Pfizer, Castle Biosciences, Checkpoint Therapeutics, Incyte, Bristol-Myers Squib. I have stock options from Checkpoint Therapeutics and Avstera Therapeutics. I have received research funding from Regeneron, Kartos Therapeutics, Xilio Therapeutics, NeoImmune Tech, Inc, Project Data Sphere, ECOG-ACRIN and the American Skin Association.

Overview

Background on the therapeutic landscape for MCC
Review data on options in the post-anti-PD1 setting
Discuss unmet needs

Therapy	Study	Line of Therapy	N	Objective Response (%)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Avelumab	Javelin¹	1	39	62	NR	NR
Avelumab	Javelin^2,3	≥2	88	33	3	13
Pembrolizumab	CITN-09⁴	1	50	56	17	NR
Nivolumab	CheckMate-358⁵	1	15	73	24.8	NR
Nivolumab	CheckMate-358⁵	≥2	10	50	21.3	NR
Nivolumab + Ipilimumab	CheckMate-358⁶	1	33	64	15.4	35.58
Nivolumab + Ipilimumab	Moffitt IST⁷	1	13	100	NR	NR
Nivolumab + Ipilimumab	CheckMate-358⁶	≥2	10	40	2.74	8.56
Nivolumab + Ipilimumab	Moffitt IST⁷	≥2	12	42	4.2	14.9
Retifanlimab	POD1UM-201⁸	1	65	52	NA	NA
References: ¹ D'Angelo et al. (2018) ² Kaufman et al. (2018) ³ Kaufman et al. (2016) ⁴ Nghiem et al. (2016) ⁵ Topalian et al. (2017) ⁶ Bhatia et al. (2023) ⁷ Kim et al. (2022) ⁸ Grignani et al. (2021)

Therapy	Study	Line of Therapy	N	Objective Response (%)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Avelumab	Javelin	1	39	62	NR	NR
Pembrolizumab	CITN-09	1	50	56	17	NR
Nivolumab	CheckMate-358	1	15	73	24.8	NR
Nivolumab + Ipilimumab	CheckMate-358	1	33	64	15.4	35.58
Nivolumab + Ipilimumab	Moffitt IST	1	13	100	NR	NR
Retifanlimab	POD1UM-201	1	65	52	NA	NA

Therapy	Study	Line of Therapy	N	Objective Response (%)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Avelumab	Javelin	1	39	62	NR	NR
Pembrolizumab	CITN-09	1	50	56	17	NR
Nivolumab	CheckMate-358	1	15	73	24.8	NR
Nivolumab + Ipilimumab	CheckMate-358	1	33	64	15.4	35.58
Nivolumab + Ipilimumab	Moffitt IST	1	13	100	NR	NR
Retifanlimab	POD1UM-201	1	65	52	NA	NA
Aggregate	Aggregate	1	215	61	NA	NA

Unmet Need

Therapies in the post-PD1 setting are lacking

Rationale of anti-CTLA4

CTLA-4 regulates T-cell activation lymphoid tissue(Buchbinder and Desai 2016)
Combination anti-PD-1/anti-CTLA-4 has a long history of efficacy and a known safety profile (Larkin et al. 2015)

Targeting CTLA-4 in MCC

Efficacy in the first line setting

Patient	Sex	Age at First Diagnosis (years)	First Diagnosis	Initial Tumor Localization	Therapies Before Ipilimumab	Start of Ipilimumab	Adjuvant/Additive	Number of Cycles	Best Response	PFS (months)	Therapies Following Ipilimumab	OS (months)
Ipilimumab As First Line Systemic Therapy
1	M	55	07/13	Left inguinal lymph nodes	Left inguinal lymph node dissection and radiation, right inguinal lymph node dissection and radiation	03/14	No	4	PD	2.8	None	3.5
2	M	70	07/12	Right thigh	Right inguinal/iliac/paracaval lymphadenectomy and radiation, radiation to left iliac lymph nodes	01/14	No	4	SD	12.0	Radiation to cervical lymph nodes, nivolumab, radiation to left paraaortal lymph node, etoposide	>36.2
3	M	81	12/10	Right lower leg, inguinal sentinel lymph node	Right inguinal lymph node dissection and radiation, excision right thigh and radiation	01/12	Additive (surgery)	3	SD	4.8	Radiation to right retroperitoneal lymph nodes, radiation to right renal bed	15.8
4	M	61	07/13	Left inguinal lymph nodes	Left inguinal lymph node dissection, left iliac lymph node dissection, radiation to left pelvis, low-dose interferon, radiation to paraaortal lymph node	08/14	Adjuvant (radiation)	4	CR	12.6	Radiation to paraaortal lymphatic pathways, ipilimumab	>28.6
5	F	50	02/11	Left knee, inguinal sentinel lymph node	Right inguinal lymphadenectomy, radiation to the knee and right inguinal	01/15	Additive (radiation)	4	CR	23.5	None	>23.5

α-CTLA-4 in Post PD1 MCC

Letter to the editor in the Annals of Oncology

“Breaking avelumab resistance with combined ipilimumab and nivolumab in metastatic Merkel cell carcinoma?”

A 60-year-old male with progressive disease on avelumab exhibited a complete response to 4 doses of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg

α-CTLA-4 in Post PD1 MCC

Dual institutional retrospective report (Johns Hopkins and University of Washington/Fred Hutchinson Cancer Center) of 13 patients previously treated with checkpoint blockade

Case	Patient Age, Sex, MCPyV Status	Therapy #1	Response #1	Therapy #2	Response #2	Therapy #3	Response #3	Therapy #4	Response #4
Therapies Administered and Corresponding Disease Outcomes
1	67 M, unknown	Pembrolizumab 2mg/kg q3wks	PD at 2 months	Ipilimumab 3mg/kg + Nivolumab 1mg/kg q3wks x 4	irPR at 9 wks PD at 30 wks	Ipilimumab 3mg/kg + Nivolumab 1mg/kg q3wks x 4	PD at 14 wks	Avelumab 10 mg/kg q2wks + RT	PR at 8 wks PD at 12 mos
2	79 M, unknown	Pembrolizumab 2mg/kg q3wks	PD at 9 wks	RT + Ipilimumab 3mg/kg + Nivolumab 1mg/kg q3wks x 4 then Nivolumab 3mg/kg q2wks	PR at 17 weeks ongoing at 8 mos. Pt died at 10 mos of complications related to encephalopathy
3	59 M, Positive	Multiple systemic therapies prior to anti PD-1	Variable	Pembrolizumab + MCPyV-specific T cells	PD at 2 months & at 4 months	Ipilimumab 0.5mg/kg initially (Pembrolizumab added later)	Near CR lasting 2 years	Multiple systemic therapies after Ipilimumab	PD
4	71 M, Positive	Multiple systemic therapies prior to anti PD-1	Variable	Nivolumab	CR lasting 26 months then PD	Ipilimumab 1mg/kg + Nivolumab Q6Wks ongoing	CR lasted 10 months
5	64 F, unknown	Pembrolizumab 2mg/kg q3wks	PD at 4 mos	Ipilimumab 3mg/kg IV every 3 weeks	Died at 10 weeks from PD
6	51 M, Unknown	Pembrolizumab 2mg/kg q3wks	CR for 14 mos then PD in CNS only	RT + Ipilimumab 3mg/kg + Nivolumab 1mg/kg q3wks x 4	PD; died at 6 months from leptomeningeal MCC
7	67 F, Unknown	RT + Pembrolizumab 2mg/kg q3wks	PD at 2 months	RT + Ipilimumab 1mg/kg x 1	Ipilimumab discontinued due to toxicity; PD at 3 months	RT+ Avelumab 10 mg/kg q2wks	PD at 2 months
8	75 M, Unknown	Avelumab 10 mg/kg q2wks	PD at 16 wks	Nivolumab 3mg/kg q3wks + Ipilimumab 1mg/kg q6wks	PD at ~9 wks	RT	Partial regression of irradiated lesions
9	21 F, Positive	Nivolumab Avelumab	PD	Avelumab + IFN + MCPyV-specific T cells	PD at 1 month	Ipilimumab 1mg/kg + Nivolumab x1 dose	PD	Multiple systemic therapies	PD
10	71 M, Negative	Pembrolizumab	PR lasting 6 months	Ipilimumab 0.5mg/kg + Pembrolizumab x4 doses	PD at 3 months	Ipilimumab 1mg/kg + Pembrolizumab	PD at 7 months
11	63 M, Positive	Avelumab +RT+ MCPyV-specific T cells	PD	Ipilimumab 1mg/kg + Nivolumab	PD at 3 months	Multiple systemic therapies	PD
12	67 M, Negative	Avelumab	PR lasting 12 months	Ipilimumab 1mg/kg + Nivolumab x4 doses	Stable disease for 3 months	Nivolumab	PD at 1 month
13	63 M, Negative	Adjuvant Avelumab	PD at 2 months	Ipilimumab 1mg/kg + Nivolumab x2 doses	PD
Table S1: Therapies administered and corresponding disease outcomes for patients with advanced Merkel cell carcinoma refractory to anti-PD-1 or anti-PD-L1. (CLL, chronic lymphocytic leukemia; CR, complete response; PR, partial response; irPR, immune-related partial response; MCPyV, Merkel cell polyomavirus; PD, progressive disease; RT, radiotherapy)

Therapy	Study	N	Objective Response (%)	Complete Response (%)	Median DOR (months)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Ipilimumab +/- anti-PD1	Hopkins/Fred Hutch Retrospective¹	13	31	15.4	NA	NA	NA
References: ¹ LoPiccolo et al. (2019)

α-CTLA-4 in Post PD1 MCC

Dual institutional retrospective report (BWH/DFCI and MGH) of 13 patients previously treated with checkpoint blockade

α-CTLA-4 in Post PD1 MCC

Report of 14 patients from the multi-center institutional skin cancer registry ADOREG

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

Outcome	Results
Outcome Associated with Later-Line IPI/NIVO
IPI/NIVO
BOR
CR 1/14	7.1% (1/14)
PR 6/14	42.9% (6/14)
SD 0/14	0% (0/14)
PD 7/14	50% (7/14)
PFS
Median (range)	5.07 (2.43–NA)
1-year rate (%) (95% CI)	42.9 (23.4 to 78.5)
2-year rate (%) (95% CI)	26.8 (10.9 to 66.0)
OS
Median (range)	NR (3.75–NA)
1-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
2-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
3-year rate (%) (95% CI)	64.3 (43.5 to 95.0)
Median follow-up (months) (IQR)	18.85 (17.63–22.40)

α-CTLA-4 in Post PD1 MCC

Dual institution (Moffitt Cancer Center and the Ohio State University James Cancer Hospital and Solove Research Institute ) prospective clinical trial of 26 patients

Outcome Measures	Total		Group A (combined nivolumab and ipilimumab)		Group B (combined nivolumab and ipilimumab plus SBRT)
Objective Response and Durability of Response
Outcome Measures	ICI Naive (n=24)	Previous ICI (n=26)	ICI Naive (n=13)	Previous ICI (n=12)	ICI Naive (n=11)	Previous ICI (n=14)
ORR (95% CI)¹	100 (82–100)	31 (15–52)	100% (72–100)	42% (16–71)	100% (63–100)	21% (6–51)
BOR
CR	9/22 (41%)	4 (15%)	7 (54%)	3 (25%)	2/9 (22%)	1 (7%)
PR	13/22 (59%)	4 (15%)	6 (46%)	2 (17%)	7/9 (78%)	2 (14%)
SD	0	1 (4%)	0	1 (8%)	0	0
PD	0	17 (65%)	0	6 (50%)	0	11 (79%)
Median PFS (months)	NR		NR	2.7 (2.2-7.6)	NR	2.7 (2.2-7.6)
Median OS (months)	NR		NR	14.9 (0.3-NE)	NR	9.7 (5.0-NE)
¹ Data are n (%) unless otherwise stated. Percentages are rounded to the nearest whole number. BOR=best overall response. CR=complete response. DOR=duration of response. ICI=immune-checkpoint inhibitor.NE=non-estimable. ORR=objective response rate. PD=progressive disease. PR=partial response. SBRT=stereotactic body radiotherapy. SD=stable disease. *Two partial responders in the previous-ICI cohort had unconfirmed partial responses. †Two patients deemed non-evaluable as the target lesion was irradiated. ‡Includes 30 responders with at least 6 months of follow-up.

Outcome Measures	Total		Group A (combined nivolumab and ipilimumab)		Group B (combined nivolumab and ipilimumab plus SBRT)
Objective Response and Durability of Response
Outcome Measures	ICI Naive (n=24)	Previous ICI (n=26)	ICI Naive (n=13)	Previous ICI (n=12)	ICI Naive (n=11)	Previous ICI (n=14)
ORR (95% CI)¹	100 (82–100)	31 (15–52)	100% (72–100)	42% (16–71)	100% (63–100)	21% (6–51)
BOR
CR	9/22 (41%)	4 (15%)	7 (54%)	3 (25%)	2/9 (22%)	1 (7%)
PR	13/22 (59%)	4 (15%)	6 (46%)	2 (17%)	7/9 (78%)	2 (14%)
SD	0	1 (4%)	0	1 (8%)	0	0
PD	0	17 (65%)	0	6 (50%)	0	11 (79%)
Median PFS (months)	NR		NR	2.7 (2.2-7.6)	NR	2.7 (2.2-7.6)
Median OS (months)	NR		NR	14.9 (0.3-NE)	NR	9.7 (5.0-NE)
¹ Data are n (%) unless otherwise stated. Percentages are rounded to the nearest whole number. BOR=best overall response. CR=complete response. DOR=duration of response. ICI=immune-checkpoint inhibitor.NE=non-estimable. ORR=objective response rate. PD=progressive disease. PR=partial response. SBRT=stereotactic body radiotherapy. SD=stable disease. *Two partial responders in the previous-ICI cohort had unconfirmed partial responses. †Two patients deemed non-evaluable as the target lesion was irradiated. ‡Includes 30 responders with at least 6 months of follow-up.

Outcome Measures	Total		Group A (combined nivolumab and ipilimumab)		Group B (combined nivolumab and ipilimumab plus SBRT)
Objective Response and Durability of Response
Outcome Measures	ICI Naive (n=24)	Previous ICI (n=26)	ICI Naive (n=13)	Previous ICI (n=12)	ICI Naive (n=11)	Previous ICI (n=14)
ORR (95% CI)¹	100 (82–100)	31 (15–52)	100% (72–100)	42% (16–71)	100% (63–100)	21% (6–51)
BOR
CR	9/22 (41%)	4 (15%)	7 (54%)	3 (25%)	2/9 (22%)	1 (7%)
PR	13/22 (59%)	4 (15%)	6 (46%)	2 (17%)	7/9 (78%)	2 (14%)
SD	0	1 (4%)	0	1 (8%)	0	0
PD	0	17 (65%)	0	6 (50%)	0	11 (79%)
Median PFS (months)	NR		NR	2.7 (2.2-7.6)	NR	2.7 (2.2-7.6)
Median OS (months)	NR		NR	14.9 (0.3-NE)	NR	9.7 (5.0-NE)
¹ Data are n (%) unless otherwise stated. Percentages are rounded to the nearest whole number. BOR=best overall response. CR=complete response. DOR=duration of response. ICI=immune-checkpoint inhibitor.NE=non-estimable. ORR=objective response rate. PD=progressive disease. PR=partial response. SBRT=stereotactic body radiotherapy. SD=stable disease. *Two partial responders in the previous-ICI cohort had unconfirmed partial responses. †Two patients deemed non-evaluable as the target lesion was irradiated. ‡Includes 30 responders with at least 6 months of follow-up.

Outcome Measures	Total		Group A (combined nivolumab and ipilimumab)		Group B (combined nivolumab and ipilimumab plus SBRT)
Objective Response and Durability of Response
Outcome Measures	ICI Naive (n=24)	Previous ICI (n=26)	ICI Naive (n=13)	Previous ICI (n=12)	ICI Naive (n=11)	Previous ICI (n=14)
ORR (95% CI)¹	100 (82–100)	31 (15–52)	100% (72–100)	42% (16–71)	100% (63–100)	21% (6–51)
BOR
CR	9/22 (41%)	4 (15%)	7 (54%)	3 (25%)	2/9 (22%)	1 (7%)
PR	13/22 (59%)	4 (15%)	6 (46%)	2 (17%)	7/9 (78%)	2 (14%)
SD	0	1 (4%)	0	1 (8%)	0	0
PD	0	17 (65%)	0	6 (50%)	0	11 (79%)
Median PFS (months)	NR		NR	2.7 (2.2-7.6)	NR	2.7 (2.2-7.6)
Median OS (months)	NR		NR	14.9 (0.3-NE)	NR	9.7 (5.0-NE)
¹ Data are n (%) unless otherwise stated. Percentages are rounded to the nearest whole number. BOR=best overall response. CR=complete response. DOR=duration of response. ICI=immune-checkpoint inhibitor.NE=non-estimable. ORR=objective response rate. PD=progressive disease. PR=partial response. SBRT=stereotactic body radiotherapy. SD=stable disease. *Two partial responders in the previous-ICI cohort had unconfirmed partial responses. †Two patients deemed non-evaluable as the target lesion was irradiated. ‡Includes 30 responders with at least 6 months of follow-up.

Therapy	Study	N	Objective Response (%)	Complete Response (%)	Median DOR (months)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Ipilimumab +/- anti-PD1	Hopkins/Fred Hutch Retrospective¹	13	31	15	NA	NA	NA
Ipilimumab + Nivolumab	ADOREG Registry²	14	50	7	NA	5.07	NR
Ipilimumab + Nivolumab	MGB Retrospective³	13	0	0	NA	1.3	4.7
Ipilimumab + Nivolumab	Moffitt IST⁴	12	42	25	15.1	4.2	14.9
Ipilimumab + Nivolumab + RT	Moffitt IST⁴	14	21	7	4.9	2.7	9.7
Ipilimumab + Nivolumab	Case Report⁵	1	100	100	24+	24+	24+
Ipilimumab + Nivolumab	Case Report⁶	1	0	0	NA	NA	10+
Ipilimumab + Nivolumab	Case Report⁷	1	100	100	43+	43+	43+
References: ¹ LoPiccolo et al. (2019) ² Glutsch et al. (2022) ³ Shalhout et al. (2022) ⁴ Kim et al. (2022) ⁵ Khaddour et al. (2020) ⁶ Ferdinandus et al. (2021) ⁷ Leven et al. (2023)

Therapy	Study	N	Objective Response (%)	Complete Response (%)	Median DOR (months)	Median PFS (months)	Median OS (months)
Immunotherapy for Merkel Cell Carcinoma
Ipilimumab +/- anti-PD1	Hopkins/Fred Hutch Retrospective¹	13	31	15	NA	NA	NA
Ipilimumab + Nivolumab	ADOREG Registry²	14	50	7	NA	5.07	NR
Ipilimumab + Nivolumab	MGB Retrospective³	13	0	0	NA	1.3	4.7
Ipilimumab + Nivolumab	Moffitt IST⁴	12	42	25	15.1	4.2	14.9
Ipilimumab + Nivolumab + RT	Moffitt IST⁴	14	21	7	4.9	2.7	9.7
Ipilimumab + Nivolumab	Case Report⁵	1	100	100	24+	24+	24+
Ipilimumab + Nivolumab	Case Report⁶	1	0	0	NA	NA	10+
Ipilimumab + Nivolumab	Case Report⁷	1	100	100	43+	43+	43+
Ipilimumab + Nivolumab	Aggregate	67	31	12	NA	NA	NA
References: ¹ LoPiccolo et al. (2019) ² Glutsch et al. (2022) ³ Shalhout et al. (2022) ⁴ Kim et al. (2022) ⁵ Khaddour et al. (2020) ⁶ Ferdinandus et al. (2021) ⁷ Leven et al. (2023)

Summary

Options for patients with advanced MCC that have progressed on anti-PD1 therapy are limited
Enrollment in a clinical trial, if possible, remains the “standard”
For those patients for whom a clinical trial is not available or appropriate a thorough evaluation of the risks and benefits of available therapy should be discussed
Ipilimumab/nivolumab may be a reasonable options for some patients
Additional therapies with the potential for clinical benefit include cytotoxic chemotherapy and radionuclide therapy (e.g. lutetium Lu 177 dotatate)
Comfort care is also appropriate for some patients in this setting

References

Atkins, Michael B., Sandra J. Lee, Bartosz Chmielowski, Ahmad A. Tarhini, Gary I. Cohen, Thach-Giao Truong, Helen H. Moon, et al. 2023. “Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq TrialECOG-ACRIN EA6134.” Journal of Clinical Oncology 41 (2): 186–97. https://doi.org/10.1200/jco.22.01763.

Buchbinder, Elizabeth I., and Anupam Desai. 2016. “CTLA-4 and PD-1 Pathways.” American Journal of Clinical Oncology 39 (1): 98–106. https://doi.org/10.1097/coc.0000000000000239.

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