21 50 Stars From 11 Reviews Jason D Meier Md

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Cancer. Author manuscript; bachelor in PMC 2014 Apr 14.

Published in final edited grade as:

PMCID: PMC3986037

NIHMSID: NIHMS544181

Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Establish, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center and Academy Hospital of Lausanne experience

Jason J. Luke, Doc,^{1, ∧} Margaret K. Callahan, MD, PhD,^{2, ∧} Michael A. Postow, MD,^two Emanuela Romano, MD, PhD,ⁱⁱⁱ Nikhil Ramaiya, Md,^iv Mark Bluth, Physician,⁵ Anita Giobbie-Hurder, MA,^{half dozen} Donald P. Lawrence, MD,⁷ Nageatte Ibrahim, MD,ⁱ Patrick A. Ott, MD, PhD,¹ Keith T. Flaherty, Physician,⁷ Ryan J. Sullivan, MD,⁷ James J. Harding, MD,² Sandra D'Angelo, MD,² Mark Dickson, Dr.,² Gary Grand. Schwartz, MD,² Paul B. Chapman, Medico,² Jedd D. Wolchok, MD, PhD,² F. Stephen Hodi, Dr.,¹ and Richard D. Carvajal, MD^{two, *}

Jason J. Luke

¹Section of Medical Oncology, Dana-Farber Cancer Institute

Margaret One thousand. Callahan

^twoDepartment of Medicine, Memorial Sloan-Kettering Cancer Eye

Michael A. Postow

ⁱⁱSection of Medicine, Memorial Sloan-Kettering Cancer Centre

Emanuela Romano

ⁱⁱⁱDepartment of Oncology, Academy Hospital of Lausanne

Nikhil Ramaiya

⁴Department of Radiology, Dana-Farber Cancer Establish

Mark Bluth

⁵Department of Radiology, Memorial Sloan-Kettering Cancer Middle

Anita Giobbie-Hurder

⁶Section of Biostatistics, Dana-Farber Cancer Found

Donald P. Lawrence

⁷Department of Medicine, Massachusetts General Hospital

Nageatte Ibrahim

ⁱSection of Medical Oncology, Dana-Farber Cancer Institute

Patrick A. Ott

¹Section of Medical Oncology, Dana-Farber Cancer Institute

Keith T. Flaherty

⁷Department of Medicine, Massachusetts General Hospital

Ryan J. Sullivan

⁷Section of Medicine, Massachusetts General Infirmary

James J. Harding

²Section of Medicine, Memorial Sloan-Kettering Cancer Center

Sandra D'Angelo

ⁱⁱSection of Medicine, Memorial Sloan-Kettering Cancer Center

Marking Dickson

^twoSection of Medicine, Memorial Sloan-Kettering Cancer Centre

Gary Thou. Schwartz

^twoDepartment of Medicine, Memorial Sloan-Kettering Cancer Center

Paul B. Chapman

²Department of Medicine, Memorial Sloan-Kettering Cancer Center

Jedd D. Wolchok

²Department of Medicine, Memorial Sloan-Kettering Cancer Center

F. Stephen Hodi

¹Department of Medical Oncology, Dana-Farber Cancer Constitute

Richard D. Carvajal

²Section of Medicine, Memorial Sloan-Kettering Cancer Heart

Abstract

Background

Uveal melanoma exhibits a loftier incidence of metastases and no systemic therapy clearly improves outcomes. The anti-CTLA-4 antibiotic ipilimumab is a standard of intendance for metastatic melanoma; all the same, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.

Methods

To assess ipilimumab in this setting, we performed a multicenter, retrospective analysis of four hospitals in the United States and Europe. Clinical characteristics, toxicities and radiographic disease burden as determined by central, blinded radiology review were adamant.

Results

Thirty-nine patients were identified (34 treated with 3 mg/kg and five treated with x mg/kg). Using the immune-related response criteria and modified WHO criteria, response rate (RR) and combined response plus stable disease (SD) rate were assessed later 12 weeks, 23 weeks and total (median follow-upward 50.4 weeks (12.vi months)). At calendar week 12, the RR and response plus SD rate were 2.6% and 46.0%, at week 23: 2.6% and 28.2%. There was one complete response and i late fractional response (at 100 weeks afterwards initial SD) for irRR of 5.1%. Immune-related adverse events (irAE) were observed in 28 (71.8%) patients, with seven (17.nine%) class iii-4 events. irAEs were more frequent in patients receiving 10 mg/kg versus iii mg/kg. The median overall survival from first dose of ipilimumab was ix.half-dozen months (confidence interval 6.3-13.4 months, range: 1.6-41.6 months). Performance status, LDH and absolute lymphocyte count ≥1000 cells/μL at week 7 were significantly associated with survival.

Conclusions

In uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed.

Keywords: uveal melanoma, ipilimumab, CTLA-four, immunotherapy, absolute lymphocyte count

Introduction

Uveal melanoma is a rare class of melanoma that represents about 3-v% of the incidence of cutaneous melanomas.^ane Metastasis in uveal melanoma is common with approximately l% of patients developing afar cancer within 15 years of initial diagnosis.² Uveal melanoma harbors a unique set of genetic alterations compared with cutaneous melanoma. Whereas cutaneous melanoma often harbors activating mutations in BRAF and NRAS, mutations in the heterotrimeric Chiliad poly peptide blastoff-subunits, GNAQ and GNA11, accept been reported in approximately lxxx% of uveal melanomas.ⁱⁱⁱ GNAQ and GNA11 mutations are not, however, correlated with disease complimentary survival or the development of metastasis.⁴

The issue for patients with metastatic uveal melanoma is dismal, with a median survival of approximately 12 months,⁵ and no systemic therapy has improved survival.⁶ Drugs commonly used to treat advanced cutaneous melanoma rarely reach durable responses in patients with uveal melanoma. Treatment with dacarbazine (DTIC), carmustine (BCNU), cisplatin, and tamoxifen (Dartmouth regimen) was reported to show a response rate of 6% and a phase Ii report of carboplatin, paclitaxel and sorafenib described no objective responses^{7, viii}. A retrospective review of 143 patients treated with chemotherapy at MD Anderson Cancer Center reported a single objective response and other reviews of the Eastern Cooperative Oncology Grouping (ECOG) and Southwestern Oncology Group described similar findings.^{9, 10}

Immunotherapy for the treatment of metastatic uveal melanoma has besides conceptually been of involvement. It is hypothesized that uveal melanoma may be more immunogenic than other tumors since information technology arises in the immunologically privileged site of the center. Further, uveal melanoma has high expression of multiple cancer antigens known to be immunogenic, including gp100, MAGE, MART-one, tyrosinase and TRP-1.^{xi, 12} Clinical experience with immunotherapy in uveal melanoma is express with case reports describing success; however, larger series showed equivocal benefit.^{13, fourteen}

Ipilimumab (Bristol-Myers Squibb, Princeton, NJ) is a fully human being monoclonal antibody that augments anti-tumor immunity through blockade of cytotoxic T lymphocyte antigen-four. Ipilimumab has become a standard of care for the treatment of patients with metastatic melanoma after an overall survival benefit was demonstrated.¹⁵ The activity of ipilimumab in uveal melanoma, notwithstanding, has non been well described. A retrospective serial of xiii patients with metastatic uveal melanoma treated with ipilimumab reported three patients with stable disease as the all-time response,¹⁶ and a smaller review described two out of five patients with stable affliction at 11 months.¹⁷ But preliminary data describing patients with uveal melanoma treated with ipilimumab in expanded access programs have been presented.¹⁸ Given the express therapeutic options available to patients with uveal melanoma, determining the efficacy of ipilimumab in uveal melanoma is essential.

Nosotros conducted a multicenter, retrospective analysis of 39 patients with metastatic uveal melanoma treated with ipilimumab nether an expanded access clinical program or using commercial drug. We report the clinical activity and toxicity observed from 4 bookish hospitals in the The states and Europe.

Methods

Patients and Clinical Characteristics

Afterwards obtaining institutional review lath approving at each site, patients with metastatic uveal melanoma treated with ipilimumab were identified from the databases of 4 institutions (Dana-Farber Cancer Establish, Massachusetts Full general Hospital, Memorial Sloan-Kettering Cancer Center, United states of america and University Hospital of Lausanne, Switzerland). Patients treated on clinical protocols and with commercial drug were included. Patients receiving ipilimumab in combination with other agents or as re-induction therapy were excluded. Relevant clinical parameters were collected including age, gender, ECOG performance condition, site(s) of metastatic disease, lines of prior therapy equally well every bit dose of ipilimumab received. Laboratory parameters were nerveless including lactate dehydrogenase (LDH) at time of first ipilimumab infusion, and absolute lymphocyte count (ALC) before treatment likewise as at approximately seven weeks later on initiation of therapy. Handling response and prophylactic data were besides determined. All information was aggregated following patient de-identification.

Efficacy and Toxicity Cess

Efficacy outcomes were determined past a radiologist at each site who was blinded to outcome. Beneficial effects of ipilimumab were categorized every bit complete response (CR), partial response (PR) or stable disease (SD). Response plus SD rate was calculated as the percentage of patients achieving a CR, PR or SD at 12 weeks, 23 weeks or longer later starting ipilimumab handling. The allowed-related response criteria (irRC) and modified World Wellness Organization (mWHO) criteria were practical to decide each patient'southward response.¹⁹ Overall survival (Os) was calculated by Kaplan-Meier methodology from first dose of ipilimumab to date of death past any cause. Toxicity was assessed through chart review and graded using Mutual Terminology Criteria for Adverse Events (version 4.0). Special attending was given to events of special interest or immune-related adverse events (irAE) including rash, colitis, hepatitis, thyroiditis and hypophysitis.

Univariate comparisons of OS for ipilimumab dose (ten mg/kg or 3 mg/kg), baseline LDH, ECOG functioning status, and ALC were conducted using Kaplan-Meier estimates; differences were assessed using the log-rank test. LDH was divided as above or below the institutional upper limit of normal; ALC was divided into low (<yard cells/μL) or normal (≥1000 cells/μL). ECOG functioning status was classified as fully agile versus whatever restriction (0 versus 1-two). Statistically significant predictors in the univariate comparisons were then included in a multivariable Cox proportional hazards regression model. The Cox regression was stratified past number of prior therapies (treatment-naive versus other) to permit for underlying differences in the baseline hazards of death between these two groups. Landmark analyses were conducted to compare OS betwixt seven-week ALC levels (low versus normal) as this has been suggested as a biomarker of ipilimumab efficacy in cutaneous melanoma.^{20, 21} Comparisons of rates of adverse events were based on Fisher's exact test. Statistical significance was defined every bit p < 0.05.

Results

Patient and Clinical Characteristics

The clinical characteristics of the thirty-ix patients included in the assay are shown in Table 1. Patients were predominately male with a median age of 61 years and median ECOG condition of 0. The median number of prior therapies was ane with approximately half of patients being treated as role of the Bristol-Myers Squibb expanded access clinical protocol ({"type":"entrez-nucleotide","attrs":{"text":"CA184045","term_id":"35121424","term_text":"CA184045"}}CA184045). Five patients (thirteen%) received ipilimumab at 10 mg/kg while others received 3 mg/kg. The median number of ipilimumab doses was four (range i-16). 3 patients received maintenance dosing.

Table one

Patient Characteristics

Total n		39
Age, median (Range), years		61	(39-84)
Sex	Male	23	59%
	Female	xvi	41%
ECOG PS pretreatment	0	22	56%
(median ECOG 0, range 0-2)	1	8	21%
	2	iv	10%
	Unknown	5	13%
Sites of Metastatic Affliction (≥v% only)	Liver	32	82%
	Lung	15	38%
	Bone	9	23%
	Soft Tissue	7	18%
	Skin	3	8%
	Lymph Node	3	8%
	Pancreas	two	5%
	Brain	two	5%
Pretreatment median LDH (range)		300	(171-5132)
Patients with elevated LDH (%)		thirty	63%
Pretreatment median ALC		1.ii	(0.5-ii.66)
Prior lines of therapy, north (%)	0	4	x%
	1	22	56%
	2	ix	23%
	≥iii	iv	10%
Median prior lines of therapy		1	(0-5)
Ipilimumab dose	3 mg/kg	34	87%
	10mg/kg	5	thirteen%
Median dose of ipilimumab		3 mg/kg
Median doses ipilimumab, n (range)		4	(1-16)
Protocol		21	54%
Commercial		18	46%

Response Analysis

Of the 39 full patients identified, 35 were evaluable for radiographic assessment of changes in tumor brunt following ipilimumab. The four patients who were non assessable either died prior to assessment of change in tumor burden or were transitioned to palliative care but without subsequent imaging. These patients were assumed to have had progressive disease and were included in all analyses.

Given that tumor assessments were performed both on and off protocol, the timing of restaging radiography was somewhat variable in the report population. With that caveat, it was observed that the first through quaternary scans took place at medians of 10.7, 16.i, 23.0 and 31.3 weeks. When adjusting for the twelve patients who were restaged prior to completing ipilimumab consecration (prior to ten weeks), the median fourth dimension to first scan was 12.0 weeks. In the twelve patients who had early restaging performed, the median time to commencement browse was 6.2 weeks.

By irRC, at the time of the get-go radiographic assessment (approximately week 12) there were one irCR and 17 irSD. The irCR was confirmed on subsequent scans, and, notably, i patient who had irSD at calendar week 12 and calendar week 23 developed a late response, achieving irPR at approximately week 100. Prior to week 23, six irSD had progressive disease (PD). One irSD had a confirmatory scan for SD but was not yet evaluable at 23 weeks. Additionally, 3 patients who had irSD at week 12 and 23 later had PD (at weeks 28, 31 and 33). Data on response and response plus SD rate are listed in Tabular array 2A. In evaluation of the full study accomplice (median follow-up of 50.iv weeks (12.six months)), there was ane irCR, ane irPR and six irSD. Seventeen patients had PD at the fourth dimension of the first scan; however, merely seven of these patients had the required follow-upwardly scan documenting progression, as required by irRC. The response charge per unit in full follow upwards by irRC was five.1% (two/39).

Tabular array 2

Clinical outcomes for benefiting patients (A) and details for those benefiting at 6 months (B)

A
	At Last Follow-up	12 weeks	23 weeks
CR	1	1	i
PR	1	0	0
SD	6	17	10
RR	5.1%	2.half-dozen%	2.6%
CR+PR+SD	xx.v%	46.1%	28.two%

B
Study #	Historic period	Pre LDH	Pre ALC	ALC vii weeks	Modify in ALC	Study vs. Standard Exercise	Dose	Sites of metastatic disease at baseline	irAE	Prior Rx	Fourth dimension from get-go dose to death or follow up (months)	Current Status	Alive
8	51	376	1.22	one.88	0.66	Standard	iii	Liver, Lung, Soft Tissue	None	Ganetespib	10.8	PD at week 31	No
19	44	176	i.92	3.07	1.15	Standard	3	Liver, Lung	G1 Rash	None	half dozen.6	SD at week 26+	Yep
20	49	203	ane.52	ane.93	0.41	Standard	3	Lung	G2 Rash	None	11.vii	SD at week 39+	Yes
22	66	2363	0.84	one.two	0.36	Standard	3	Liver, Pancreas, Lymph nodes	None	Temozolomide	viii.1	SD at week 32+	Yeah
25	76	312	1.3	1.4	0.1	Study	ten	Liver	G3 Hepatitis	Pegylated arginine deiminase	19.0	PD at week 33	No
28	threescore	133	1.5	1.8	0.3	Written report	10	Lung	G3 Hypophysitis	None	xix.3	SD at week 24+	Yes
29	63	202	1.8	ii.4	0.vi	Study	10	Liver	None	Interleukin-2	ix.6	SD at week 38+	Yeah
32	sixty	240	2.4	ii.1	-0.3	Standard	3	Liver, Brain	None	None	8.ix	PD at calendar week 28	Yeah
37	55	296	1.iv	ii.7	one.iii	Standard	iii	Brain, Soft Tissue	None	Temozolomide, Everolimus	7.half dozen	SD at week 30+	Yep
27	54	169	1.three	1.half-dozen	0.3	Study	x	Liver, Lung	None	Selumetinib, Pegylated arginine deiminase	41.6	PR at week 140+	Yes
21	68	185	1.6	two.62	1.02	Standard	3	Liver, Skin, Soft Tissue	G1 rash	Temozolomide	fifteen.five	CR at week fifty+	Yes

Past the mWHO criteria, at first radiographic assessment (week 12), one CR and xv SD were observed. Seventeen patients had PD at the time of the beginning scan. Two patients classified as SD by the irRC were reclassified equally having PD by mWHO given the appearance of new lesions. One patient was initially classified as having SD but entered greater than l% tumor reduction at approximately week 100. In evaluation of the total study accomplice at final follow-up, the overall response charge per unit by mWHO was identical to the response rate by the irRC (five.1%, ii/39 patients).

The changes in disease burden from baseline by individual patient are shown in Effigy ane. The patient who accomplished a CR past both irRC and mWHO was treated with ipilimumab at 3 mg/kg and has had a durable response currently ongoing at 62 weeks. This patient had received handling with temozolomide chemotherapy prior to ipilimumab and experienced class 1 rash during handling. Sites of responding disease in this patient included liver, soft tissue and skin metastases. The patient who achieved mWHO SD only tardily irPR by irRC was previously treated with selumetinib and pegylated arginine deiminase. This response is on-going at 140 weeks. This patient had late toxicity with the development of form four uveitis approximately 2.v years post-obit the initiation of ipilimumab. Sites of responding disease included brain and soft tissue metastases. Some other notable patient achieved irSD though had pregnant tumor shrinkage through both 12 and 23 weeks. This patient was previously treated with temozolomide and everolimus and the response to ipilimumab is on-going at xxx.four weeks. Sites of responding disease in this patient included liver and lung metastases. Farther clinical details for patients with response or stable disease at 23 weeks are described in Tabular array 2B.

Change in disease burden for each patient over time

Star indicates that patient 27 experienced initial irSD, inbound irPR at approximately week 100 with on-going response at week 140 and patient 21 experienced irCR that is on-going at week 62.

The biochemical parameters of patients experiencing response or SD at at last follow up included LDH level that was within normal limits in all but iii patients, with ii of those beingness just slightly out of range. All patients experiencing experiencing response or SD at last follow up had a ascent in ALC from baseline to week 7 (median increase of 600 cells/μL), except for one patient who had a very slight decrease of 300 cells/μL. Half of patients obtaining response or SD at final follow up experienced irAE including two patients with irSD who experienced grade 3 hepatitis and grade four hypophysitis, respectively.

Overall Survival Analysis

After a median follow-up of 12.vi months for survivors, the median overall survival by Kaplan-Meier methodology for the entire accomplice was nine.6 months, with a 95% confidence interval (CI) of half-dozen.3 to 13.4 months (Figure 2). In univariate analysis, neither dose of ipilimumab (3 mg/kg vs. x mg/kg) nor baseline ALC (depression vs. normal) was significantly associated with survival (log-rank p=0.41 and 0.10, respectively). Nonetheless, ECOG performance status (0 vs 1-2, log-rank p < 0.0001), lines of prior handling (0 vs any, log-rank p = 0.04) and LDH within normal limits (normal vs. elevated, log-rank p=0.005) were associated with improved survival. The median length of time between diagnosis of metastatic cancer and first dose of ipilimumab was 12.one months (range 0.6 to 47 months). Based on a multivariable Cox proportional hazard model of overall survival with ECOG condition and LDH class as covariates, ECOG condition of 0 demonstrated an 87% reduction in the chance of death compared with ECOG 1-2 (hazard ratio (HR): 0.13, 95% CI (0.04 to 0.44), p=0.001) and LDH within institutional normal limits showed an 82% reduction in the chance of death (Hr: 0.18, 95% CI (0.05 to 0.73), p=0.02).

Overall survival for entire cohort

The median overall survival for the total cohort was nine.6 months, 95% CI (vi.3 to 13.4 months).

A landmark analysis of week 7 ALC indicated statistically significant differences in OS between normal and low ALC levels (Figure iii). For the 31 patients who were alive and had ALC measurements at week 7, ALC ≥1000 cells/μL (n = 22) was associated with a median Os of 13.four months, 95% CI (9.6 to ∞) compared with a median of iv.8 months, 95% CI (3.half dozen to 7.0) in patients with ALC < 1000 cells/μL (northward=nine) (log-rank p=0.004). All patients with SD, PR or CR at 23 weeks had ALC ≥thousand cells/μL at week 7. The landmark analysis excluded six patients with survival times less than vii weeks and ii additional patients with ALC missing at week 7.

Overall survival stratified by ALC at seven weeks

ALC ≥ one (Solid Line): median overall survival of 13.4 months, 95% CI (ix.vi to ∞), ALC < 1 (Dotted Line): median overall survival of four.8 months, 95% CI (iii.half dozen to 7.0).

Toxicity Analysis

The overall incidence of irAE was 71.viii% (Table iii). Rash was the virtually common irAE, affecting 11 patients. Two patients had diarrhea and in both cases, grade 3 colitis was confirmed via colonoscopy. These patients were treated with intravenous corticosteroids followed by tiresome steroid taper with rapid resolution of diarrhea. There were four patients reported to take thyroiditis (form i), i patient each with hepatitis and pancreatitis (both grade 3) and two patients reported to have hypophysitis (both form 3). One patient experienced grade 4 uveitis. Patients with course iii-4 liver and pancreatic toxicities received prompt corticosteroid intervention with resolution of symptoms in all cases without recurrence afterwards steroid taper. Some patients required systemic steroids for direction of irAEs. Ii patients with thyroiditis and both patients with hypophysitis required on-going hormone replacement after ipilimumab treatment. The patient with uveitis had significant vision loss impacting her activities of daily living that has persisted despite attempted corticosteroid pulse and taper. Though numbers were small, the overall incidence of immune-related toxicities was greater in patients receiving ten mg/kg vs. 3 mg/kg: 67.vi% (23 of 34) of patients receiving 3 mg/kg had irAEs of any course compared with 100% of patients at 10 mg/kg (5 of 5). However, the comparison was non statistically significant (Fisher'due south exact p-value = 0.xxx). The rates of grade 3-4 events were higher, though not statistically significant, in the x mg/kg group (2 of 5, xl%) compared with the 3 mg/kg grouping (5 of 34, 14.7%) (Fisher's verbal p-value = 0.21).

Table iii

Toxicities

	Ipilimumab 3 mg/kg				Ipilimumab ten mg/kg				Total
irAE	Whatever G	%	G3-4	%	Whatsoever G	%	G3-four	%	Any K	%	G3-4	%
Dermatitis	14	41.two%	0	0.0%	2	40.0%	0	0.0%	16	41.0%	0	0.0%
Colitis	3	eight.8%	2	5.9%	0	0.0%	0	0.0%	3	7.7%	ii	5.1%
Thyroiditis	3	8.8%	0	0.0%	1	20.0%	0	0.0%	4	10.three%	0	0.0%
Uveitis	1	2.9%	1	2.9%	0	0.0%	0	0.0%	1	two.6%	ane	ii.6%
Pancreatitis	ane	2.9%	1	2.9%	0	0.0%	0	0.0%	1	2.6%	ane	2.half dozen%
Hepatitis	0	0.0%	0	0.0%	one	20.0%	i	20.0%	1	2.six%	one	ii.vi%
Hypophysitis	one	2.nine%	ane	ii.9%	1	20.0%	one	20.0%	ii	five.one%	2	5.i%
Total	23	67.half-dozen%	5	fourteen.seven%	5	100.0%	2	40.0%	28	71.8%	7	17.nine%

Discussion

Our retrospective study evaluating the activity of ipilimumab in 39 patients from iv academic centers in the Usa and Europe is the largest report to date of the activity of ipilimumab in uveal melanoma and provides the first evidence that ipilimumab tin can generate mWHO and irRC responses, equally well as stable disease, in patients with metastatic uveal melanoma. The response charge per unit at last follow upwards in our study was 5.1%. This is similar to the reported response rates for ipilimumab in cutaneous melanoma of iv.2-10.9% and is higher than any published therapy specifically for uveal melanoma.^{15, 22, 23} The median overall survival by Kaplan-Meier methodology in our study was 9.6 months. Several patients had on-going on-going stable illness at the fourth dimension of the analysis, with two patients having durable responses of >lx weeks. These durable responses underscore the potential utility of allowed-cheque point blockade for the treatment of patients with metastatic uveal melanoma.

The toxicity of ipilimumab in our series also suggests that it can be given safely in this patient population. Previous descriptions of grade 3-four toxicities with ipilimumab take reported rates around 10%.¹⁸ The grade 3-4 toxicity rate in this study is higher, at 17.9%; however this appears to have been weighted by those patients who received ten mg/kg of ipilimumab. Importantly, all grade three-4 irAEs, with the exception of uveitis in a patient who had been treated for over 2 years, resolved with prompt initiation of high-dose corticosteroids followed by a slow steroid taper. This is like to what has been described in the management of irAE in cutaneous melanoma and underscores the need for vigilance by the treating medico regarding these potential events.

In that location take been many studies published on various handling regimens for metastatic uveal melanoma though no clear standard therapy exists. Multiple reviews of chemotherapy take described response rates in the unmarried digits.^{ix, ten} Biochemotherapy, by and large combining cisplatin, vinblastine, dacarbazine with interleukin-2 and interferon-α, has been advocated in retrospective assay to be associated with improved survival nevertheless the treatment is associated with pregnant toxicity which many patients volition be unable to tolerate.²⁴

More recently, in that location has been a focus on the emerging molecular biological science of uveal melanoma. Preliminary efficacy has been reported for an ongoing randomized stage II study of selumetinib versus temozolomide, with responses observed in four of 21 (19%) patients treated with the MEK inhibitor.²⁵ However, in the stage I study of the MEK inhibitor trametinib, eight of 16 patients with uveal melanoma met criteria for SD though no responses were seen and the median progression free survival was merely ane.8 months.²⁶ In a stage II trial of the VEGF-trap, aflibercept, 5 of ten patients with uveal melanoma were noted to exist progression free at 4 months, though in that location were no responses seen.²⁷

While several of these molecularly targeted approaches are promising, durable benefit remains elusive. In our report of ipilimumab, two patients (v.1%) had responses and nine (23.1%) had SD lasting beyond 33 weeks by irRC and mWHO. This is similar to what has been described for ipilimumab in cutaneous melanoma where a "tail on the curve" phenomenon indicates that some patients have durable clinical benefit over years.²⁸ Fifty-fifty removing the potential for long term benefit however, we observed three and six calendar month stable disease rates of 46.1% and 28.two%. Prior experiences with DTIC and temozolomide in metastatic uveal melanoma have reported median progression times of approximately one.five months, and a progression-costless survival of iv months has been proposed as a significant improvement in stable affliction for uveal melanoma in clinical trials (ClinicalTrials.gov Identifier: NCT01143402). Though our data is express past its retrospective nature, ipilimumab seems to compare favorably to other published systemic therapies for patients with metastatic uveal melanoma.

Our data also suggest that the timing for use of ipilimumab may be of import also. Though sample sizes are pocket-sized, nosotros observed significant associations between both ECOG performance condition and LDH with survival from the time of ipilimumab treatment. This suggests that the maximum benefit from ipilimumab is likely to come early in the handling course of these patients, prior to acceleration of cancer growth and pass up in functional status. Early on treatment is also reinforced by the possibility for late allowed induction with anti-tumor upshot. Though we did not observe a patient who met criteria for progression with subsequent response, we did observe a patient with SD who eventually adult a PR. Allowing fourth dimension for late induction of an immune-related anti-tumor event can exist difficult and this emphasizes the importance of performance condition in consideration of ipilimumab treatment.

Information technology has been suggested that ascent in ALC during ipilimumab treatment may associated with clinical benefit and overall survival.²⁰ We noted ten of xi patients obtaining response or SD at terminal follow up had a ascension in ALC and that ALC ≥m cells/μL at week 7 significantly stratified patients past median overall survival (thirteen.4 versus four.8 months, log-rank p = 0.004). All patients experiencing response or SD at last follow upwardly had ALC ≥1200 cells/μL at seven weeks. These data recommend ALC at week vii for further report equally a biomarker of activity for ipilimumab in uveal melanoma. Given the aggressiveness of this disease, the potential for an early biomarker of treatment efficacy would exist very useful in the clinical management uveal melanoma.

Our investigation is limited by several factors. Toxicities were captured past chart review and thus may have led to a bias toward under-reporting, though the fact that just over half of the patients were treated on a clinical protocol may aid to alleviate this to some degree. Additionally, though the databases of four melanoma referral centers were utilized, the study sample size of 39 patients is relatively small. As such, the data may exist subject to variability with obfuscation of significant differences that might exist among different patient sub-sets. Finally, our cohort was heterogeneous with patients treated on protocol and off, in various lines of therapy and with dissimilar doses of ipilimumab.

Despite these limitations, this investigation represents a robust evaluation of the clinical experience with ipilimumab in patients with metastatic uveal melanoma and is the first to report responses to ipilimumab in patients with uveal melanoma. A further forcefulness of this written report is that approximately half of our patients were treated off protocol in a standard clinical do setting, as compared with prior reports where patients were restricted to an expanded admission program (ClinicalTrials.gov Identifier: NCT00495066). Further, by drawing on the feel from four academic centers, we may have minimized institutional biases that might be present inside a single center.

It appears that further exploration of the molecular biology of uveal melanoma will pb to novel targeted therapeutic strategies; however, our data suggest that ipilimumab is a treatment that can induce responses or stable disease for some patients and is already available in standard practice. The toxicity we observed was manageable and not significantly dissimilar than that seen in the treatment of metastatic cutaneous melanoma. Prospective studies of ipilimumab in metastatic uveal melanoma are on-going to improve delineate the exact clinical utility of this amanuensis. Based on our data, we would advise that ipilimumab exist considered a reasonable therapeutic selection for this patient population. Patients with uveal melanoma should be included in future clinical studies evaluating novel immunotherapeutic approaches.

Acknowledgments

Funding: This work had no specific funding

Footnotes

Disclosure: Dr's Wolchok and Hodi have served as consults to Bristol-Myers Squibb

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986037/

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