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Keywords:

  • uveal melanoma;
  • ipilimumab;
  • cytotoxic T-lymphocyte—associated protein 4;
  • immunotherapy;
  • absolute lymphocyte count

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.

METHODS

To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated.

RESULTS

Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥1000 cells/μL at week 7 were associated significantly with survival.

CONCLUSIONS

In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed. Cancer 2013;119:3687–3695. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Uveal melanoma is a rare form of melanoma that represents approximately 3% to 5% of the incidence of cutaneous melanomas.[1] Metastasis in uveal melanoma is common, and approximately 50% of patients develop distant cancer within 15 years of their 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 G protein-α (GNA) subunits GNAQ and GNA11 have been reported in approximately 80% of uveal melanomas.[3] GNAQ and GNA11 mutations, however, are not correlated with disease-free survival or the development of metastasis.[4]

The outcome 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 achieve durable responses in patients with uveal melanoma. Treatment with dacarbazine (DTIC), carmustine (BCNU), cisplatin, and tamoxifen (the Dartmouth regimen) reportedly produced a response rate of 6%; and a phase 2 study of carboplatin, paclitaxel, and sorafenib produced no objective responses.[7, 8] A retrospective review of 143 patients who received chemotherapy at The University of Texas MD Anderson Cancer Center reported a single objective response, and other reviews by the Eastern Cooperative Oncology Group (ECOG) and Southwestern Oncology Group described similar findings.[9, 10]

Immunotherapy for the treatment of metastatic uveal melanoma, as a concept, also has been of interest. It is hypothesized that uveal melanoma may be more immunogenic than other tumors, because it arises in the immunologically privileged site of the eye. Furthermore, uveal melanoma has high expression of multiple cancer antigens known to be immunogenic, including glycoprotein 100 (gp100), melanoma associated antigen (MAGE), melanoma antigen recognized by T cells (MART-1) and tyrosinase related protein 1 (TRP 1).[11, 12] Clinical experience with immunotherapy in uveal melanoma is limited, with case reports describing success; however, larger series have demonstrated equivocal benefit.[13, 14]

Ipilimumab (Bristol-Myers Squibb, Princeton, NJ) is a fully human monoclonal antibody that augments antitumor immunity through blockade of cytotoxic T-lymphocyte–associated antigen 4. Ipilimumab became 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, however, has not been well described. A retrospective series of 13 patients with metastatic uveal melanoma who received ipilimumab reported 3 patients with stable disease as the best response,[16] and a smaller review described 2 of 5 patients with stable disease at 11 months.[17] Only preliminary data have been presented describing patients with uveal melanoma who received ipilimumab in expanded-access programs.[18] Given the limited therapeutic options available to patients with uveal melanoma, determining the efficacy of ipilimumab in uveal melanoma is essential.

We conducted a multicenter, retrospective analysis of 39 patients with metastatic uveal melanoma who received treatment with ipilimumab under an expanded-access clinical program or using commercial drug. We report the clinical activity and toxicity observed from 4 academic hospitals in the United States and Europe.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patients and Clinical Characteristics

After obtaining institutional review board approval at each site, patients with metastatic uveal melanoma who had received treatment with ipilimumab were identified from the databases of 4 institutions (Dana-Farber Cancer Institute, Massachusetts General Hospital, and Memorial Sloan-Kettering Cancer Center in the United States and the University Hospital of Lausanne in Switzerland). Patients who were treated on clinical protocols and with commercial drug were included. Patients who had received ipilimumab in combination with other agents or as reinduction therapy were excluded. Relevant clinical parameters were collected, including age, sex, ECOG performance status, site(s) of metastatic disease, lines of prior therapy, and ipilimumab dose received. Laboratory parameters also were collected, including the lactate dehydrogenase (LDH) level at the time of first ipilimumab infusion and the absolute lymphocyte count (ALC) both before treatment and approximately 7 weeks after the initiation of therapy. Treatment response and safety data also were determined. All data were aggregated after patient deidentification.

Efficacy and Toxicity Assessment

Efficacy outcomes were determined by a radiologist at each site who was blinded to outcome. Beneficial effects of ipilimumab were categorized as a complete response (CR), a partial response (PR), or stable disease (SD). The response plus SD rate was calculated as the percentage of patients who achieved a CR, a PR, or SD at 12 weeks, 23 weeks, or later after starting ipilimumab treatment. Immune-related response criteria (irRC) and modified World Health Organization (mWHO) criteria were applied to determine each patient's response.[19] Overall survival (OS) was calculated using the Kaplan-Meier method from the first dose of ipilimumab to the date of death from any cause. Toxicity was assessed through chart review and was graded using Common Terminology Criteria for Adverse Events (version 4.0). Special attention was given to events of special interest or to immune-related adverse events (irAE), including rash, colitis, hepatitis, thyroiditis, and hypophysitis.

Univariate comparisons of OS for ipilimumab dose (10 mg/kg or 3 mg/kg), baseline LDH, ECOG performance status, and ALC were conducted using Kaplan-Meier estimates; and differences were assessed using the log-rank test. LDH was divided into categories above or below the institutional upper limit of normal; ALC was divided into low ALC (<1000 cells/μL) and normal ALC (≥1000 cells/μL). ECOG performance status was classified as fully active versus any restriction (0 vs 1-2). Statistically significant predictors that were identified in the univariate comparisons were then included in a multivariable Cox proportional hazards regression model. The Cox regression model was stratified according to the number of prior therapies (treatment-naive vs other) to allow for underlying differences in the baseline hazard of death between these 2 groups. Landmark analyses also were conducted to compare OS between 7-week ALC levels (low vs normal), because this has been suggested as a biomarker of ipilimumab efficacy in patients with cutaneous melanoma.[20, 21] Comparisons of rates of adverse events were based on the Fisher exact test. Statistical significance was defined as P < .05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient and Clinical Characteristics

The clinical characteristics of the 39 patients who were included in the analysis are listed in Table 1. Patients were predominately men, the median age was 61 years, and the median ECOG status was 0. The median number of prior therapies was 1, and approximately 50% of patients were treated as part of the Bristol-Myers Squibb expanded-access clinical protocol (CA184045). Five patients (13%) received ipilimumab at 10 mg/kg, and the others received 3 mg/kg. The median number of ipilimumab doses was 4 (range, 1-16 doses). Three patients received maintenance dosing.

Table 1. Patient Characteristics, N = 39
CharacteristicNo. of Patients (%)
  1. Abbreviations: ALC, absolute lymphocyte count; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase.

Age: Median [range], y61 [39–84]
Sex 
Men23 (59)
Women16 (41)
Pretreatment ECOG PS 
Median [range]0 [0–2]
022 (56)
18 (21)
24 (10)
Unknown5 (13)
Sites of metastatic disease in ≥5% of patients 
Liver32 (82)
Lung15 (38)
Bone9 (23)
Soft tissue7 (18)
Skin3 (8)
Lymph node3 (8)
Pancreas2 (5)
Brain2 (5)
Pretreatment LDH: Median [range], U/L300 [171–5132]
No. of patients with elevated LDH (%)30 (63)
Pretreatment ALC: Median [range], ×1000 cells/μL1.2 [0.5–2.66]
Prior lines of therapy 
04 (10)
122 (56)
29 (23)
≥34 (10)
Median no. of prior lines of therapy [range]1 [0–5]
Ipilimumab dose, mg/kg 
334 (87)
105 (13)
Median dose, mg/kg3
Median no. of doses [range]4 [1–16]
Received protocol drug21 (54)
Received commercial drug18 (46)

Response Analysis

Of the 39 total patients identified, 35 were evaluable for radiographic assessment of changes in tumor burden after ipilimumab. The 4 patients who were not assessable either died before the assessment of change in tumor burden or were transitioned to palliative care only without subsequent imaging. We assumed that these patients had developed progressive disease, and they were included in all analyses.

Because tumor assessments were performed both on and off protocol, the timing of restaging radiography varied somewhat in the study population. With that caveat, we observed that the first through fourth scans took place at a median of 10.7 weeks, 16.1 weeks, 23.0 weeks, and 31.3 weeks, respectively. When adjusting for the 12 patients who were restaged before completing ipilimumab induction (before 10 weeks), the median time to the first scan was 12.0 weeks. In the 12 patients who underwent early restaging, the median time to the first scan was 6.2 weeks.

According to irRC, at the time of the first radiographic assessment (approximately week 12), there was 1 immune-related CR (irCR), and 17 patients had immune-related SD (irSD). The irCR was confirmed on subsequent scans, and it is noteworthy that 1 patient who had irSD at weeks 12 and 23 developed a late response, achieving an immune-related PR (irPR) at approximately week 100. Before week 23, 6 patients with irSD had progressive disease (PD). One patient with irSD had a confirmatory scan for SD but still was not evaluable at week 23. In addition, 3 patients who had irSD at weeks 12 and 23 later had PD (at weeks 28, 31, and 33). Data on response and the response plus SD rate are listed in Table 2. In an evaluation of the total study cohort (median follow-up, 50.4 weeks [12.6 months]), 1 patient had an irCR, 1 patient had an irPR, and 6 patients had irSD. Seventeen patients had PD at the time of the first scan; however, only 7 of those patients had the required follow-up scan documenting progression, as required by irRC. The response rate in total follow-up by irRC was 5.1% (2 of 39 patients).

Table 2. Clinical Outcomes for Benefiting Patients
 No. of Patients
Outcome VariableAt Last Follow-UpAt 12 WeeksAt 23 Weeks
  1. Abbreviations: CR, complete response; PR, partial response; RR, response rate; SD, stable disease.

CR111
PR100
SD61710
RR, %5.12.62.6
CR + PR + SD, %20.546.128.2

According to mWHO criteria, at the first radiographic assessment (week 12), 1 patient had a CR, and 15 patients had SD. Seventeen patients had PD at the time of the first scan. Two patients who were classified with SD according to irRC were reclassified with PD according to mWHO criteria given the appearance of new lesions. One patient was classified initially with SD but had >50% tumor reduction at approximately week 100. In an evaluation of the entire study cohort, at last follow-up, the overall response rate according to mWHO criteria was identical to the response rate according to irRC (5.1%; 2 of 39 patients).

The changes in disease burden from baseline by individual patient are illustrated in Figure 1. The patient who achieved a CR according to both irRC and mWHO criteria received ipilimumab at 3 mg/kg and achieved a durable response that is currently ongoing at 62 weeks. This patient had previously received temozolomide chemotherapy before ipilimumab and experienced grade 1 rash during treatment. Sites of responding disease in this patient included liver, soft tissue, and skin metastases. The patient who achieved SD according to mWHO criteria but had a late irPR according to irRC had previously received selumetinib and pegylated arginine deiminase. The response in this patient is ongoing at 140 weeks. This patient had late toxicity with the development of grade 4 uveitis approximately 2.5 years after the initiation of ipilimumab. Sites of responding disease included brain and soft tissue metastases. Another noteworthy patient achieved irSD and had significant tumor shrinkage through both week 12 and week 23. This patient was had previously received temozolomide and everolimus, and the response to ipilimumab is ongoing at 30.4 weeks. Sites of responding disease in this patient included liver and lung metastases. Further clinical details for patients who had a response or SD at 23 weeks are described in Table 3.

image

Figure 1. Change in disease burden is illustrated for each patient over time. Stars indicate Patient 27, who experienced an initial response of immune-related stable disease, had an immune-related partial response at approximately week 100, and had an on-going response at week 140; and Patient 21, who experienced an immune-related complete response (irCR) that was ongoing at week 62.

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Table 3. Details of Patients Benefiting at 6 Months
   ALC, ×1000 cells/μL        
Patient No.Age, yPre LDH, U/LPretreatmentAt 7 WeeksChangeStudy vs Standard PracticeDose, mg/kgSites of Metastatic Disease at BaselineirAEPrior RxTime From First Dose to Death or Follow-Up, moCurrent StatusAlive
  1. Abbreviations: CR, complete response; irAE, immune-related adverse event; PR, partial response; Pre, pretreatment; RR, response rate; Rx, treatment; SD, stable disease.

8513761.221.880.66Standard3Liver, lung, soft tissueNoneGanetespib10.8PD at wk 31No
19441761.923.071.15Standard3Liver, lungGrade 1 rashNone6.6SD at wk 26+Yes
20492031.521.930.41Standard3LungGrade 2 rashNone11.7SD at wk 39+Yes
226623630.841.20.36Standard3Liver, pancreas, lymph nodesNoneTemozolomide8.1SD at wk 32+Yes
25763121.31.40.1Study10LiverGrade 3 hepatitisPegylated arginine deiminase19.0PD at wk 33No
28601331.51.80.3Study10LungGrade 3 hypophysitisNone19.3SD at wk 24+Yes
29632021.82.40.6Study10LiverNoneInterleukin-29.6SD at wk 38+Yes
32602402.42.1−0.3Standard3Liver, brainNoneNone8.9PD at wk 28Yes
37552961.42.71.3Standard3Brain, soft tissueNoneTemozolomide, everolimus7.6SD at wk 30+Yes
27541691.31.60.3Study10Liver, lungNoneSelumetinib, pegylated arginine deiminase41.6PR at wk 140+Yes
21681851.62.621.02Standard3Liver, skin, soft tissueGrade 1 rashTemozolomide15.5CR at wk 50+Yes

Biochemical parameters of the patients who experienced a response or had SD at last follow-up included an LDH level that was within normal limits in all but 3 patients, and, in 2 of those patients, the level was just slightly out of range. All patients who experienced a response or had SD at last follow-up had a rise in ALC from baseline to week 7 (median increase, 600 cells/μL), except for 1 patient who had a very slight decrease of 300 cells/μL. Half of the patients who obtained a response or had SD at last follow-up experienced irAEs, including 2 patients with irSD who experienced grade 3 hepatitis and grade 4 hypophysitis, respectively.

Overall Survival Analysis

After a median follow-up of 12.6 months for survivors, the median OS for the entire cohort according to the Kaplan-Meier method was 9.6 months (95% confidence interval [CI], 6.3-13.4 months) (Fig. 2). In univariate analysis, neither ipilimumab dose (3 mg/kg vs 10 mg/kg) nor baseline ALC (low vs normal) was associated significantly with survival (log-rank P = .41 and P = .10, respectively). However, ECOG performance status (0 vs 1-2; log-rank P < .0001), lines of prior treatment (0 vs any; log-rank P = .04), and an LDH level within normal limits (vs elevated LDH; log-rank P = .005) were associated with improved survival. The median time between a diagnosis of metastatic cancer and the first ipilimumab dose was 12.1 months (range, 0.6-47 months). On the basis of a multivariable Cox proportional hazards model of OS in which ECOG status and LDH were included as covariates, an ECOG performance status of 0 indicated an 87% reduction in the hazard of death compared with a performance status of 1 or 2 (hazard ratio, 0.13; 95% CI, 0.04-0.44; P = .001), and an LDH level within institutional normal limits indicated an 82% reduction in the hazard of death (hazard ratio, 0.18; 95% CI, 0.05-0.73; P = .02).

image

Figure 2. Overall survival is illustrated for the entire cohort. The median overall survival for the total cohort was 9.6 months (95% confidence interval [CI], 6.3-13.4 months).

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A landmark analysis of the ALC at week 7 indicated a statistically significant difference in OS between patients with normal and low ALC (Fig. 3). For the 31 patients who were alive and had ALC measurements at week 7, an ALC ≥1000 cells/μL (n = 22) was associated with a median OS of 13.4 months (95% CI, 9.6 to ∞) compared with a median OS of 4.8 months (95% CI, 3.6-7.0 months) in patients who had an ALC <1000 cells/μL (n = 9; log-rank P = .004). All patients who had SD, a PR, or a CR at 23 weeks had an ALC ≥1000 cells/μL at week 7. The landmark analysis excluded 6 patients who had survival times <7 weeks and 2 additional patients who were missing an ALC measurement at week 7.

image

Figure 3. This graph illustrates overall survival stratified by absolute lymphocyte count (ALC) at 7 weeks. For patients who had an ALC ≥1000 cells/μL at 7 weeks (solid line), the median overall survival was 13.4 months (95% confidence interval, 9.6 months to ∞). For patients who had an ALC <1000 cells/μL at 7 weeks (dashed Line), the median overall survival was 4.8 months (95% confidence interval, 3.6-7.0 months).

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Toxicity Analysis

The overall incidence of irAEs was 71.8% (Table 4). Rash was the most common irAE, affecting 11 patients. Two patients had diarrhea; and, in both patients, grade 3 colitis was confirmed by colonoscopy. These patients received intravenous corticosteroids followed by slow steroid taper and experienced a rapid resolution of diarrhea. There were 4 patients reported with thyroiditis (grade 1), 1 patient each with hepatitis and pancreatitis (both grade 3), and 2 patients with hypophysitis (both grade 3). One patient experienced grade 4 uveitis. Patients with grade 3 or 4 liver and pancreatic toxicities received prompt corticosteroid intervention, and all patients experienced the resolution of symptoms without recurrence after steroid taper. Some patients required systemic steroids for the management of irAEs. Two patients with thyroiditis and both patients with hypophysitis required ongoing 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. Although the numbers were small, the overall incidence of immune-related toxicities was greater in patients who received ipilimumab 10 mg/kg versus 3 mg/kg. Twenty-three of 34 patients (67.6%) who received 3 mg/kg had irAEs of any grade compared with 5 of 5 patients (100%) who received 10 mg/kg. However, the comparison was not statistically significant (Fisher exact test; P = .30). The rates of grade 3 and 4 adverse events were higher, although not statistically significant, in the 10-mg/kg group (2 of 5 patients; 40%) compared with the 3-mg/kg group (5 of 34 patients; 14.7%; Fisher exact test; P = .21).

Table 4. Toxicities
 No. of Patients (%)
 Ipilimumab 3 mg/kgIpilimumab 10 mg/kgTotal
irAEAny GradeGrade 3–4Any GradeGrade 3–4Any GradeGrade 3–4
  1. Abbreviations: CR, complete response; irAE, immune-related adverse event; PR, partial response; RR, response rate; SD, stable disease.

Dermatitis14 (41.2)0 (0)2 (40)0 (0)16 (41)0 (0)
Colitis3 (8.8)2 (5.9)0 (0)0 (0)3 (7.7)2 (5.1)
Thyroiditis3 (8.8)0 (0)1 (20)0 (0)4 (10.3)0 (0)
Uveitis1 (2.9)1 (2.9)0 (0)0 (0)1 (2.6)1 (2.6)
Pancreatitis1 (2.9)1 (2.9)0 (0)0 (0)1 (2.6)1 (2.6)
Hepatitis0 (0)0 (0)1 (20)1 (20)1 (2.6)1 (2.6)
Hypophysitis1 (2.9)1 (2.9)1 (20)1 (20)2 (5.1)2 (5.1)
Total23 (67.6)5 (14.7)5 (100)2 (40)28 (71.8)7 (17.9)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Our retrospective study evaluating the activity of ipilimumab in 39 patients from 4 academic centers in the United States and Europe is the largest report to date of the activity of ipilimumab in uveal melanoma and provides the first evidence that ipilimumab can generate mWHO criteria and irRC responses, as well as SD, in patients with metastatic uveal melanoma. The response rate at last follow-up in our study was 5.1%. This is similar to the reported response rates for ipilimumab in patients with cutaneous melanoma of 4.2% to 10.9% and is higher than any published therapy specifically for uveal melanoma.[15, 22, 23] The median OS according to Kaplan-Meier methodology in our study was 9.6 months. Several patients had ongoing SD at the time of the analysis, and 2 patients had durable responses of >60 weeks. These durable responses underscore the potential utility of immune-checkpoint 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 and 4 toxicities with ipilimumab have reported rates of approximately 10%.[18] The grade 3 and 4 toxicity rate in the current study was higher, at 17.9%; however, this appears to have been weighted by those patients who received 10 mg/kg ipilimumab. It is noteworthy that, with the exception of uveitis in a patient who had been receiving treatment for >2 years, all grade 3 and 4 irAEs resolved with prompt initiation of high-dose corticosteroids followed by a slow steroid taper. This is similar to what has been described in the management of irAEs among patients with cutaneous melanoma and underscores the need for vigilance by the treating physician regarding these potential events.

There have been many studies published on various treatment regimens for metastatic uveal melanoma, although no clear standard therapy exists. Multiple reviews of chemotherapy have described response rates in the single digits.[9, 10] Biochemotherapy, generally combining cisplatin, vinblastine, and dacarbazine with interleukin-2 and interferon-α, has been advocated in retrospective analyses and has been associated with improved survival; however, the treatment is associated with significant toxicity, which many patients will be unable to tolerate.[24]

More recently, there has been a focus on the emerging molecular biology of uveal melanoma. Preliminary efficacy has been reported for an ongoing randomized phase 2 study of selumetinib versus temozolomide, with responses observed in 4 of 21 patients (19%) who received the mitogen-activated protein kinase kinase (MEK) inhibitor.[25] However, in the phase 1 study of the MEK inhibitor trametinib, 8 of 16 patients with uveal melanoma met criteria for SD, although no responses were reported, and the median progression-free survival was only 1.8 months.[26] In a phase 2 trial of the VEGF-trap aflibercept, 5 of 10 patients with uveal melanoma reportedly were progression free at 4 months, although no responses were observed.[27]

Although several of these molecularly targeted approaches are promising, durable benefit remains elusive. In our study of ipilimumab, 2 patients (5.1%) had responses, and 9 patients (23.1%) had SD that lasted beyond 33 weeks according to irRC and mWHO criteria. This is similar to what has been described for ipilimumab in patients with cutaneous melanoma, in which a “tail on the curve” phenomenon indicates that some patients have durable clinical benefit over years.[28] Even removing the potential for long-term benefit, however, we observed 3-month and 6-month SD rates of 46.1% and 28.2%, respectively. Prior experiences with DTIC and temozolomide in metastatic uveal melanoma have reported a median time to progression of approximately 1.5 months, and a progression-free survival of 4 months has been proposed as a significant improvement in SD for patients with uveal melanoma in clinical trials (ClinicalTrials.gov Identifier: NCT01143402). Although our data are limited by their retrospective nature, ipilimumab seems to compare favorably with other published systemic therapies for patients with metastatic uveal melanoma.

Our data also suggest that the timing for use of ipilimumab may be important as well. Although the sample sizes were small, we observed significant associations between both ECOG performance status 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 treatment course for these patients, before acceleration of cancer growth and decline in functional status. The case for early treatment also is reinforced by the possibility of late immune induction with antitumor effect. Although we did not observe a patient who met criteria for progression with subsequent response, we did observe a patient with SD who eventually developed a PR. Allowing time for late induction of an immune-related antitumor effect can be difficult, and this emphasizes the importance of performance status when considering ipilimumab treatment.

It has been suggested that a rise in ALC during ipilimumab treatment may be associated with clinical benefit and OS.[20] We noted that 10 of 11 patients who obtained a response or SD at last follow-up had a rise in ALC and that an ALC ≥1000 cells/μL at week 7 significantly stratified patients by median OS (13.4 vs 4.8 months; log-rank P = .004). All patients who had a response or SD at last follow-up had an ALC ≥1200 cells/μL at 7 weeks. These data recommend further study of the ALC at week 7 as a biomarker of activity for ipilimumab in patients with uveal melanoma. Given the aggressiveness of this disease, the potential for an early biomarker of treatment efficacy would be very useful in the clinical management uveal melanoma.

Our investigation was limited by several factors. Toxicities were captured by chart review and, thus, may have led to a bias toward under-reporting, although this may be alleviated to some degree because just over half of the patients were treated on a clinical protocol. In addition, although the databases of 4 melanoma referral centers were used, the study sample size of 39 patients was relatively small. Therefore, the data may be subject to variability with obfuscation of significant differences that could exist among different patient subsets. Finally, our cohort was heterogeneous, the patients were treated both on and off protocol, and they received various lines of therapy and different 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, to our knowledge, is the first report of responses to ipilimumab in patients with uveal melanoma. A further strength of this report is that approximately half of our patients were treated off protocol in a standard clinical practice setting, compared with prior investigations in which patients were restricted to an expanded-access program (ClinicalTrials.gov Identifier: NCT00495066). Furthermore, by drawing on the experience from 4 academic centers, we may have minimized institutional biases that could be present within a single center.

It appears that further exploration of the molecular biology of uveal melanoma will lead to novel, targeted therapeutic strategies; however, our data suggest that ipilimumab is a treatment that can induce responses or SD for some patients, and it is already available in standard practice. The toxicity we observed was manageable and was not significantly different from that observed in the treatment of metastatic cutaneous melanoma. Prospective studies of ipilimumab in metastatic uveal melanoma are ongoing to better delineate the exact clinical utility of this agent. On the basis of our data, we suggest the consideration of ipilimumab as a reasonable therapeutic choice for this patient population. Patients with uveal melanoma should be included in future clinical studies that evaluate novel immunotherapeutic approaches.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Dr. Callahan has acted as a paid consultant to Bristol-Myers Squibb and GlaxcoSmithKline and has received grant support from Bristol-Myers Squibb. Dr. Dickson has acted as paid consultant to Pfizer. Dr. Harding has acted as a paid consultant to MedImmune. Dr. Hodi has received clinical trial support and reimbursement for travel expenses from Bristol-Myers Squibb and has acted as a nonpaid consultant to Bristol-Myers Squibb. Dr. Postow has received grants from Bristol-Myers Squibb and has received reimbursement for travel expenses from Bristol-Myers Squibb for investigator meetings related to immunotherapeutic agents, including ipilimumab. Dr. Wolchok has acted as a paid consultant to Bristol-Myers Squibb and has received reimbursement for travel/accommodations/meeting expenses and grant support from Bristol-Myers Squibb.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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