Ipilimumab (Anti-Ctla-4 Mab) in the treatment of metastatic melanoma: Effectiveness and toxicity management

ABSTRACT

In the last years the onset of new therapies changed the management of malignant melanoma. Anti CTLA-4 antibody ipilimumab was the first drug to achieve a significant improvement in survival of advanced stage melanoma. This new therapeutic agent is characterized by a number of side effects that are totally different from those of traditional chemotherapy, mainly caused by the immune system activation.

The purpose of this paper is to underline the central role of ipilimumab in the treatment of metastatic melanoma and to characterize related adverse events in terms of incidence, duration and severity of presentation. The early recognition of these side effects is crucial in order to ensure an appropriate management of the toxicities, thus reducing the long term clinical sequelae and the inappropriate treatment discontinuation.

Keywords:

• anti-CTL-A4
• ipilimumab
• immunotherapy
• melanoma treatment
• toxicity

Introduction

Malignant melanoma is a neoplasia arising from melanocytes, whose incidence rate has been rising in many Caucasian populations.¹ The etiology is complex and involves host and environmental risk factors such as family history, fair skin, eye and hair color, freckling, poor tanning ability and the presence of numerous nevi.^2,3 The metastatic potential of melanoma is high and it is well known that disease recurrences occur in 15%–35% of patients. Metastatic spread develops primarily as loco-regional recurrence in about two third of cases; however, haematogenous spreading with onset of distant metastases is not uncommon.⁴

Probably, the first description of cutaneous melanoma as a disease entity is attributable to Hippocrates, who first described black herpetic type lesions on the fifth century BC. However, until the beginning of the 21^st century, despite the increasing amount of knowledge of Medical community, no changes in outcome of advanced disease was observed. At the present time, immunotherapy represents a mile stone in the treatment of advanced disease, together with targeted therapies.

Role of immunotherapy in the treatment of malignancies

The role of immune system in the tumor control was detected for the first time in 1957 by Sir Frank Macfarlane Burnet. From that moment, the idea that immune response can be effectively used against tumor was extensively studied, but it was necessary to wait more than twenty years to see the first immunotherapic agents (interleukin-2 and interferon) approved by FDA for the treatment of cutaneous melanoma. The rationale for studying immunotherapies is based on evidence of spontaneous remissions and observed response to biological agents which stimulate the immune system.⁵ High-dose interleukin-2 (IL-2) was validated in the 1990s for advanced melanoma,⁶ showing a 16% objective response rate (ORR). However, these responses are durable only in few patients⁷ and side effects of this regimen were too difficult to tolerate for a significant percentage of subjects. According to main international guidelines, interferon (IFN) in adjuvant setting can be proposed to patients with thick or ulcerated primary lesions (American Joint Committee on Cancer stage IIB or IIC) or with pathological or clinical evidence of regional nodal metastasis (American Joint Committee on Cancer stage III), with a significant improvement of the 5-year survival rate.^8,9

Because of the known immunogenicity of melanoma, current efforts have been focused on improving the presentation of antigens to T cells in order to initiate an antitumor immune response.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) plays an important inhibitory role in the control of T-cell activation. Many studies raised in order to understand new evidences regarding the immunologic synapses and the immune homeostasis, thus leading to the creation of the so called check-point inhibitors.

Ipilimumab characterization

Ipilimumab is a fully humanized IgG1 monoclonal antibody that inhibits cytotoxic T lymphocyte antigen-4 (CTLA-4).^10,11 In 1987, Brunet et al. described cytotoxic CTLA-4, a 223–amino-acid protein belonging to the immunoglobulin superfamily mainly expressed in activated lymphocytes and co-induced with T-cell–mediated cytotoxicity.¹² The human homolog of the gene was subsequently cloned in 1988.¹³ CTLA-4 is a member of the CD28 family receptors and it is inducibly expressed on the activated CD4+ and CD8+ T lymphocytes' surface.^14,15 B7.1 and B7.2 are CTLA-4 ligands on the antigen presenting cells (APCs); CTLA-4 competes with CD28 to bind B7.1 and B7.2 but shows a higher affinity for them, thus reducing CD28-dependent co-stimulation.¹⁶ Moreover CTLA-4 is constitutively highly expressed on FOXP3+ regulatory T cells, playing a role in their suppressive functions.¹⁷ In fact, when a T cell recognizes a tumor antigen, signaling through the CTLA-4 pathway prevents the co-stimulatory signal, leading to an inhibitory mechanism on the immune response.¹⁰

CTLA-4 mechanism of action has not yet been completely understood. It has been postulated that anti-CTLA-4 antibodies act by blocking inhibitory signals from effector T cells, allowing costimulatory signaling and generation of antitumor T-cell responses. In vitro studies demonstrated also that the antitumor activity of CTLA-4 blockade is mediated by Fc gamma receptor expressing macrophage and hypothesized a possible role of regulatory T cells depletion in tumor microenvironment.^10,18-21

On these bases Ipilimumab has been developed; it was originated by the University of California in Berkeley and then licensed to Mederex, which was later acquired by Bristol-Myers Squibb. On March, 25, 2011 intravenous ipilimumab 3 mg/kg was approved by the US. Food and Drug Administration to treat patients with late-stage (metastatic) melanoma regardless of line of therapy.^22,23 Then was promptly added as a category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines of systemic therapy options for advanced or metastatic melanoma.

In Europe Bristol-Myers Squibb filed a marketing application with the EMA in the first half of 2010 for ipilimumab as second-line therapy for metastatic malignant melanoma.²⁴ On November 2013, also EMA approved this drug as first-line treatment.

Ipilimumab had linear pharmacokinetics over the dose range 3 mg/kg to 10 mg/kg. The pharmacokinetic model estimated that the geometric mean clearance of ipilimumab was 14.9 mL/h with 34% inter-patient variability. Clearance increased with increased body weight.²⁵ According to a population pharmacokinetic analysis performed in patients with stage III or IV malignant melanoma (CA184-022), target serum concentrations of ipilimumab were expected to be exceeded in 95% of patients treated at a dose of 10 mg/kg, in approximately 30% of those in the 3 mg/kg group, and none of those in the 0.3 mg/kg group.²⁶

Anti-CTLA-4 antibodies have been evaluated in early clinical trials for other malignancies, such as prostate cancer, renal cell carcinoma, non-Hodgkin lymphoma and non-small cells lung cancer.^27-30

Patterns of response

The pattern of response to ipilimumab is dramatically different from that obtainable with traditional chemotherapy, as consequence of its peculiar mechanism of action.³¹ Responder patients who were treated with conventional chemotherapy shows a rapid reduction of baseline tumor without evidence of new lesions. On the contrary, patients treated with ipilimumab may experience an initial increase in their tumor burden followed by a reduction or a complete disappearance of all lesions. This type of response is believed secondary to infiltrating T-cell conglomerates around the tumors, giving the radiographic appearance of greater tumor size and hence of progressive disease. In other cases, there is a reduction in the total tumor burden but a concomitant appearance of new lesions that may after regress. This event is attributable to a late activation of the immune system and to the fact that the destruction of the tumor by T cells infiltrating occurs slowly.³¹ On the basis of these observations, the new assessment criteria of response were then made, defined as “immune related” (irRC), which have been applied in clinical trials on anti-CTL-A4.^10,31

Preclinical, clinical and safety studies

For decades, agents or combination regimens for treatment of advanced or metastatic melanoma were, at best, able to increase response rates (RR) or progression free survival (PFS) but failed to improve overall survival (OS).³² Ipilimumab was the first drug to demonstrate improvement in OS in this patient population, changing the therapeutic landscape for this disease in early 2011.

In cynomolgus macaques, administration of a CTLA-4 antibody enhanced antibody responses to hepatitis surface antigen and a human melanoma cell vaccine.³³ The injection of anti-CTLA-4 antibodies into mouse models stimulates the rejection of murine tumors such as colon, ovarian and fibrosarcoma models^34,35 and can also lead to autoimmunity in other organs.^36-39 Chemotherapy can potentiate the effects of these antibodies³⁶ thus inducing CTLA-4 knockout mice to develop fatal autoimmunity, resulting from unopposed T cell activation and reaction to self-antigens.^40-42

In several preclinical trials (Table 1)4, CTLA-4 inhibitors have been associated with the administration of GM-CSF-secreting-cell vaccines. In one study, tumor rejection was induced in all mice that were challenged with murine melanoma tumor cells. This synergistic effect was probably due to the combination of enhanced cross-priming of T cells by host antigen-presenting cells activated by the vaccine, and a potentiated T cell response due to the removal of the inhibitory effects of CTLA-4.⁴³ In a study by Gregor et al., CTLA-4 blockade was combined with a xenogeneic DNA vaccine. The blockage of CTLA-4 enhanced B16 tumor rejection in mice immunized against the melanoma differentiation antigens tyrosinase-related protein 2 and gp100.⁴⁴

Table 1. Clinical studies using Ipilimumab alone or in association with other agents.

Phase	Clinical Trial Identifier	Patient category	Therapy	Target receptor	Status
III	NCT00094653	Stage IV melanoma	gp100 ± Ipilimumab	CTLA-4	Completed
III	NCT00324155	Stage IV melanoma	DTIC+Ipilimumab vs DTIC +placebo	CTLA-4	Completed
Pilot	NCT01449279	Stage IV melanoma	Ipilimumab + RT	CTLA-4	Ongoing; recruiting completed 04/2015
I	NCT01557114	Unresectable stage III and IV melanoma	Ipilimumab + RT	CTLA-4	Ongoing; recruiting 03/2016
II	NCT01585194	Uveal melanoma	Nivolumab + Ipilimumab	CTLA-4/PD-1	Recruiting
I	NCT01621490	Unresectable stage III and stage IV	Nivolumab + Ipilimumab	PD-1/CTLA-4	Ongoing; recruiting 08/2017
I	NCT01621490	Stage IV Melanoma;	Nivolumab ± Ipilimumab vs Ipilimumab	CTLA-4/PD-1	Recruiting
II	NCT01689974	Metastatic melanoma	Ipilimumab ± RT	CTLA-4	Ongoing; recruiting 12/2016
I	NCT01703507	Melanoma and brain metastases	Ipilimumab + WBRT/SABR	CTLA-4	Ongoing; recruiting 11/2019
II	NCT01708941	Unresectable stage III and IV melanoma	Ipilimumab ± HD IFNα2b	CTLA-4	Ongoing; recruiting finished 12/2014
I/II	NCT01740297	Unresectable stage IIIb and IV melanoma	Ipilimumab+T-VEC	CTLA-4	Ongoing; recruiting 07/2017
II	NCT01783938	Advanced or Metastatic Melanoma	Ipilimumab + Nivolumab	CTLA-4/PD-1	Active, not recruiting
I	NCT01838200	Stage III and IV melanoma	BCG vaccine (and isoniazid) + Ipilimumab	CTLA-4	Ongoing; recruiting 06/2016
III	NCT01866319	Stage IV Melanoma;	Pembrolizumab vs Ipilimumab	CTLA-4/PD-1	Active, not recruiting
II	NCT01879306	Unresectable stage IV melanoma	AbraxaneTM + Bevacizumab/Ipilimumab	CTLA-4/VEGF-A	Ongoing; recruiting completed 06/2015
I	NCT01940809	Unresectable metastatic melanoma	Ipilimumab ± dabrafenib and/or trametinib	CTLA-4	recruiting completed 02/2015
II	NCT01950390	Unresectable stage III and IV melanoma	Ipilimumab ± Bevicizumab	CTLA-4/VEGF-A	Ongoing; recruiting 01/2016
II	NCT01970527	Stage IV melanoma	SABR + Ipilimumab	CTLA-4	Ongoing; recruiting 09/2016
Ib	NCT01984255	Advanced melanoma	Ipilimumab+Bavituximab	CTLA-4/phospatydylserine	Ongoing; recruiting 08/2017
I	NCT01996202	High-risk melanoma	Ipilimumab + RT	CTLA-4	Ongoing; recruiting 11/2015
II	NCT02054520	Stage IV Melanoma;	HAM/Ipilimumab/Pembrolizumab/Nivolumab	CTLA-4/PD-1	Recruiting
II	NCT02107755	Metastatic melanoma	SABR+Ipilimumab	CTLA-4	Ongoing; recruiting 06/2017
II	NCT02115139	Melanoma and brain metastases	Ipilimumab + RT	CTLA-4	Ongoing; recruiting 10/2016
II	NCT02158520	Unresectable stage IV melanoma	Ipilimumab + AbraxaneTM + Bevacizumab	CTLA-4/VEGF-A	Ongoing; recruiting completed 12/2014
II	NCT02374242	Melanoma and brain metastases	Nivolumab/Ipilimumab	CTLA-4/PD-1	Recruiting
III	NCT02460068	Melanoma and brain metastases	Fotemustine vs Fotemustine+Ipilimumab vs Ipilimumab+Nivolumab	CTLA-4	Recruiting
II	NCT02519322	Oligometastatic melanoma	Nivolumab 1 mg/kg vs 3mg/kg vs Ipilimumab	CTLA-4/PD-1	Not yet open for recruitment
II	NCT02523313	Stage IV Melanoma;	Nivolumab+Placebo vs Nivolumab + Ipilimumab vs Placebo	CTLA-4/PD-1	Recruiting

In initial phase I studies single and repetitive dosing regimens were tested with evidence of efficacy.¹⁰ In several trials conducted at National Cancer Institute, ipilimumab was administered at dosage 3 mg/kg along with a gp100 multipeptide vaccine, and then at doses between 1 mg/kg and 3 mg/kg obtaining responses longer than 2 years in some patients. Patients with onset of an immune-related adverse event (irAE) showed a better clinical response.^45,46 Another important phase I/II study was performed in order to obtain data regarding the pharmacokinetic profile and the clinical activity of the drug. Single and multiple dosing regimens were investigated.⁴⁷ Escalating single doses of up to 20 mg/kg, as well as every-3-weeks dosing at 10 mg/kg, were examined. The group of patients who received 10 mg/kg every 3 weeks had the highest disease control rate. In this trials emerged that the 19% of these patients experienced grade III and IV adverse events.

A study by Maker et al. analyzed the combination of CTLA-4 antibodies with IL-2, hoping to enhance the efficacy of IL-2 on tumor cells. Ipilimumab was given in cohorts of 0.1, 0.3, 1.0, 2.0 or 3.0 mg/kg every three weeks. Thirty-six patients were treated in these different dose cohorts with an objective response rate of 22%. The authors concluded that there was not a synergistic effect of the addition of IL-2 to anti-CTLA-4; the response rate of 22% was the sum of the expected efficacy of these two agents administered alone.⁴⁸

On these basis a randomized, multi-institution, double-blind, dose-ranging study, called CA184-022, was performed; 217 patients affected by previously treated metastatic melanoma were included in this study and randomized to doses of 0.3 mg/kg, 3 mg/kg, 10 mg/kg every 3 weeks. If patients didn't develop a progressive disease at week 24, they were treated with a maintenance administration every 12 weeks. The best overall response rates were 0%, 4.2%, and 11.1% in the 0.3 mg/kg, 3 mg/kg, and 10 mg/kg groups, respectively. In the 10 mg/kg cohort, 30% of patients were alive at 2 years, in comparison with 18% in the 0.3 mg/kg cohort. IrAEs were noticed, respectively, in 0%, 5%, and 18% of patients in the 3 dose cohorts.²⁶

In another phase II trials patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles followed by maintenance therapy every 3 months. The results of this study were consistent with those previously reported and showed a median OS of 10.2 months with a 1-year survival rate of 47.2%.⁴⁹

The efficacy and safety of the combination of ipilimumab plus dacarbazine was tested in a phase II study. Patients received ipilimumab at 3 mg/kg every 4 weeks for 4 doses either alone or with dacarbazine. The RR was 14.3% with ipilimumab plus dacarbazine despite 5.4% with ipilimumab alone.⁵⁰ These data were confirmed in a phase III study on 502 patients with previously untreated metastatic melanoma, randomly assigned in a 1:1 ratio, to ipilimumab 10 mg/Kg plus dacarbazine or dacarbazine plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. OS was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months), with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%).⁵¹

Schadendorf et al. reported an analysis of 1861 patients treated in 12 prospective and retrospective trials. This study reported a median OS of 11.4 months (95% CI: 10.7–12.1). This report also included 254 patients with a 3-year follow-up. Three-year OS rate was 22% for the entire population, 26% for treatment naıve patients, and 20% for previously treated patients. Moreover, three phase II studies^26,47,49 demonstrated 4-year OS rates between 13.8% and 49.5%.

The ipilimumab expanded access program (EAP) included data from 2985 patients affected by metastatic melanoma; the median OS was 9.5 months and the 3-years OS rate was 21%. Notably patients treated in the EAP were more likely to carry unfavorable prognostic factors, such as brain metastatic disease, performance status 2, multiple prior therapies or non- cutaneous (ocular or mucosal) melanoma.⁵²

Altogether, these data demonstrate that ipilimumab provides durable responses and a survival benefit to a subset of patients with metastatic melanoma.

Ipilimumab in the real life

The encouraging results obtained from the multicenter randomized phase III⁵³ and the first-line trials⁵⁴ have rapidly led to the approval from FDA and EMA of ipilimumab in both setting. Thus, the opportunity to treat patients without restrictions and free of charge drives to the publication of numerous works that have given additional information on wider series and with a longer follow-up and on specific groups of patients, such as those with uveal melanoma or brain metastases, that were excluded from the first clinical trials.

Data from the 855 patients enrolled in the Italian expanded access program⁵⁵ showed an objective immune RR of 13%, with a median PFS of 3.7 months and an OS of 7.2 months, confirming the effectiveness of Ipilimumab in pretreated patients. For patients treated in the Netherland,⁵⁶ a median PFS of 2.9 months and an OS of 7.5 months were found, whereas the median OS in the Spanish expanded access program was 6.9 months.⁵⁷ In the same cohorts, the independent prognostic role of LDH was confirmed.^56,57 More recently, a retrospective study on 193 patients treated in UK outside clinical trials has been published.⁵⁸ The follow-up was significantly longer than in other published series (median 23 months); however, the median OS (6.1 months) and 1-year and 2-years OS (31% and 15% respectively) were significantly lower than in registration trial,⁵³ probably due to wider eligibility criteria. Taken together, these data confirmed that anti CTLA-4, despite the low clinical response rates, plays a crucial role in the survival improvement by the enhancement of the immune response.

Both Italian⁵⁵ and UK⁵⁸ expanded access programs gave useful data regarding the possibility of treatment with ipilimumab of advanced uveal melanoma patients, who were excluded from the registration trial due to different biology and behavior. In both series, the outcome of these patients were not significantly different from that of other advanced melanoma patients, with a 1-year OS of 39% and 31%, respectively.

As regards patients with brain metastases, a previous phase II trials demonstrated the activity of ipilimumab at the dose of 10 mg/kg, especially for stable, asymptomatic metastases that do not need corticosteroid treatment.⁵⁹ Patients were stratified on the basis of the presence of symptoms and the concomitant therapy with steroids and received four doses of ipilimumab at 10 mg/kg every 3 weeks. A disease control was reached in 24% of asymptomatic patients and only in 10% of patients with previous neurological symptoms, with similar toxicities. These data were confirmed also by two other studies^60,61 that reported a RR of 25% and 16%, with a control rate of 30% and 41.6% respectively, suggesting a role of ipilimumab in the treatment also of small and asymptomatic brain metastases. The inclusion of patients with brain metastases in the expanded access programs confirmed the possibility of obtaining a response in a small percentage of these patients also for the dose of 3 mg/kg. In the majority of studies,^57,58,62 the median survival in this subgroup of patients remains very low; however, the UK study demonstrated that the overall survival of patients with or without brain metastases was significantly different at 1 year (34 vs. 17%), but was almost superimposable at 2 years (15 vs. 13%), suggesting a possible long-term control of the disease also in this category of patients.

Several studies⁵⁷ confirmed also that in elderly patients the efficacy and tolerability of ipilimumab was similar to that of the overall patient population.

Ipilimumab toxicities

Given its peculiar mechanism of action, the Ipilimumab safety profile is significantly different from that of drugs traditionally used in the treatment of metastatic melanoma. However, irAEs are not uncommon^63-67 and their management requires acquisition of specific skills by the clinicians. The identification and early treatment of these events is in fact needed for the safety of the patient and for guaranteeing the possibility of complete treatment cycles, in order to obtain the best possible outcome.

The ipilimumab-related AEs has been described both at the currently approved 3 mg/kg dose and at the investigational 10 mg/kg dose and may affect a number of organs and systems, including the eye, the skin, the gastroenteric and the endocrine. Recently, the ipilimumab overall safety profile has been evaluated in a retrospective analysis including 14 phase I–III clinical trials on patients with advanced melanomas, without previous history of autoimmune disease or immunosuppressive treatment.⁶⁴ This pooled analysis reported an irAEs incidence of 84.4%, with 25.3% of grade 3/4; nevertheless, irAEs-related deaths occurred only in about 1% of treated patients.⁶⁴ Similar results are more recently published on a large monocentric series, in which the 85% of patients experienced irAEs of any grade and 31% of grade 3-4,⁶⁸ whereas data obtained on an Italian multi-centric expanded access cohort reported an occurrence of irAEs of any grade in 33% of treated patients, with grade 3/4 described in only 6% of the cases.⁵⁵ Patients affected by autoimmune disorders, especially multiple sclerosis, rheumatoid arthritis, and ulcerative colitis are most at risk of developing collateral events, and in fact these conditions represent a potential contraindication to the use of ipilimumab. However, some reports have been recently published about the possibility of using this drug in a safe and effective way also in these patients.⁶⁹

The most common irAEs affect the gastrointestinal tract and include aphthous ulcers, esophagitis, gastritis, diarrhea and colitis.^64,70 Serious complications such as bowel perforation are rare but potentially fatal.⁷⁰ Unfortunately, no specific serological markers for anti-CTLA-4 colitis have been identified to date. Stool test should be performed in order to rule out infectious causes of diarrhea and few reports suggest a potential role of fecal calprotectin as diagnostic or prognostic tool; the sensitivity of fecal leukocytes has not yet been known.⁷¹ Endoscopy shows inflammatory changes, but early examination in absence of symptoms has not a prognostic value.

Other common irAEs include dermatitis, liver toxicity, fatigue and uveitis,⁵⁵ whereas neurotoxicity and pneumonitis are rare.⁶⁸ The most common endocrinopathy related to the Ipilimumab treatment is represented by hypophysitis, that can present as either panhypopituitarism or isolated anterior pituitary hormone deficiency, with or without pituitary enlargement.^72-76 The risk to develop hypopituitarism is estimated around 1-6%⁶⁶ and is higher for males and for those patients who previously received brain radiation.⁷⁶ Enlargement of pituitary or others radiological manifestations compatible with hypophysitis has been found in at least 2/3 of patients with ipilimumab-related hypophysitis and fatigue and headache were the most common symptoms.

The median time of onset of irAEs vary from 3 to 17.3 weeks and the higher incidence of irAEs has been demonstrated after the dose number 2; cutaneous AEs have shorter time to onset than those affecting the gastrointestinal tract, liver, or endocrine system.^65,66 Ipilimumab-related colitis has been described more than 4 months after receiving the last dose.⁷¹ Median time to resolution of longest-lasting irAEs is approximately 20 weeks.

The correct management of irAEs involves prompt medical attention and the early administration of high-dose systemic corticosteroids for grade 3/4 events, whereas grade 1/2 events can take advantage from symptomatic treatments and the use of topical steroids. The duration and intensity of the corticosteroid intervention and the decision of ipilimumab discontinuation are based on the severity of the toxicity.^65,68 Corticosteroids-resistant cases of colitis may respond to infliximab or others tumor necrosis factor-α inhibitors, whereas surgery should be reserved to patients with bowel perforation or failure of medical therapy.⁷¹ A randomized, double-blind, placebo-controlled, phase II study (CA184-007) comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide demonstrated that budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy.⁷⁷ Systemic high dose steroid treatment seems not to improve the outcome of I pilimumab-related hypophysitis.⁷⁸

Specific guidelines to assist health-care professionals in the management of irAEs have been developed on the basis of the experience acquired during clinical trials.^63,65

Extreme caution should be used in the reinitiating therapy with ipilimumab in patients with severe side effects, particularly in those who developed gastrointestinal toxicity of grade 3/4. However, some authors report a significant correlation between the onset of irAEs and response to the drug,^79,80 and therefore the possibility of re-induction must be carefully evaluated.

Future perspectives

The numerous studies that have confirmed the ipilimumab effectiveness in metastatic melanoma have opened the way for further and new possibilities for using it.

Some authors have suggested the possibility of using a customized dose of ipilimumab in individual patients, based on the notion of individual thresholds of antigen recognition.⁸¹ However, the most important question is represented by maintenance therapy and retreatment. As previously demonstrated in a retrospective analysis,⁵⁴ retreatment with ipilimumab can induce durable responses in almost 13% of patients who develop a progressive disease after an initial response or stabilization. So, as recently recommended by the National Comprehensive Cancer Center Network guidelines,⁸² re-induction should be considered for progressive patients who do not experienced previous severe toxicities.

The main current challenge is given by the possibility to combine ipilimumab with other modifiers of the immune system that have different mechanism of action, with the objective of enhancing the effectiveness. Another member of the immune checkpoint modulators family is the programmed death 1 (PD-1) protein that is a co-inhibitory receptor expressed on B cells and activated or exhausted T cells. The PD-1 ligand named PDL-1 is expressed in different tumors and associated with worse prognosis.⁸³ The discover that the PD-1/PD-L1 pathway is used by tumor cells for their own protection from T cells mediated immunological responses led to development of inhibitors of PD-1 pathway, as nivolumab and pembrolizumab; their clinical activity in melanoma is well demonstrated,^84-86 with mainly immune toxicities similar to those described from ipilimumab.⁸⁷ Recent data have demonstrated an additional benefit in term of ORR and OS if ipilimumab is administered in combination with anti-PD-1 agents. In a sequential schedule in which patients were treated with 4 doses of ipilimumab followed by nivolumab,⁸⁸ 40% of objective responses were observed; however, about one-half of the patients experienced grade 3 or 4 treatment-related AEs. Encouraging data regarding the superiority of the combination also emerge from the study recently published by Larkin.⁸⁹ This study included 945 naïve patients that were treated with nivolumab, nivolumab plus ipilimumab or ipilimumab alone, and demonstrate a PFS of 11.5 months for patients treated with the combination, compared to 2.9 months for those treated with ipilimumab and 6.0 months for those treated with nivolumab. Also the ORR of 57.5% obtained by the combination was significantly higher than in other groups of patients. However, also in this study, patients treated with combination showed a higher incidence of grade 3-4 IrAEs, with a frequent involvement of more than one organ.^90,91 Several studies (www.clinicaltrials.gov) are ongoing with the objective to confirm the safety and the effectiveness of the combination of ipilimumab with anti-PD1 or anti-PDL1 MAbs (NCT01783938;NCT02054520; NCT02523313; NCT01621490) and to better clarify the optimal dose and sequencing of treatment (.NCT01866319). Other studies have been planned to evaluate the role of this combination for the treatment of specific subset of patients as well as those affected by uveal melanoma or brain metastases (NCT01585194; NCT02460068; NCT02374242) or the potential role of this combination in the adjuvant setting (NCT02306850; NCT02519322). The studies are summarized in Table 1.

Another possible combined immunotherapeutic approach is represented by the combination of Ipilimumab with T-VEC, an oncolytic virus that includes a gene that encodes for GM-CSF.⁹² Preliminary data from a recent trial that enrolled 18 patients demonstrate a ORR of 56% with a median PFS of 10.6 months; 12- and 18-month survival were 72.2 and 67% and no dose-limiting toxicities were observed. Larger clinical trials are needed to confirm these positive initial results.

Instead, the possibility of combining ipilimumab and target therapies is not feasible, due to the high toxicity of this association; data from phase I studies demonstrated an increased liver toxicity for patients treated with ipilimumab plus vemurafenib and an higher risk of bowel perforation for those treated with ipilimumab plus dabrafenib and tramentinib.^93,94 Both phase I trials were stopped because of the seriousness of the side effects and are not currently planned additional extensions. Since the anti-PD1 /PD-L1 are less toxic of ipilimumab, its potential association with the target therapies is conceivable.

In the last years several studies suggested the potential induction of an abscopal effect with the combination of ipilimumab and radiotherapy⁹⁵; in fact, radiotherapy reduces circulating levels of immunosuppressive melanoma cells and expose novel melanoma antigens to T cells, enhancing the specific immunological response. Unfortunately, the majority of studies in which ipilimumab has been combined with radiotherapy included patients with brain metastases.^96,97 The potential bad prognosis of these patients and the frequent need for steroid therapy support has probably given conflicting results. Indeed, while according to some authors^96,98 patients treated with radiotherapy and ipilimumab show a more favorable course than those treated with radiotherapy alone, for others there are no significant differences between the two groups.^97,99 Ongoing prospective studies are necessary to clarify this aspect.

Another intriguing approach is represented by the combination of ipilimumab with electrochemotherapy (ECT), a therapeutics modality that consists in the local application of short duration, high-voltage electric pulses which transiently increase cell membrane permeability and facilitate the uptake of bleomycin, cisplatin or others cytotoxic chemotherapic drugs.¹⁰⁰ Although ECT is a predominantly local treatment, it can play an important role in activating the immune system. In fact, the ECT-mediated cellular damage can lead to releasing tumor cellular antigens, with a consequent inflammatory reaction. A recent retrospective study¹⁰¹ enrolled 15 patients that received ipilimumab at standard dose and were treated with ECT after the first ipilimumab infusion. The treatment was well tolerated, and a local objective response was observed in 67% of cases. The possible role of combined ECT and ipilimumab in the immune system activation is also confirmed by the observation of vitiligo-like lesions, exclusively developed around the site of previous ECT in a patients treated sequentially with ipilimumab.¹⁰²

Recently, several clinical trials evaluated the potential role of anti-CTLA-4 antibodies for the treatment of solid tumor other than melanoma. In particular, encouraging results for prostate cancer, renal cell carcinoma, non-Hodgkin lymphoma and non-small cells lung cancer (NSCLC) has been reported.^27-30 In advanced NSCLC, a randomized phase II trial¹⁰³ demonstrated the efficacy of ipilimumab in combination with chemotherapy. The clinical benefit of this association was confirmed in another phase II trial,¹⁰⁴ even if both trials failed to show any significant OS difference between the two arms. Morever, a clinical phase I/II trial exploring the feasibility of nivolumab plus ipilimumab combination (NCT02060188). is ongoing on patients with metastatic colorectal cancer. On the contrary, a single-arm phase II trial enrolling 27 patients demonstrated the ineffectiveness of monotherapy with ipilimumab in patients with advanced pancreatic cancer.¹⁰⁵

Conclusions

The new immunotherapy, based on CTL-A4 blockade, has dramatically changed the scenario of the treatment of advanced melanoma. A large number of phase I, II and III clinical trials demonstrated the safety and efficacy of ipilimumab, with a significant improvement in overall survival (exceeding 4 years) in a selected group of patients. However, the majority of patients experienced an any grade drug-related irAEs; most of these are of low toxicity, but a minority of patients may also experience severe and life-threatening irAEs that require the acquisition of special clinical skills. Despite greater understanding in the biology, pharmacokinetics, safety, and efficacy of ipilimumab, several aspects remain to be investigated. In particular, it is not completely known the potential of this drug in combination with other modulators of the immune response and with the new target therapies.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.