Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors C Ciccarese, S Alfieri, M Santoni, D Santini, M Brunelli, C Bergamini, L Licitra, R Montironi, G Tortora & F Massari To cite this article: C Ciccarese, S Alfieri, M Santoni, D Santini, M Brunelli, C Bergamini, L Licitra, R Montironi, G Tortora & F Massari (2015): New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors, Expert Opinion on Drug Metabolism & Toxicology, DOI: 10.1517/17425255.2016.1120287 To link to this article: http://dx.doi.org/10.1517/17425255.2016.1120287

Accepted author version posted online: 13 Nov 2015. Published online: 08 Dec 2015. Submit your article to this journal

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Review

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New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors 1.

Introduction

2.

Ctla-4 inhibitors

3.

Blocking the PD-1/PD-L1 axis

C Ciccarese*, S Alfieri*, M Santoni,†† D Santini, M ††Brunelli, C Bergamini, L Licitra, R Montironi, G Tortora & F Massari†

4.

Combination therapies



5.

Discussion

6.

Expert opinion

Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy

Introduction: Tumor development results from a cancer-induced immunosuppression (immune-editing). Immunotherapy has revolutionized the treatment paradigm for many malignancies, putting clinicians before novel toxicities, of immune-mediated etiology (immune-related adverse events). Areas covered: Immune-mediated toxicity depends on both innate and adaptive immunity mechanisms. Healthy tissue damage depends on an aspecific T-cell hyperactivation response causing cross-reaction with normal tissues, which leads to an overproduction of CD4 T-helper cell cytokines and an abnormal migration of cytolytic CD8 T-cells. By stimulating a diffuse T-cell repertoire expansion, immune-checkpoint inhibitors counteract tumor growth but reduce the self-tolerance, damaging healthy organs. In this review, we summarize the toxicity profile of the novel immune-checkpoint inhibitors and their clinical implications, we are convinced that a deep understanding and a prompt resolution of the paradigmatic toxicities of these drugs will result in clinical benefits to patients and an enhanced antitumor effect. Expert opinion: A focus on immunotoxicity is important in the education of clinicians and will improve patient safety. There is a willingness to tailor specific immune-therapies to each cancer patient, and to stimulate researchers through understanding of the physiopathogenesis, using the hypothesis that immune-mediated toxicities can be used as predictors of response or a prognostic sign of survival, thereby guiding therapeutic decisions. Keywords: adverse events, immune-checkpoint inhibitors, immunotherapy, safety profile, toxicity Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

The interaction of human immunity and cancer has been object of study over the last six decades based on the idea that the immune system plays an essential role in controlling cancer progression. Assessing the way cancer may overcome the immune system inhibitory “brakes” represents one of the main topics of cancer research. Until recently, immunotherapy represented an over-promising but underdelivering anticancer approach. Cytokines (interleukin-2 and interferon-α) have been used for decades, mainly in melanoma and renal cell carcinoma (RCC) patients (two of the most “immunogenic” cancer studied so far), although with a limited activity and a noteworthy toxicity profile, restricting their routinely use in daily clinical practice.[1,2] *Equal contributors. †† They share the last co-authorship. 10.1517/17425255.2016.1120287 © 2015 Taylor & Francis. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

1

C. Ciccarese et al.

Article highlights

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● Recently, several new molecules, such as immune-checkpoint protein inhibitors, have been evaluated, showing a promising activity on different cancer types with a peculiar toxicity profile. ● Ipilimumab (IPI) is a monoclonal antibody that enhances the immune system by blocking CTLA-4. It is approved at 3 mg/kg dose every 3 weeks for up to four treatments for previously treated advanced (unresectable or metastatic) melanoma patients and for the first-line treatment of advanced melanoma. It has prevalently immunerelated adverse events. ● Nivolumab is a fully human IgG4 monoclonal antibody targeting the immune-checkpoint PD-1. It is approved at 3 mg/kg every 2 weeks for the treatment of metastatic melanoma after progression of IPI and/or a v-Raf murine sarcoma viral oncogene homolog B (BRAF)-inhibitor (in BRAF-mutated disease), and recently to treat patients with advanced (metastatic) squamous non-small cell lung cancer with progression on or after platinumbased chemotherapy. It appears well tolerated, being fatigue, rash, diarrhea and pruritus the peculiar drugrelated AEs. ● Pembrolizumab is a IgG4 engineered humanized monoclonal antibody directed against PD-1 and it was approved, at the 2mg/kg dose administered intravenously every 3 weeks, for the treatment of metastatic melanoma patients previously treated with IPI and a BRAF inhibitor. It has a good toxicity profile, similar to nivolumab, showing few Grade 3–4 toxicities in clinical trials. ● Several other immune-checkpoint inhibitors targeting PD-L1 (the main PD-1 ligand) or NKG2D (the surface receptor expressed mainly on NK cells) are currently under clinical evaluation. ● Several combinations of immune-checkpoints antibodies with other different molecules (immune agents, chemotherapies and tyrosine kinase inhibitors) are under evaluation. The main limit of this strategy concerns the potential overlapping toxicities. This box summarizes key points contained in the article.

Only in the last years, some new promising immunotherapeutic agents emerged, stimulating a great debate and relative production in the scientific community. Tumor cells proliferation is favored by a cancer-induced immunosuppression status, necessary to elude the antitumor immune activity (a process defined as immunoediting) by expressing proteins that shut down the immune response binding to specific inhibitory surface receptors on immune cells (the cytotoxic T-lymphocyte antigen-4 [CTLA-4] and programmed death-1 [PD-1]). The remarkable improvement of knowledge in immunology led to the identification of immune checkpoint receptors (like CTLA-4 and PD-1), expressed on T cells that trigger inhibitory pathways dampening T-cell activity, whose inhibition enhances the antitumor immunity. CTLA-4, expressed on activated T CD4+ and CD8+ lymphocytes, binds to B7-1 and B7-2 (costimulatory molecules present 2

on antigen presenting cell surface), counteracting CD28mediated signals, thus constraining T-cell activation. Analogously, a co-inhibitory signal for T-cell effector functions derives from the interaction between the receptor PD-1 (expressed on T cells and on other immune cells of the inflamed tumor microenvironment) and its ligands PD-L1/ L2 (expressed on myeloid dendritic cells, activated T cells, some non-hematopoietic tissues and tumor cells). The PD-1/ PD-L1 axis physiologically limits tissue damage during inflammation, avoids the development of auto-immunity by promoting tolerance to self-antigens and, in cancer, inhibits the antitumor immune response. Novel immune-checkpoint molecules that block CTLA-4 (ipilimumab (IPI)) or the PD-1/PD-L1 axis (i.e. nivolumab, pembrolizumab and atezolizumab), reactivating T-cell activity against cancer cells, represent one of the major oncological breakthroughs. Not surprisingly, advanced melanoma is the first setting in which these immune-stimulating agents demonstrate a significant survival benefit.[3,4] Impressive long-lasting responses (due to antitumor immune memory) and significant benefit in clinical outcomes have been also observed in other cancer types, including renal-cell carcinoma,[5] non-small cell lung cancer (NSCLC),[6] and more recently in bladder cancer [7] and head and neck tumor patients.[8] The drug-mediated hyperactivation of immune system mainly (but not exclusively) directed against cancer cells can, however, results in damage to healthy tissues, especially in those organs (skin, lung and gastrointestinal tract) where the abundant lymphocytic infiltrate is under a delicate constant control that regulates the balance between tolerance toward self-antigens and defense against potentially dangerous exogenous antigens. The pharmacologic activation of the immune system response, no longer able to discriminate between neoplastic and normal cells, generating “autoinflammatory” processes explains the pathogenesis of the selected adverse events (AEs) with a potential immunemediated causality (previously named “immune-related AEs” or “AEs of special interest”).[9] Considering their good cost-effectiveness ratio (significant survival advantage in different cancer settings, and a novel, peculiar but manageable toxicity profile), these new immune-checkpoint inhibitors are really keeping all their initial promises. This review aims to summarize the safety profile of the novel immunotherapy agents, mainly focusing on immunecheckpoint CTLA-4 and PD-1/PD-L1 inhibitors and their clinical implications.

2. 2.1.

Ctla-4 inhibitors Ipilimumab

IPI (previously known as MDX010 or BMS-734016) has been approved at 3 mg/kg dose on 2011 by U.S. Food and Drug Administration (FDA) and European Medicines

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

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New toxicity profile for novel immunotherapy agents

Agency for previously treated advanced (unresectable or metastatic) melanoma patients and on 2013 by EMA for the first-line treatment of advanced melanoma. IPI is a monoclonal antibody that enhances the immune system response in terms of T-cell activation by binding and, subsequently, blocking CTLA-4, an important co-inhibitory receptor on T-lymphocyte surface. IPI demonstrated a survival advantage either in treatmentnaïve or heavily treated melanoma patients.[3,10] Hodi et al. reported 80.2% of pretreated patients experiencing any grade drug-related AEs, with 22.9% of Grade 3 or 4 AEs.[3] This Phase III trial and all IPI Phase I–II trials were included in a pooled safety analysis (1498 patients) confirming this distribution of AEs: 84.8% and 25.3% for any grade and Grade 3–4 drug-related toxicities, respectively.[11] It is important to underline that the toxicity of IPI is dose-dependent. In fact, this dose–toxicity relationship is clearly manifested when IPI is used at 10 mg/kg, dose associated with an increased frequency of AEs.[12] Analogously, in the adjuvant setting, IPI at 10 mg/kg every 3 weeks was associated with a considerable toxicity (Grade 3–4 gastrointestinal immune-related AEs 16%, hepatic 11%, and endocrine 8%), leading to treatment discontinuation in about 50% of patients and causing five (1%) drug-related deaths.[13] Among drug-related AEs, the most common were the immune-related adverse events (irAEs), so defined if any other etiology is unknown, thus consisting an immune phenomenon (inflammatory in nature). A 64.2% of patients experienced an irAE of any grade in the pooled safety analysis mentioned above with the majority of them of low grade (Grade 1 or 2) and just a minor part resulting in life-threatening (18.4%) or in death (less than 1%), which is further reduced when excluding patients treated with high doses (10 mg/kg) of IPI (5% of drug-related serous AEs when the dose was decreased at 3 mg/kg).[11] The most common irAEs affected skin (rash and pruritus) and gastrointestinal tract (diarrhea and colitis). Generally, skin is the first and the most common immune-related side effect expected with IPI treatment (from 47% to 68% of patients after an average of 3–6 weeks). Gastrointestinal disorders are the second one in terms of temporal course and frequency (about 40% of patients starting from 5th to 7th week). Moreover, prophylaxis of diarrhea and colitis with an oral systemically nonabsorbed corticosteroid, such as budenoside, at 9 mg daily during IPI treatment (at 10 mg/kg dose), was unsuccessfully tested in a double-blind, placebo-controlled Phase II study. [14] Liver dysfunction (i.e. hypertransaminasemia) does usually affect 3–9% of melanoma cancer population since the 6th or 7th week of IPI therapy, while endocrinologic AEs (i.e. hypophysitis) occur in 1–6% of patients in a latter period of observation (after about 9 weeks).[15] Moreover, several analyses demonstrated the lack of differences in terms of safety among diverse subgroups of melanoma patients treated with IPI. First of all, IPI seems to be equally tolerated by the age. In fact, while the frequency of

irAEs is increased with IPI dose, it is quite the same in elderly (>65 years) compared to young patients.[16–18] A comparable safety IPI profile based on the age was confirmed in Italian Expanded Access Programme (EAP), in which 193 patients aged >70 years were assessed for efficacy and safety outside of a clinical trial setting.[19] The amount of any grade or Grade 3–4 treatment-related effects, and the median time to onset (6 weeks) and resolution (2 weeks) of irAEs were similar to that reported for all patients treated (N = 855) in the Italian EAP. The Italian EAP analysis showed how the mutational v-Raf murine sarcoma viral oncogene homolog B (BRAF) and/or neuroblastoma RAS viral (v-ras) oncogene homolog status does not influence the IPI safety.[20] Similarly, the primary melanoma subsites (ocular and mucosal) or poor prognostic subgroups of melanoma patients (brain metastases) do not change the safety profile of the drug.[16] Finally, the Italian EAP study showed the absence of a significant correlation between the response to IPI therapy and the clinical development of irAEs, thus denying their potential predictive value (Table 1). 3.

Blocking the PD-1/PD-L1 axis

The safety profile of the two main anti-PD1 inhibitors (nivolumab and pembrolizumab) is remarkably comparable. 3.1.

Nivolumab

Nivolumab (also known as BMS-936558, ONO-4538 or MDX-1106) is a fully human IgG4 monoclonal antibody targeting the immune-checkpoint PD-1, thus disrupting PD1 interaction with its ligands (PD-L1 and PD-L2), thereby releasing PD-1 pathway-mediated inhibition of the immune response and restoring antitumor immunity. Nivolumab (at 3 mg/kg) reached the FDA accelerated approval in December 2014 for the treatment of metastatic melanoma after progression of IPI and/or a BRAF inhibitor (in BRAF-mutated disease) on the basis of demonstrated superior efficacy, as compared to chemotherapy, in a large Phase III trial (objective responses were reported in 31.7% with nivolumab versus 10.6% in the chemotherapy group). [21] Recently, nivolumab demonstrated an overall survival advantage over dacarbazine (1-year OS 72.9% in the nivolumab group, as compared with 42.1% in the dacarbazine group – HR 0.42; 99.79% CI, 0.25 to 0.73; P < 0.001) in previously untreated advanced BRAF wild-type melanoma patients,[4] leading the EMA to recommend the granting of a marketing authorization of nivolumab for treating advanced melanomas. Even more recently (May 2015), and of equally relevant clinical impact, is the approval of nivolumab for the treatment of locally advanced or metastatic squamous cell NSCLC after failure of first-line chemotherapy, based on the evidence of a survival, response rate and progression-free survival (PFS) advantage compared with docetaxel.[6]

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

3

4

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

ALT: Alanine aminotransferase.

Advanced Melanoma (855)

Melanoma (440)

Ipilimumab 3 mg/kg + gp100 Ipilimumab 3 mg/kg gp100 Ipilimumab 3 mg/kg

0.3 mg/kg 3 mg/kg 10 mg/kg

Melanoma (217) 72 71 71

Cancer type (N patients)

Ipilimumab

Drug dose (mg/ kg)

78.8% 47%

80.2%

88.9%

8.3% 18.3% 26.7%

AEs any grade

Table 1. Ipilimumab: adverse events.

17.4% 22.9% 11.4%

0% 8.4% 21.1%

AEs Grade 3–4

Nausea 6% 12% Fatigue/asthenia %8% Rash 8% Pruritus 7% Diarrhea 7%

Diarhea (38, 33, 20) Fatigue (36, 42, 31) Nausea (34, 35, 39) Decreased appetite (23, 27, 22)

Fatigue (22, 17, 22.5) Diarrhea (17, 25, 39) Nausea (15, 18, 24) Rash (–, 24, 22.5) Pruritus (–, 21, 32)

Type total% (dosedependent %)

AST + ALT increased (2) Diarrhea (2%

Diarrhea (0, 1.4, 14) Vomiting (0, 1.4, –) Rash (0, 1.4, –) Pruritus (0, 1.4, 2.8) Colitis (0, 1.4, 2.8) Fatigue (0, –, 2.8) Fatigue (5, 7) Diarrhea (4.5, 3)

Type (%)

Treatment discontinuation for AEs

Ipilimumab + gp100 Grade 3–4 10.2% [Any G 58.2%] Ipilimumab Grade 3–4 14.5% [Any G 61.1%] Grade 3–4 6% [Any G 33%]

2.9%



Grade 3–4 0% [Any G 26%] 5.5% Grade 3–4 7% [Any G 6 4.7%] 12.6% Grade 3–4 25% [Any G 70.4%] 28.1%

irAEs Grade 3–4 total % (dosedependent %)

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Ascierto, EAP [20]

Hodi, Phase 3 [3]

Wolchok, Phase 2 [12]

Author

C. Ciccarese et al.

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New toxicity profile for novel immunotherapy agents

A promising antitumor activity of nivolumab has also been demonstrated in kidney cancer (in which immunotherapy plays a historical role), showing a survival advantage and durable responses regardless of dose levels and PD-L1 expression.[22] A confirmation of efficacy comes from the results of the recently published Phase 3 trial (CheckMate 025) comparing nivolumab versus everolimus in subjects with metastatic clear cell RCC who have received prior antiangiogenic therapy.[23] The impressive results of immune-checkpoint inhibitors (especially nivolumab) mentioned above have opened new frontiers of investigation, including brain tumors, pancreatic adenocarcinoma, gastric cancer, bladder urothelial tumors, squamous carcinoma of the head and neck and breast cancer, where it seems that they can bring a substantial contribution in changing the natural history of these malignancies. In terms of safety, it is important to underline that

of treatment, as observed in melanoma patients treated with nivolumab for 3 or more years.[26,27] Therefore, close monitoring conducted early at the beginning of immune therapy remains essential. ● There is no a clear linear relationship between dose

escalation of nivolumab (from 0.3 to 10 mg/kg) and the increase of toxicity, in terms of frequency, type of AE or severity.[22,28] ● The exposure-adjusted toxicity rate is not cumulative, unlike what often happens with chemotherapy,[26] making more difficult to identify patients at risk of developing side effects. ● The tumor histology can influence the toxicity profile, being lung cancer patients more susceptible to develop pneumonitis,[6,29] while fatigue, rash, diarrhea and elevated hepatic transaminases levels characterize melanoma and kidney cancer patients.[22,26]

● According to other anti-PD1 antibodies, nivolumab

seems to be far less toxic than CTLA4 inhibitors, showing an easily manageable toxicity profile.[24] As demonstrated by Topalian and colleagues in a large Phase I dose-escalation trial assessing the safety of nivolumab in 296 cancer patients, the most common treatment-related side effects were fatigue, rash, diarrhea, pruritus, nausea and hyporexia, presenting Grade 3–4 in 11% of cases.[9] Adverse reactions having an immunological genesis are of particular interest, both for their peculiar clinical features (up to now little known to oncologists) and for the potential severity that requires a fast and prompt diagnosis and therapy. Among them, gastrointestinal disorders (colitis and hepatitis), endocrinopathies (hypophysitis and thyroiditis) and skin reactions (vitiligo and pruritus) were reversible if treated with a temporary suspension of nivolumab, steroid therapy and/or hormonal replacement therapy. Pneumonitis (3% of all grades, 1% Grade 3–4), if unresponsive to corticosteroids, caused death in 1% of patients (two patients with non-small cell lung cancer and one with colorectal carcinoma).[9] ● Immune-related AEs (as well as responses) can occur

during the treatment, but also after the interruption of the therapy, and may take longer to resolve than with IPI, highlighting the necessity to continue monitoring patients. As for anti-CTLA-4, irAEs show a peculiar kinetic of appearance also with anti-PD-1 antibodies. Typically, endocrine dysfunctions present a late onset, while gastrointestinal and skin disorders are more precocious. Nonetheless, a chronic oral prednisone therapy may be required for the management of prolonged Grade 2 gastrointestinal and cutaneous toxicities.[25] It is important to emphasize, however, that in most cases immune-mediated side effects arise within the first 6 months

In particular, in the pooled analysis of two Phase 3 studies in melanoma, the most commonly reported adverse reactions were fatigue (33%), rash (20%), pruritus (18%), diarrhea (16%) and nausea (14%), most of which were mild to moderate (Grade 1 or 2). Grade 3 or 4 AEs related to nivolumab were uncommon (about 5%), including elevated alanine aminotransferase (ALT) levels and diarrhea, leading to treatment discontinuation in roughly 6–7% of cases.[4,21] It is important to focus the attention on certain immune-related AEs. A broad spectrum of immunemediated cutaneous reactions (maculopapular, follicular, erythematous, pruritic, macular, popular, pustular, vesicular rash, acneiform or exfoliative dermatitis) may appear in about one third of patients, with no cases of Grade 4 or 5, and characterized by a slow resolution (4.6 months) with steroid therapy in only 50% of patients. Diarrhea or immune-related colitis can occur during nivolumab treatment (16.5%, with 3.2% of Grade 2, and 1.3% of Grade 3), with 1.9 months of median time to onset, a median duration of 1.1 months and a complete clinical resolution in most cases. The liver function may be impaired in 6.8% of patients (Grade 4 toxicity reported in 0.8%), usually with a quick complete resolution. Dyspnea, cough, breathing difficulties and hypoxia can be the clinical manifestations of a potentially fatal pneumonitis or an interstitial lung disease, described in 2.3% of cases, all of Grade 1 or 2 in severity. Severe endocrine disorders, including thyroid dysfunction (4.2% of Grade 2, 0.2% of Grade 3), adrenal insufficiency, hypophysitis and diabetes mellitus (0.2% each), have been observed with nivolumab treatment for melanoma patients. An immune-mediated nephritis, presenting as an asymptomatic rise in creatinine and/or a contraction of the diuresis, has been described in about 2% of melanoma patients during nivolumab treatment, mainly transient (1.25 months for resolution) and mild to moderate in severity.

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In the NSCLC population, fatigue (24%, 3% of Grade 3– 4), decreased appetite (12%) and diarrhea (10%) were confirmed to be the treatment-related side effects of all grades most commonly observed among patients enrolled in the Phase I dose-escalation cohort expansion trial of nivolumab. [29] If considering immune-mediated treatment-related AEs, skin (16%), gastrointestinal (12%) and lung (7%, 3% of grade ≥3, comprising one Grade 5 pneumonitis) disorders cover a prominent role, both for frequency and for gravity. Extremely interesting is to underline the lower severe toxicity of nivolumab (serious events of any grade in 7%, 2% of Grade 3 or 4) compared with docetaxel chemotherapy (all grade 24%, Grade 3–4 19%). Treatment-related select (of immunological nature) AEs most frequently observed with nivolumab include diarrhea (8%), pneumonitis (5%), rash (4%), hypothyroidism (4%) and renal dysfunction (3%). These toxicities were uncommon and of low severity. No deaths were ascribed to nivolumab.[6] With respect to RCC, a dose-escalation cohort-expansion Phase I study of nivolumab, conducted in 34 patients with previously treated advanced RCC, suggested the manageable toxicities of PD-1 blockade in this setting.[30] Grade 3–4 treatment-related AEs occurred in 18% of patients, while Grades 3–4 immune-mediated AEs were observed in 9% of cases, including pruritus, macular rash, increased ALT and acute respiratory failure. The confirmation of nivolumab safety in RCC comes from the Phase II trial, laying the groundwork to demonstrate the efficacy of this treatment in the ongoing Phase 3 study. Although treatment-related side effects of any grade occurred up to 73% of patients (the most frequent being fatigue), Grade 3–4 toxicities were reported only in 11% of cases. Elevation of liver transaminases was the most common cause for treatment-related discontinuation. No Grade 3–4 pneumonitis or treatment-related deaths were described (Table 2).[22] Recently, at the 2015 ESMO Annual Meeting, Motzer and colleagues presented the results of the CheckMate 025 Phase III trial, demonstrating a survival advantage of nivolumab compared to everolimus in previously treated advanced RCC patients.[23] About 79% and 88% of patients experienced treatment-related AEs of any grade with nivolumab and everolimus, respectively, fatigue (33%), nausea (14%) and pruritus being the most common nivolumabrelated AEs. Grade 3 or 4 treatment-related AEs occurred in 19% of the nivolumab patients (compared to 37% of patients treated with everolimus), leading to treatment discontinuation in 8% of cases (versus 13% in the everolimus arm).

3.2.

Pembrolizumab

Pembrolizumab (previously known as MK-3475 or lambrolizumab) is an IgG4 engineered humanized monoclonal antibody against PD-1. This agent, at the 2 mg/kg dose administered intravenously every 3 weeks, received approval by FDA on September 2014 for treatment of metastatic melanoma patients previously treated with IPI and a BRAF 6

inhibitor (just for BRAF V600 mutated patients). Currently, pembrolizumab is under investigation in other cancer populations. Firstly, pembrolizumab showed clinical activity and good safety in a Phase I trial, which evaluated pembrolizumab at 1, 3 and 10 mg/kg in a classic 3 + 3 trial design in patients (n = 9) with any histology advanced solid tumors refractory to conventional treatment.[31] Then, as the maximum tolerated dose (MTD) was not reached, an expansion cohort started enrolling only patients with diagnosis of metastatic melanoma (n = 135) who received pembrolizumab at 10 mg/ kg dose every 2 or 3 weeks or at 2 mg/kg dose every 3 weeks. [32] Of the 135 patients, 79% reported any grade drugrelated AEs, with only 13% of Grade 3 or 4 AEs. Grade 3–4 skin disorder (rush and pruritus) were described in 3% of cases while all the other Grade 3–4 toxicities were regularly distributed, regardless of drug dose, among hepatic and renal failure, fatigue and decreased appetite, diarrhea and abdominal pain or hypothyroidism at 1% maximum each. In the group of G1–2 toxicities, the most common side effects were generalized symptoms, such as fatigue, asthenia, fever, myalgias and headache, ranging from 30% (fatigue) to 7% (fever). Skin disorders (rush, pruritus and vitiligo) were also represented in the half of patients while gastrointestinal problems (diarrhea, nausea and decreased appetite) in 30% of cases. Overall, AE were more frequent (23%) with the highest pembrolizumab dose (10 mg/kg every 2 weeks) than that reported with lower doses (4% and 9% for 10 mg/kg every 3 weeks and 2 mg/kg every 3 weeks, respectively). A similar safety profile with pembrolizumab was reported by Robert and colleagues in a expansion cohort of a Phase I trial, randomizing 173 IPI refractory advanced melanoma patients to 2 mg/kg or 10 mg/kg every 3 weeks.[33] As Hamid et al., this trial showed pembrolizumab as a welltolerated drug, without differences between the 3-weekly schedules. The only Grade 3–4 drug-related AE occurred in more than 1% of patients was fatigue, registered in just 3% of 2 mg/kg pembrolizumab group. The incidence of Grade 3–4 treatment-related AEs was similar in KEYNOTE-002 trial, in which pembrolizumab was studied at 2 mg/kg and 10 mg/kg every 3 weeks in IPI refractory population versus chemotherapy: 11 and 14%, respectively, for pembrolizumab groups.[34] Consistent with previous results, the 3-weekly schedules of pembrolizumab analyzed did not differ. The most common Grade 3–4 treatment-related AEs in the pembrolizumab 2 mg/kg treatment group were fatigue, generalized edema and myalgia (1% each). The most frequent Grade 3–4 treatment-related AEs observed in those given pembrolizumab 10 mg/kg were hypopituitarism, colitis, decreased appetite, hyponatremia, diarrhea and pneumonitis (1% each), the latter two potentially life-threatening, and with similar incidence in pembrolizumab groups (1% each). Further steps in pembrolizumab safety profile analysis were recently offered by Robert et al. who compared

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

84% total 76.5% 78% 97% 88% 70%

Melanoma (107)

Melanoma (418)

Nivolumab 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg

Nivolumab 3 mg/kg versus DTIC

74.3%

58%

70.5% total 64% 68% 76%

70% total 78% 58% 75% 68% 69%

AEs any grade

Nivolumab Squamous 3 mg/kg versus docetaxel NSCLC (272)

NSCLC (129)

Advanced cancer (296)

Nivolumab 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg

Nivolumab 1 mg/kg 3 mg/kg 10 mg/kg

Cancer type (N patients)

Drug dose (mg/kg)

Table 2. Nivolumab: adverse events.

Fatigue 19.9% Pruritus 17 % Nausea 16.5%

Fatigue 24% (22, 26, 24, 24, 25) Decreased appetite 8% (6, 11, 8, 10, 8) Rash 12% (17, 11, 20, 8, 9) Diarrhea 11% (6, 11, 19, 6, 9) Pruritus 10% (0, 11, 17, 8, 7) Nausea 8% (0, 5, 6, 14, 9) Fatigue 24% (24, 19, 27) Decreased appetite 12.4% (12, 11, 14) Diarrhea 10% (12, 11, 8.5) Fatigue 16% Decreased appetite 11% Asthenia 10% Nausea 9% Diarrhea 8% Fatigue 32% (29, 28, 34, 47, 20) Rash 23% (18, 17, 37, 12, 20) Diarrhea 18% (6, 11, 29, 12, 20) Pruritus 13% (0, 6, 23, 18, 10)

Type total % (dosedependent %)

11.7%

22% 29% 17% 14% 35% 25%

7%

14% total 15% 13.5% 14%

14%

AEs Grade 3–4

Diarrhea (1%) Rash (0.5%) Pruritus (0.5%) Vomiting (0.5%)

Fatigue (1.9%) Diarrhea (1.9%) Abdominal pain (1.9%) Leukopenia (2.8%)

Fatigue (1%) Decreased appetite (1%) Leukopenia (1%)

Fatigue (3%) Lymphopenia (2.3%) Pneumonitis (2.3%)

Fatigue (2%) Diarrhea (1%) Abdominal pain (1%) ALT increased (1%) AST increased (1%) Hypophosphatemia (1%) Pneumonitis (1%) Lymphopenia (1%)

Type (total)

Treatment discontinuation for AEs

Grade 3–4 5% [any G 54%] Skin 0% [any G 36%] Diarrhea 2% [any G 18%] Colitis 1% [any G 2%] Endocrinopathies 2% [any G 13%] Hepatic 1% [any G 6.5%] Diarrhea (1%) ALT increased (1%)

6.8%



Grade 3–4 4.7% [Any G – 41%] GI 0.8% Pulmonary 2.3% Hepatic 8.0% Infusion reaction 0.8% 3% Nephritis Pneumonitis Colitis

Total Grade 3–4 6% 5% [any G 41%] Pneumonitis 1% (0, 0, 3, 0, 1) AST increased 1% (0, 0, 0, 2, 1) ALT increased 1% (0, 0, 0, 0, 2) Allergic rhinitis 1% (0, 0, 0, 0, 2)

irAEs Grade 3–4 total % (dose-dependent %)

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(continued )

Robert, Phase 3 [4]

Topalian, Phase I [26]

Brahmer, Phase 3 [6]

Gettinger, Phase I [29]

Topalian, Phase I [9]

Author

New toxicity profile for novel immunotherapy agents

7

8

Cancer type (N patients)

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

RCC (168)

RCC (821)

Nivolumab 0.3 mg/kg 2 mg/kg 10 mg/kg

Nivolumab 3 mg/kg versus everolimus

ALP: Alkaline phosphatase.

RCC (36)

Nivolumab 1 mg/kg 10 mg/kg

Nivolumab 3 mg/kg Melanoma versus DTIC or CBDCA/ (631) TXL

Drug dose (mg/kg)

79% versus 88%

73% total 75% 67% 78%

85% total 83% 87%

68%

AEs any grade

Table 2. Nivolumab: adverse events. (continued).

Fatigue 25% Pruritus 16% Diarrhea 12% Nausea 9% Fatigue 41% (33, 50) Rash 26.5% (39, 12.5) Diarrhea 18% (28, 6) Pruritus 18% (22, 12.5) ALT increased 12% (11, 12.5) Fatigue (24, 22, 35) Nausea (10, 13, 13) Pruritus (10, 9, 11) Diarrhea (3, 11, 15) Hypersensitivity (2, 2, 17) Fatigue 33% Pruritus 14% Nausea 14% Diarrhea 12% Decreased appetite 12%

Type total % (dosedependent %)

19% versus 37%

11% total 5% 17% 13%

18% total 11% 25%

G3 8% G4 1%

AEs Grade 3–4

Fatigue (2%) Anemia (2%) Diarrhea (1%) Pneumonitis (1%) Hyperglycemia (1%)

Nausea (2, 2, 0%) Pruritus (0, 2, 0%) Arthralgia (0, 0, 2%)

Increased lipase (1%) Fatigue (1%) Anemia (1%) Increased ALT (1%) Pruritus (3%) ALP increased (3%) Hypophosphatemia (6%)

Type (total)

3%

Treatment discontinuation for AEs

7% total 2% 11% 7%

8% versus 13%

Hepatic (2, 4, 0%) Skin (0, 4, 0%) Endocrine (0, 4, 0%) GI (0, 2, 0%) –

Grade 3–4 9% [any G – 56%] Pruritus 2.9% Macular rash 2.9% Increased ALT 2.9% Acute respiratory failure 2.9%

Grade 3–4 3% Liver function abnormalities

irAEs Grade 3–4 total % (dose-dependent %)

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Motzer, Phase 3 [23]

Motzer, Phase 2 [22]

McDermott, Phase I [30]

Weber, Phase 3 [21]

Author

C. Ciccarese et al.

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New toxicity profile for novel immunotherapy agents

pembrolizumab versus IPI within a large Phase 3 trial, randomizing 834 advanced melanoma patients to pembrolizumab at 10 mg/kg every 2 or 3 weeks or to IPI at 3 mg/kg every 3 weeks (4 doses).[35] As well as compared with chemotherapy,[34] pembrolizumab also showed better tolerability in comparison with other immune-checkpoint inhibitors, such as IPI. In fact, Grade 3–4 AEs were lesser in two pembrolizumab groups (13.3% and 10.1%, respectively) than that resulted in IPI group (19.9%). Comparing pembrolizumab (in both schedules used, bi- or tri-weekly) with IPI, the KEYNOTE-006 trial showed a lower rate of permanent discontinuation (4%, 6.9% and 9.4%, respectively), a longer time to the first Grade 3–4 AE (64, 59 and 39.5 days, respectively) and a longer duration of treatment (164, 151 and 50 days, respectively) in favor for pembrolizumab groups. The only treatment-related drug was reported in the IPI arm (cardiac arrest secondary to metabolic disorders associated with IPI-induced diarrhea). No difference was seen between the two schedules of pembrolizumab used, with the confirmation of most common any-grade AEs previously reported ranging from 20% to less than 10% in the following order: general symptoms (asthenia and fatigue), gastrointestinal disorders (nausea and diarrhea) and skin (pruritus, rash and vitiligo). Among the AEs of special interest, thyroid (i.e. hyperthyroidism and hypothyroidism) disorders were the most frequent in the pembrolizumab groups. Recently, Garon et al. published the results from a Phase III (KEYNOTE 001) trial enrolling patients (N = 495) with advanced NSCLC to pembrolizumab at a dose of 10 mg/kg every 2 or 3 weeks or at 2 mg/kg every 3 weeks.[36] Total any grade treatment-related AEs was 70.9% with less than 10% (9.5%) of Grade 3–4 AEs. The most common of anygrade AEs were fatigue (19.4%), pruritus (10.7%) and decreased appetite (10.5%). In a lung cancer population, the frequency of pneumonitis was particularly expected. Even though in NSCLC patients there are some preexisting disease-related risk factors, the overall rate of pneumonia was 3.6% (with half of cases with toxicity higher than Grade 3) which is not so higher than that reported in KEYNOTE-002 and KEYNOTE 006 for melanoma patients (almost 2% in 3-weekly schedules of both studies). At the 2015 ASCO Annual Meeting, Seiwert and Plimack presented the preliminary results from the head and neck and urothelial cancer expansion cohorts of the KEYNOTE-012 study, respectively.[8,37] Similar percentages of AEs were observed between these two groups and previous literature mentioned above: 59.8% and 60.5% of all any-grade AEs, 9.8% and 15.2% of only Grade 3-4 AEs for head and neck and urothelial cancer, respectively. Fatigue was the most common any grade AE in both settings (Table 3). 3.3.

PD-L1 inhibitors

An interesting way to stimulate the host’s immune system enhancing the antitumor activity is the disruption of PD-1/

PD-L1 interaction by blocking PD-L1. PD-L1 is the main PD-1 ligand, selectively over-expressed on tumor cells surface, stromal and immune cells, where it inhibits the cytolytic activity of tumor-infiltrating PD-1 + T-cells.[38,39] Several molecules that target PD-L1 are currently under evaluation. BMS-936559 is a fully human IgG4 monoclonal antibody that targets PD-L1, preventing the tie of PD-L1 to both PD1 and CD80. The safety and adverse-event profiles of BMS936559 were evaluated in a 207-cancer-patients Phase I study.[40] Interestingly, even blocking the ligand, the toxicity profile did not differ from that of the PD-1 blocking antibodies. In particular, AEs were frequent (AEs of any grade reported in 91% of patients), but predominantly of low grade, with drug-related events of Grade 3 or 4 documented only in 9% of cases, regardless of the dose levels. Fatigue, infusion reactions, nausea, diarrhea, rash, pruritus, arthralgia and headache represented the most frequent treatment-related AEs, while rash, hypothyroidism, diabetes mellitus, sarcoidosis, myasthenia gravis and endophtalmitis were described as toxicities with immune-mediated etiology (39%, mainly mild). A similar toxicity profile was reported with atezolizumab (MPDL3280A), another high-affinity human IgG1 monoclonal antibody that specifically blocks PD-L1, avoiding the interaction with PD-1 and B7-1. A modification in the Fc domain of the antibody eliminates the ADCC activity (which can target activated T cells, limiting MPDL3280A efficacy) at clinically relevant doses, preventing depletion of activated T cells and therefore enhancing its antitumor properties.[41,42] A Phase Ia multicenter, dose-escalation trial of MPDL3280A in advanced cancer patients demonstrated promising safety, tolerability and clinical activity results.[43] The drug was well tolerated, with no MTD and no dose-limiting toxicities observed. Fatigue, associated with low-grade fever, was the most common treatmentrelated event. Moreover, MPDL3280A-related Grade 3–4 AEs (fatigue, decreased appetite, headache, asthenia, influenza-like illness, vomiting and anemia) were detected in 13% of patients, with severe immune-related AEs accounting for no more than 1%. In the expansion cohort of this trial, recruiting metastatic bladder cancer patients, initially selected by PD-L1 expression and then extended also to enroll patients regardless of PD-L1 status, demonstrated noteworthy anticancer activity with no toxicity concerns. [7] Treatment-related AEs, reported in 57% of the safetyevaluable population, were mostly of low grade (Grade 3 described only in 4% of cases – asthenia, thrombocytopenia, hypophosphatemia, no Grade 4 or 5 events mentioned), transient in nature, not affecting vital organs (with fatigue and decreased appetite as the most frequent AEs) and sparing renal injury. A Phase 3 trial is evaluating the efficacy and safety of MPDL3280A compared with chemotherapy in patients with metastatic urothelial bladder cancer after failure of a platinum-containing chemotherapy (NCT02302807).

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

9

10

Expert Opin. Drug Metab. Toxicol. (2015) 12(1)

[vs IC-chemoth]

2 mg/kg Q3W 10 mg/kg Q3W

Pembrolizumab

10 mg/kg Q3W

Pembrolizumab 2 mg/kg Q3W

0.005-10 mg/kg Q3W 2mg/kg Q3W 10 mg/kgQ3W Lambrolizumab 10 mg/kg Q2W 10 mg/kg Q3W 2 mg/kg Q3W

1 mg/kg Q2W 3 mg/kg Q2W 10 mg/kg Q2W

Advanced melanoma (540)

Advanced melanoma (173)

Advanced melanoma (135)



82%

79%

0%

Rash 17.9% Diarrhea12.7% Arthralgia 12.1% –

Fatigue 34.7% Pruritus 22.5%

25% Total 11% 14%

12%

Fatigue 30% 13% Rash 21% Pruritus 21% Diarrhea 20% Myalgia 12% Asthenia 10% Headache 10% Nausea 10% AST increased 10%

Nausea 23% Pruritus 17% Decreased appetite 13% Hypothyroidism 7%

Fatigue 33%

70%

Pembrolizumab

Advanced cancer 32)

AEs any Type total % (dose- AEs grade dependent %) Grade 3–4

Drug dose (mg/kg) Cancer type (N patients)

Table 3. Pembrolizumab: adverse events.

Fatigue (1) Generalised oedema (1) Myalgia (1) 10 mg/kg Hypopituitarism (1) Colitis (1) Diarrhea (1) Decreased appetite (1) Hyponatraemia (1) Pnemonitis (1)

2 mg/kg

Rash (2%) Pruritus (1%) AST increased (2%) Renal failure (2%) Fatigue (1%) Diarrhea (1%) Abdominal pain (1%) Hypothyroidism (1%) Decreased appetite (1%) Fatigue (3 %) All other Grade 3–4 AEs

New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors.

Tumor development results from a cancer-induced immunosuppression (immune-editing). Immunotherapy has revolutionized the treatment paradigm for many m...
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