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The development of immunotherapy in older adults: New treatments, new toxicities?
JGO-00362; No. of pages: 9; 4C: J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 6 ) XX X–XX X
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The development of immunotherapy in older adults: New treatments, new toxicities? Carole Helisseya , Cécile Vicierb , Stéphane Champiatb,c,⁎ a
Department of Medical Oncology — Clinical Research Unit, Military Hospital Begin, Saint-Mandé, France Inserm U981, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France c Drug Development Department (DITEP), Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France b
AR TIC LE I N FO
ABS TR ACT
Article history:
Monoclonal antibodies targeting immune checkpoint molecules CTLA-4, PD-1 or PD-L1 are
Received 7 February 2016
emerging as promising anticancer therapeutics in multiple cancer subtypes resulting in
Received in revised form
remarkable and long-lasting clinical responses. These immune checkpoint blockers (ICBs)
23 March 2016
have already obtained approval for the treatment of patients with metastatic melanoma,
Accepted 31 May 2016
advanced/refractory non-small cell lung cancer and renal cell cancer. ICBs enhance immune responses against cancer cells but can also lead to inflammatory side effects
Keywords:
called immune-related adverse events (irAEs). Such toxicities are distinct from those
Neoplasms
associated with traditional chemotherapeutic agents or molecularly targeted therapies.
Aged
Although severe irAEs remain rare (~ 10% of cases under monotherapy), they can become
Toxicity
life-threatening if not anticipated and managed appropriately. As malignancies are
Immunotherapy
frequently diagnosed in older patients, ICB treatment of elderly presents a unique
Medical oncology
challenge. However, the knowledge about efficacy and toxicity of these molecules in this
Immune checkpoint
specific population is limited, as most of the studies have involved a low number of older
PD1
patients. In this review, we will discuss about the different ICB efficacy data available for
PD-L1
older patients. We will then highlight the specific spectrum of immunotherapy toxicities
CTLA4
and talk about their management in the context of older adults. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Advanced age is an important risk factor of cancer and is associated with poor prognosis.1,2 The exciting revolution of immune checkpoint blocker (ICB) development in oncology arouses great expectations for our older patients. Indeed, ICBs have been approved for patients with melanoma, non-small cell lung cancer, and renal cell cancer.3–8 Clinical indications of immunotherapeutic agents are expected to increase as clinical responses with ICB are observed in many different cancer
subtypes: small cell lung cancer (15% ORR),9 urothelial cancer (25% ORR),10 head and neck squamous cell carcinoma (12–25% ORR),11,12 gastric cancer (20% ORR),13 hepatocellular carcinoma (20% ORR),14 ovarian cancer (15% ORR),15,16 triple negative breast cancer (20% ORR),17 mismatch repair deficient colorectal cancer (60% ORR)18 and Hodgkin lymphoma (65–85% ORR).19,20 Moreover, ICB monotherapy studies have shown a good safety profile with ~10% of severe toxicities. ICBs represent a new opportunity for older patients as approximately half of all malignancies are diagnosed in
Abbreviations: IC, immune checkpoint; ICB, immune checkpoint blocker; irAE, immune-related adverse event; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; RCC, renal cell carcinoma. ⁎ Corresponding author at: Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. E-mail address: [email protected] (S. Champiat).
http://dx.doi.org/10.1016/j.jgo.2016.05.007 1879-4068/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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patients older than 65 years.21 However, the knowledge about efficacy and toxicity of these molecules is limited, as most of these studies have involved a low number of older patients. Elderly comorbidities and their immune system age-related impairment might affect the effect and tolerance of immune checkpoint blockade. In this review, we will discuss about the different ICB efficacy data available for older patients. We will then highlight the specific spectrum of immunotherapy toxicities and talk about their management in the context of older adults.
2. Principles of targeting immune checkpoints Immune checkpoints (ICs) are receptors and ligands involved in the modulation of immune responses. Indeed, after antigen recognition by the T cell receptor, T cell activation is regulated by a balance between costimulatory and inhibitory signals that are mediated by these ICs. Their physiological roles are to maintain tolerance of self and to modulate the intensity and duration of immune responses.22 Interestingly, tumor cells are able to divert these immunological checkpoints in order to evade the immune system. Therefore, ICB mechanism of action is a true paradigm shift in oncology: instead of targeting the tumor cells itself, these therapies aim to overcome the immunosuppression induced by the tumor and its microenvironment. By releasing the brakes of the immune system, immune checkpoint blockers can induce prolonged anti-tumor responses.23 Many IC activator or inhibitory proteins have been identified and can potentially be targeted to develop new therapeutics.24 IC co-inhibitory molecules such as CTLA-4 or PD1 and PD-L1 have been the first to be developed in the clinic.
2.1. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) CTLA4 is one of the best-studied co-inhibitory molecules. It counteracts the activity of the T cell costimulatory receptor, CD28. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (also known as B7.2). CTLA4 has a much higher overall affinity for both ligands. CTLA4 is expressed on activated CD4+ and CD8+ T cell and it is constitutively
expressed on regulatory T cells (Tregs).22 The activation of CTLA4 enhances the suppressive function of Tregs, but also decreases IL2 production and IL2 receptor expression. Therefore, CTLA4 blockade amplifies the cytotoxic T-cell activity and inhibits the Tregs cell-dependant immunosuppression, leading to antitumor effects.
2.2. PD1/PDL1 pathway The programmed cell death 1 (PD1) is another key immune checkpoint co-inhibitory receptor expressed by activated T cells in peripheral tissues. PD1 binds to its ligands PDL1 (B7H1) and PDL2 (B7DC), which are expressed not only on antigen presenting cells but also on cancer cells and in the tumor microenvironment.22,25 Thus PD1-ligand expression creates an immuno-suppressive environment. This immuneescape mechanism that uses IC-ligand expression can be intrinsic through constitutive oncogenic signaling or induced in response to inflammatory signals (IFNg) that are produced by an active antitumor immune response.22,26,27 Thus, PDL1 expression was described in many histological cancer types. By inhibiting the inhibitors of local tumor-specific immune responses, the blockade of the PD1/PD-L1 pathway can lead to prolonged tumor control.
3. ICB efficacy data in older patients Several molecules are targeting CTLA4 or PD1/PD-L1 pathways (Table 1) and three of them are currently approved (FDA/EMA): anti-CTLA-4 antibody (ipilimumab) and anti-PD1 monoclonal antibodies (nivolumab and pembrolizumab). In 2015, a meta-analysis of ICB randomized trials28 has studied ICB efficacy in older patients compared to young adults. This analysis included a total of 3322 patients from six phase III randomized control trials of ICB with three ipilimumab trials, two nivolumab trials and one tremelimumab trial. The underlying malignancies included were melanoma (4 trials), prostate cancer (1 trial) and non–small-cell lung cancer (1 trial). Five trials used 65 years and one trial used 70 years as an age cut-off to conduct subgroup analyses. For 2078 younger patients, the pooled hazard ratio (HR) for overall survival (OS) showed
Table 1 – : Molecules targeting CTLA4 or PD1/PD-L1 pathways currently approved or in development. Target
Drug
Company
CTLA4
Ipilimumab
BMS
PD1
Tremelimumab Nivolumab
MedImmune BMS
Pembrolizumab MK3475
Merck — MSD
Pidilizumab CT-011 Atezolizumab MPDL3280A Durvalumab MEDI-4736 Avelumab MSB0010718C
CureTech Genentech-Roche Astra-Zeneca/Medimmune Pfizer/Merck Serono
PD-L1
Development stage FDA approved (melanoma) Phase I–III multiple tumors Phase I–III multiple tumors FDA approved (melanoma, NSCLC, RCC) Phase III multiple tumors (NSCLC, melanoma, RCC, HNSCC, GBM, gastric) FDA approved (melanoma, NSCLC) Phase III multiple tumors (HNSCC, NSCLC, melanoma, bladder, gastric/GE) Phase II multiple tumors (pancreatic, CRC, RCC, prostate, CNS) Phase III multiple tumors (NSCLC, bladder, RCC, TNBC) Phase III multiple tumors (NSCLC, HNSCC) Phase III (NSCLC)
Abbreviations: BMS: Bristol-Myers Squibb, CNS: Central Nervous System, CRC: Colorectal Cancer, FDA: US Food and Drug Administration, GBM: Glioblastoma multiforme, GE: gastro-esophageal, HNSCC: head and neck squamous cell carcinoma, MSD: Merck Sharp and Dohme, NSCLC: non-small cell lung cancer, RCC: renal cell carcinoma, TNBC: triple negative breast cancer.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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significant difference between ICB and controls (HR, 0.73; 95% CI, 0.66–0.81; P < 0.001). For 1244 older patients, ICB also significantly improved OS (HR, 0.72; 95% CI, 0.58–0.90; P = 0.004) in comparison with controls. This meta-analysis revealed that there was no statistically significant difference between subgroups of younger and older patients concerning the pooled HR for OS (P = 0.93). We detail below elderly efficacy data in some of the key reported phase 3 trials of CTLA4 or PD1/PD-L1 targeting agents.
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in a phase III study.31 655 were included, 328 in tremelimumab group and 327 in chemotherapy group. Unfortunately, there was no difference in OS in the two groups, 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = 0.127). In this study, 200 (31%) patients were aged over 65 years, 110 in tremelimumab group and 90 in chemotherapy group. There was no difference in overall survival between these groups in the elderly population (HR = 0.87, P = 0.384).
3.1. Ipilimumab Ipilimumab is a fully humanized monoclonal antibody directed against CTLA4. This therapeutic agent was the first immune checkpoint inhibitor to be approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. In a phase 3 trial, ipilimumab, with or without a glycoprotein 100 (gp100) peptide vaccine, was compared with gp100 alone in patients with previously treated metastatic melanoma.29 676 patients were included in the study; 403 were randomly assigned to receive ipilimumab, at a dose of 3 mg per kilogram of body weight, plus gp100, 137 to receive ipilimumab alone, and 136 to receive gp100 alone. Ipilimumab was administered once every 3 weeks for four treatments. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P < 0.001). The median overall survival (OS) with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Among these 676 patients on this trial, 196 (29%) were aged over 65 years. 112 patients were randomized in the group with Ipilimumab and gp100, 42 in the group with gp100 alone and 42 in the group with Ipilimumab alone. Analyses of OS in these subgroups showed that the effect of ipilimumab was independent of age. In the elderly population, a 31% reduction in the risk of death was noted with ipilimumab plus gp100, as compared with gp100 alone (hazard ratio, 0.69 (0.47–1.01)), and a 39% reduction in risk of death was seen with ipilimumab alone as compared with gp100 alone (hazard ratio, 0.61 (0.38–0.99)). Sileni et al. assessed the efficacy and safety of ipilimumab at its approved dose of 3 mg/kg in elderly patients within an expanded access program.30 193 patients over 70 years were included and among these patients, 27 were aged over 80 years. The immune related disease control rate (irDCR) was 38%, with 2% of irCR (complete response), 13% with irPR (partial response) and 23% with irSD (stable disease). The median duration of irDC was 11.5 months (95% CI 9.3–13.7). There was no difference in median OS between ≥70 years (8.9 months (95% CI 7.2–10.6)) and < 70 years (7.0 months (95% CI 6.1–7.9)) P = 0.17.
3.2. Tremelimumab Tremelimumab is a fully human IgG2 monoclonal antibody directed against CTLA4. Ribas et al. assessed the efficacy and safety of tremelimumab (15 mg/kg once every 90 days) versus chemotherapy in patients with treatment-naive, unresectable stage IIIc or IV melanoma,
4. Anti-PD1 agents: nivolumab and pembrolizumab 4.1. Nivolumab Nivolumab (BMS 936558, MDX 1106, ONO-4538), is a fully human IgG4 monoclonal antibody against the PD1 receptor, blocking its binding with its ligands (PD-L1 and PD-L2). In a phase III study, Borghaei et al. assessed the efficacy and tolerance of nivolumab in non-small cell lung cancer (NSCLC) patients, in second line of treatment after platinumbased doublet chemotherapy.32 582 patients were included, 287 were randomly assessed to receive nivolumab (3 mg/kg every 2 weeks) and 268 received docetaxel (5 mg/m2 every 3 weeks). Nivolumab has shown an improvement in OS compared to docetaxel with a median of OS at 12.2 months (95% CI, 9.7 to 15.0) in the nivolumab group versus 9.4 months (95% CI, 8.1 to 10.7) in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P = 0.002). At 1 year, the OS rate was 51% (95% CI, 45 to 56) in nivolumab group versus 39% (95% CI, 33 to 45) in the docetaxel group. In this trial, 200 (34%) patients were aged between 65 and 75 years old and a set of 43 (7%) were aged over 75 years. A 37% reduction of the risk of death was observed in the nivolumab group, compared to docetaxel group (hazard ratio, 0.63 (0.45–0.89)) in ≥65 to <75 years group. A 10% reduction in the risk of death was noted with nivolumab, as compared with docetaxel (hazard ratio, 0.90 (0.43–1.87)) in ≥ 75 years group. Motzer et al., in a randomized phase III trial in advanced renal cell carcinoma (RCC), reported a 27% reduction risk of death with nivolumab as compared with everolimus.33 In this study, 324 patients (39%) were aged over 65 years old. This benefit was showed in patients aged between 65 and 75 years old with a 36% reduction of the risk of death with nivolumab compared with everolimus (hazard ratio, 0.64 (0.45–0.91)). However, this benefit was not observed in the group over 75 years old (hazard ratio, 1.23 (0.66–2.31)), potentially due to lack of power in this subgroup.
4.2. Pembrolizumab Pembrolizumab is a humanized IgG4 antibody against PD1. In a phase III study, Robert et al., compared pembrolizumab (10 mg/kg, every 2 weeks or every 3 weeks) to four doses of ipilimumab (at 3 mg/kg every 3 weeks) in patients with advanced melanoma.34 834 patients were included, 279 were randomly assigned to receive pembrolizumab every 2 weeks, 277 to receive pembrolizumab every 3 weeks, and 278 to receive ipilimumab. OS rates at 1 year were 74.1% for patients receiving pembrolizumab every 2 weeks (hazard ratio for
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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death as compared with the ipilimumab group, 0.63; 95% CI, 0.47 to 0.83; P < 0.0005), 68.4% for the pembrolizumab group every 3 weeks (hazard ratio for death as compared with the ipilimumab group, 0.69; 95% CI, 0.52 to 0.90; P = 0.004), and 58.2% for the ipilimumab group. It was a one year estimate of survival. In this study, 238 (29%) patients were aged over 65 years.
5. Anti-PD-L1 agents: Atezolizumab and Durvalumab Atezolizumab (MPDL3280A, humanized IgG4) and Durvalumab (MEDI 4736, fully human IgG1) are human antibodies targeting PD-L1 (IgG4 and IgG1 respectively). These two agents have shown promising efficacy in multiple cancer subtypes, however no data is currently available concerning efficacy in older patients.35,36 As reported above, the current data is very promising, showing similar benefit of anti-CTLA4 and anti PD-1 therapeutics in older patients as compared to the overall population. Nevertheless, these preliminary results are limited to subgroup analysis and dedicated studies are therefore needed to confirm efficacy of ICBs in older patients with cancer. Moreover, to avoid bias due to studies heterogeneity, future meta-analysis studies should focus on approved ICB individually and be limited to specific tumor types.
6. ICB toxicity profile: immune-related adverse events (irAEs) ICB may be responsible for specific toxicities called “immunerelated adverse events” (irAEs). These irAEs are related to the infiltration of normal tissues by activated T cells responsible for autoimmunity. Since ICs have a key physiological role and are not only expressed by tumor cells, blocking IC can potentially amplify any immune response present in the patient and nearly all organs can be affected (Fig. 1). As reported in the literature,3–8,37 immune toxicities can affect the skin (maculopapular rash, vitiligo, psoriasis, Lyell syndrome, DRESS), the gastrointestinal tract (enterocolitis, gastritis, pancreatitis, coeliac disease), the endocrine glands (hypo- or hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes), the lung (pneumonitis, pleural effusion, sarcoidosis), the nervous system (peripheral neuropathy, aseptic meningitis, Guillain–Barré syndrome, encephalopathy, myelitis, meningo– radiculo-neuritis, myasthenia), the liver (hepatitis), the kidney (granulomatous interstitial nephritis, lupus-like glomerulonephritis), hematological cells (hemolytic anemia, thrombocytopenia, neutropenia, pancytopenia), the musculo-articular system (arthritis, myopathies), the heart (pericarditis, cardiomyopathy) and/or the eyes (uveitis, conjunctivitis, blepharitis, retinitis, choroiditis, orbital myositis). Fortunately, most of these serious immune-related adverse events are individually rare(<1%).3–5
However, this low frequency leads to difficulties in diagnosis and treatment due to lack of experience. The spectrum of toxicities observed with anti CTLA4 or anti PD1/PD-L1 is similar but the frequencies differ.34,35,38,39 Indeed, anti-CTLA4 is more toxic than anti-PD1/PD-L1: The rate of grade 3–4 toxicities with anti-CTLA4 is around 20–30% versus 10–15% for anti PD-1. For anti-CTLA 4, the most commonly observed toxicities (>10%) are diarrhea, rash, pruritus, fatigue, nausea, vomiting, anorexia and abdominal pain.3,6 For anti-PD1 the most commonly observed toxicities (>10%) are fatigue, rash, pruritus, diarrhea, nausea and arthralgia.4,5,7,8 The main ICB life-threatening toxicities are dysimmune colitis (more common for anti-CTLA4) and interstitial pneumonitis (for the anti-PD1). Other severe toxicities were reported, including infusion reactions, Guillain–Barré syndrome, type 1 diabetes with ketoacidosis, Stevens Johnson syndromes or autoimmune anemia and thrombocytopenia with bleeding complications. Interestingly, it seems that the detection and early treatment of irAEs could limit their severity. Most irAEs are mild and can be treated symptomatically. Depending on their severity, irAEs require close monitoring, interruption or discontinuation of the ICB, introduction of corticosteroid therapy, and in some cases more immunosuppressive medications such as of anti-TNF therapy (infliximab). Several guidelines have been proposed for the management of these irAEs.40–43 It has to be noted that the current recommendations are only based on experts' consensus since no prospective study has been done to date to evaluate the different managements. The kinetics of onset and resolution of these toxicities is particularly different from what is observed with conventional anti-cancer treatments. Despite the fact that the majority of irAEs usually occur within the first 4 months of treatment,44 immune toxicities can also occur at any time during treatment: at the beginning, during treatment course, but also several months after discontinuation. This feature of irAEs supports a careful monitoring throughout the treatment and after termination. In the absence of sufficient experience, it is now accepted that this monitoring should continue for at least one year after stopping immunotherapy.
6.1. ICB combinations are associated with higher toxicities ICB combinations or associated with targeted therapy or conventional chemotherapy have systematically shown an increased toxicity. The combination of ipilimumab (anti-CTLA4) with nivolumab (anti-PD1) is responsible for 55% grade 3–4 adverse events.38 The combination of ipilimumab with conventional chemotherapy in lung cancer causes 58% of grades 3–4 toxicities (against 52% in the sequential arm and 42% in the chemotherapy alone arm).45 Finally, ipilimumab combination with vemurafenib in melanoma is responsible for asymptomatic but severe liver toxicity with an early elevation of transaminases
Fig. 1 – Spectrum of immune-related adverse events (irAEs). From: Champiat, S., Lambotte, O., Barreau, E., Belkhir, R., Berdelou, A., Carbonnel, F., et al. (2015). Management of Immune Checkpoint Blockade Dysimmune Toxicities: a collaborative position paper. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, mdv623. http://doi.org/10.1093/annonc/mdv623. Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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or bilirubin within 3 weeks after initiation of ipilimumab.46 Given the toxicity observed in the early patients, this phase I trial was stopped.
6.2. Do irAEs differ in older patients? Immune-related side effects may be more challenging in older patients due to reduced functional reserve and age-associated comorbidities.1,2 Furthermore the “immunosenescence” phenomenon,47,48 which is the term given to age-associated impairments of the immune system, could affect the efficacy and/or the toxicity of immune checkpoint blockade. In fact, during aging, the expression patterns of T cell co-stimulatory or co-inhibitory proteins change considerably: the expression of inhibitory receptors such as PD-1 or LAG-3 is enhanced, associated with a decrease of the costimulatory molecules. Paradoxically, immunosenescence is also coupled with higher concentrations of inflammatory cytokines, called “inflammaging”. Finally, older patients are known to have a higher prevalence of autoantibodies49,50 and one can expect that ICB may reveal subclinical autoimmune diseases. Using ipilimumab in elderly melanoma patients, Sileni reported that patients over 70 years old presented irAE with a similar frequency compared to overall population.30 A retrospective analysis of irAEs in melanoma patients <65 compared to those > 65 treated with nivolumab was recently reported.51 Data pooled 148 patients treated with nivolumab plus peptide vaccine or nivolumab alone every two weeks for at least 12 weeks. Frequency, grade, and characteristics of irAEs were analyzed among patients > 65 and < 65 years of age. This study showed no statistically significant difference in incidence of irAEs and the irAE profile was similar in the two groups. Thus, despite speculation about the specificities of
older adult immunity, the current safety data appears to be similar to the population at large. Across the different approved ICBs, no overall differences in safety were reported in elderly patients (≥65 y.o.) and no dose adjustment is recommended.3–8 The currently approved ICBs have not been evaluated in patients with severe renal or hepatic impairment. Nevertheless, no dose adjustment is recommended for patients with mild or moderate renal impairment (i.e. ≥30 ml/min creatinine clearance) or mild hepatic impairment (i.e. total bilirubin > upper limit normal to 1.5 N). As older patients with cancer are often taking medications for other comorbidities, it is important to note that the currently approved ICB monoclonal antibodies are not metabolized by cytochrome P450 enzymes, therefore enzymatic competition is not expected. The use of corticosteroids may hypothetically interfere with ICB efficacy (even if it has not been evaluated by proper studies) and is recommended to avoid at baseline. Patients treated by anticoagulants or anti-aggregants must be carefully monitored in case of colitis symptoms (risk of gastrointestinal hemorrhage) or autoimmune thrombocytopenia.
7. Principle of clinical management of irAEs Clinical management of irAEs is new to many oncologists and expertise is still limited. Here are some key principles that have been proposed to properly manage patients treated by ICB40 (Fig. 2).
7.1. Prevent Before initiation of immunotherapy, it is recommended to detect any personal or family history of autoimmune disease
Fig. 2 – Principle of clinical management of irAEs. From: Champiat, S., Lambotte, O., Barreau, E., Belkhir, R., Berdelou, A., Carbonnel, F., et al. (2015). Management of Immune Checkpoint Blockade Dysimmune Toxicities: a collaborative position paper. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, mdv623. http://doi.org/10.1093/annonc/mdv623. Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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or chronic viral infection which pathogenesis might be potentiated by the ICB treatment. Nevertheless, a controlled autoimmune disease is not considered as a contraindication for currently approved ICBs. In such case, ICBs should be used with caution after careful consideration of the potential risk– benefit on an individual basis.3,6 To facilitate early identification of symptoms related to irAEs, it is key to inform the patient, his/her family and his/her caregivers about the nature and specificity of irAEs. It is important to ask the patient to promptly report any new symptoms or worsening of pre-existing symptoms to allow proper assessment without delay. Patients must also be informed that immune-adverse reactions may occur at any time: at the beginning, during or after treatment discontinuation.
7.2. Anticipate Since patients with cancer can present with toxicity sequelae from previous treatments, physical examination, laboratory tests and imaging performed at baseline must be used as a reference for any new abnormality occurring during immunotherapy. Any baseline comorbidity should be properly evaluated before initiation and during ICB treatment. Minimal testing should include CBC, renal function, serum electrolytes, liver function and regular thyroid evaluation (TSH). Chest imaging should be systematically performed at baseline as a reference in case a pulmonary toxicity occurs.
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– Organ-specialist advice to assess the interest of other immunosuppressive agents (such as anti-TNF for severe colitis), especially for severe, persistent or relapsing toxicities It is important to note that corticotherapy is not systematic in the treatment of irAEs: most grade 1 irAEs can be managed with symptomatic treatment only. Also, ICB dose reduction is currently not recommended for the 3 approved ICBs.
7.5. Monitor irAE resolution can highly vary across the different types of toxicities: gastrointestinal, hepatic and renal toxicities usually quickly improve when immunosuppressants are started, on the other side, rash and endocrine irAEs are more chronic. Endocrine insufficiencies often require long-term hormonal substitution.38,52,53 In case a corticotherapy is started, steroids should be gradually tapered (usually over a period of ≥1 month) to avoid recurrence or worsening of the irAE. Finally the use of prolonged immunosuppressive treatments requires proper monitoring and prophylactic treatment to avoid life-threatening opportunistic infections.54 In older adults, tolerance of irAEs should be carefully monitored as associated comorbidities may decompensate more easily. Moreover the use of some symptomatic treatments (such as antihistamine for pruritis) or corticosteroids may expose older patients to iatrogenic events such as diabetes worsening, mental status disturbance, hypertension and delirium.
7.3. Detect New symptoms or increase of pre-existing symptoms should be systematically suspected to be an irAE. However irAE frequency is relatively low compared to other etiologies such as disease progression or intercurrent infection and these must be first ruled out. Nevertheless, dysimmune toxicities should always be considered and lead to proper investigations. Baseline assessment is then essential because it will serve as a reference. In clinical practice one must pay particular attention to the occurrence of respiratory (cough, dyspnea), gastrointestinal (diarrhea) or skin (rash, pruritus) symptoms. Non-specific general signs must suggest endocrine toxicity (especially thyroid dysfunction). Laboratory tests particularly will look at hematological toxicity (anemia, thrombocytopenia), hepatic (transaminase elevation) and kidney (increased serum creatinine) toxicities. TSH should be regularly checked (every 2– 3 months). Since irAEs can be delayed, patients' clinical and biological monitoring should be maintained after therapy discontinuation (every 3–6 months).
7.4. Treat Suspicion or diagnosis of an irAE always requires close monitoring to detect any worsening or relapse. Facing the diagnosis of an irAEs, several elements must be discussed: – – – –
Patient information about self-monitoring elements Symptomatic treatment Suspension or termination of immunotherapy agent Corticosteroid therapy
8. Conclusion ICBs such as anti-CTLA4 and anti PD1/PD-L1 are already part of the approved treatments for patients with advanced melanoma, NSCLC and RCC. As most of ICB studies have involved a low number of older patients it remains difficult to confirm the impact of these new therapeutics in elderly. One could expect that clinical specificity of older patients (comorbidities, co-medications, reduced functional reserve) and immunosenescence may affect ICB efficacy and tolerance in this population. However, ICB preliminary data presented in this review are very encouraging and suggest that older adults will benefit from the ICB revolution in oncology without increased toxicity. ICB toxicities are new to clinicians as they are distinct from those associated with traditional chemotherapeutic agents or molecularly targeted therapies. The use of immunotherapy agents will likely be widely expanded in the near term and it is critical that healthcare practitioners become more familiar with immune-related toxicities. The current experience with irAEs is limited and the current management guidelines are based on experts' consensus. Collaborative initiatives will be needed to evaluate and standardize the management of the different irAEs. Finally, as malignancies are often diagnosed in older patients, dedicated studies in elderly are necessary to properly and safely use these immunotherapeutics.
Disclosures and conflict of interest statements The authors have no conflicts of interest to report.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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Author contributions All of the authors have participated to the writing of the manuscript and approved its content. REFERENCES
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17. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18–22. Philadelphia, PA: American Association for Cancer Research 2015. [Abstract 6317]. 18. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 2015, http://dx.doi.org/10.1056/NEJMoa1500596. 19. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 2014;141206100011003. 20. Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013) [abstract]. Blood 2014;124(21) [Abstract 290]. 21. NIH Surveillance, Epidemiology and end results program. http://seer.cancer.gov 22. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012;12(4):252–264. 23. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 2015 [JCO.2014.56.2736]. 24. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13(4): 227–242. 25. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res. 2012;18(24):6580–6587. 26. Crane CA, Panner A, Murray JC, et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 2008;28(2):306–312. 27. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 2006;13(1):84–88. 28. Funakoshi Tomohiro, Muss Hyman, Moschos Stergios. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a meta-analysis of randomized controlled trials. [abstract]. Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science Into Survival; September 16–19, 2015; New York, NY. Cancer Immunol ResPhiladelphia (PA): AACR; 2016. [Abstract nr A159]. 29. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010;363(8):711–723. 30. Chiarion-Sileni V, Pigozzo J, Ascierto PA, et al. Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme. J. Exp. Clin. Cancer Res. 2014;33(1):30. 31. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 2013;31(5):616–622. 32. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 2015;150927150118000–13. 33. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 2015;150925150201006–11. 34. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015, http://dx.doi.org/10.1056/NEJMoa1503093. 35. Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563–567.
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36. Segal NH, Antonia SJ, Brahmer JR, Maio M, Blake-Haskins A, Li X, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J. Clin. Oncol. 2014;32(5s) [suppl.; abstr. 3002]. 37. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann. Oncol. 2015 [mdv623-16]. 38. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 2015;373(13):1270–1271. 39. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 2015;372(21):2006–2017. 40. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann. Oncol. 2015:mdv623. 41. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 2012;30(21):2691–2697. 42. Kähler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges 2011;9(4):277–286. 43. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 2015: mdv383. 44. Weber JS, Antonia SJ, Topalian SL, et al. Safety profile of nivolumab in patients with advanced melanoma: a pooled analysis. J. Clin. Oncol. 2015;33 [(suppl; abstr 9018)]. 45. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized,
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double-blind, multicenter phase II study. J. Clin. Oncol. 2012;30(17):2046–2054. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 2013;368(14):1365–1366. Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 2013;14(5): 428–436. Solana R, Tarazona R, Gayoso I, et al. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin. Immunol. 2012;24(5):331–341. Manoussakis MN, Tzioufas AG, Silis MP, et al. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin. Exp. Immunol. 1987;69(3):557–565. Candore G, Grimaldi MP, Listi F, et al. Prevalence of non organ-specific autoantibodies in healthy centenarians. Arch Gerontol Geriatr Suppl 2002;8:75–80. Freeman M, Weber J. Subset analysis of the safety and efficacy of nivolumab in elderly patients with metastatic melanoma. J Immunother Cancer 2015;3(Suppl 2):P133. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 2015;150617133829002–13. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015;372(4):320–330. Kyi C, Hellmann MD, Wolchok JD, et al. Opportunistic infections in patients treated with immunotherapy for cancer. J Immunother Cancer 2014;2(1):19.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
Available online at www.sciencedirect.com
ScienceDirect
The development of immunotherapy in older adults: New treatments, new toxicities? Carole Helisseya , Cécile Vicierb , Stéphane Champiatb,c,⁎ a
Department of Medical Oncology — Clinical Research Unit, Military Hospital Begin, Saint-Mandé, France Inserm U981, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France c Drug Development Department (DITEP), Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France b
AR TIC LE I N FO
ABS TR ACT
Article history:
Monoclonal antibodies targeting immune checkpoint molecules CTLA-4, PD-1 or PD-L1 are
Received 7 February 2016
emerging as promising anticancer therapeutics in multiple cancer subtypes resulting in
Received in revised form
remarkable and long-lasting clinical responses. These immune checkpoint blockers (ICBs)
23 March 2016
have already obtained approval for the treatment of patients with metastatic melanoma,
Accepted 31 May 2016
advanced/refractory non-small cell lung cancer and renal cell cancer. ICBs enhance immune responses against cancer cells but can also lead to inflammatory side effects
Keywords:
called immune-related adverse events (irAEs). Such toxicities are distinct from those
Neoplasms
associated with traditional chemotherapeutic agents or molecularly targeted therapies.
Aged
Although severe irAEs remain rare (~ 10% of cases under monotherapy), they can become
Toxicity
life-threatening if not anticipated and managed appropriately. As malignancies are
Immunotherapy
frequently diagnosed in older patients, ICB treatment of elderly presents a unique
Medical oncology
challenge. However, the knowledge about efficacy and toxicity of these molecules in this
Immune checkpoint
specific population is limited, as most of the studies have involved a low number of older
PD1
patients. In this review, we will discuss about the different ICB efficacy data available for
PD-L1
older patients. We will then highlight the specific spectrum of immunotherapy toxicities
CTLA4
and talk about their management in the context of older adults. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Advanced age is an important risk factor of cancer and is associated with poor prognosis.1,2 The exciting revolution of immune checkpoint blocker (ICB) development in oncology arouses great expectations for our older patients. Indeed, ICBs have been approved for patients with melanoma, non-small cell lung cancer, and renal cell cancer.3–8 Clinical indications of immunotherapeutic agents are expected to increase as clinical responses with ICB are observed in many different cancer
subtypes: small cell lung cancer (15% ORR),9 urothelial cancer (25% ORR),10 head and neck squamous cell carcinoma (12–25% ORR),11,12 gastric cancer (20% ORR),13 hepatocellular carcinoma (20% ORR),14 ovarian cancer (15% ORR),15,16 triple negative breast cancer (20% ORR),17 mismatch repair deficient colorectal cancer (60% ORR)18 and Hodgkin lymphoma (65–85% ORR).19,20 Moreover, ICB monotherapy studies have shown a good safety profile with ~10% of severe toxicities. ICBs represent a new opportunity for older patients as approximately half of all malignancies are diagnosed in
Abbreviations: IC, immune checkpoint; ICB, immune checkpoint blocker; irAE, immune-related adverse event; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; RCC, renal cell carcinoma. ⁎ Corresponding author at: Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. E-mail address: [email protected] (S. Champiat).
http://dx.doi.org/10.1016/j.jgo.2016.05.007 1879-4068/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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patients older than 65 years.21 However, the knowledge about efficacy and toxicity of these molecules is limited, as most of these studies have involved a low number of older patients. Elderly comorbidities and their immune system age-related impairment might affect the effect and tolerance of immune checkpoint blockade. In this review, we will discuss about the different ICB efficacy data available for older patients. We will then highlight the specific spectrum of immunotherapy toxicities and talk about their management in the context of older adults.
2. Principles of targeting immune checkpoints Immune checkpoints (ICs) are receptors and ligands involved in the modulation of immune responses. Indeed, after antigen recognition by the T cell receptor, T cell activation is regulated by a balance between costimulatory and inhibitory signals that are mediated by these ICs. Their physiological roles are to maintain tolerance of self and to modulate the intensity and duration of immune responses.22 Interestingly, tumor cells are able to divert these immunological checkpoints in order to evade the immune system. Therefore, ICB mechanism of action is a true paradigm shift in oncology: instead of targeting the tumor cells itself, these therapies aim to overcome the immunosuppression induced by the tumor and its microenvironment. By releasing the brakes of the immune system, immune checkpoint blockers can induce prolonged anti-tumor responses.23 Many IC activator or inhibitory proteins have been identified and can potentially be targeted to develop new therapeutics.24 IC co-inhibitory molecules such as CTLA-4 or PD1 and PD-L1 have been the first to be developed in the clinic.
2.1. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) CTLA4 is one of the best-studied co-inhibitory molecules. It counteracts the activity of the T cell costimulatory receptor, CD28. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (also known as B7.2). CTLA4 has a much higher overall affinity for both ligands. CTLA4 is expressed on activated CD4+ and CD8+ T cell and it is constitutively
expressed on regulatory T cells (Tregs).22 The activation of CTLA4 enhances the suppressive function of Tregs, but also decreases IL2 production and IL2 receptor expression. Therefore, CTLA4 blockade amplifies the cytotoxic T-cell activity and inhibits the Tregs cell-dependant immunosuppression, leading to antitumor effects.
2.2. PD1/PDL1 pathway The programmed cell death 1 (PD1) is another key immune checkpoint co-inhibitory receptor expressed by activated T cells in peripheral tissues. PD1 binds to its ligands PDL1 (B7H1) and PDL2 (B7DC), which are expressed not only on antigen presenting cells but also on cancer cells and in the tumor microenvironment.22,25 Thus PD1-ligand expression creates an immuno-suppressive environment. This immuneescape mechanism that uses IC-ligand expression can be intrinsic through constitutive oncogenic signaling or induced in response to inflammatory signals (IFNg) that are produced by an active antitumor immune response.22,26,27 Thus, PDL1 expression was described in many histological cancer types. By inhibiting the inhibitors of local tumor-specific immune responses, the blockade of the PD1/PD-L1 pathway can lead to prolonged tumor control.
3. ICB efficacy data in older patients Several molecules are targeting CTLA4 or PD1/PD-L1 pathways (Table 1) and three of them are currently approved (FDA/EMA): anti-CTLA-4 antibody (ipilimumab) and anti-PD1 monoclonal antibodies (nivolumab and pembrolizumab). In 2015, a meta-analysis of ICB randomized trials28 has studied ICB efficacy in older patients compared to young adults. This analysis included a total of 3322 patients from six phase III randomized control trials of ICB with three ipilimumab trials, two nivolumab trials and one tremelimumab trial. The underlying malignancies included were melanoma (4 trials), prostate cancer (1 trial) and non–small-cell lung cancer (1 trial). Five trials used 65 years and one trial used 70 years as an age cut-off to conduct subgroup analyses. For 2078 younger patients, the pooled hazard ratio (HR) for overall survival (OS) showed
Table 1 – : Molecules targeting CTLA4 or PD1/PD-L1 pathways currently approved or in development. Target
Drug
Company
CTLA4
Ipilimumab
BMS
PD1
Tremelimumab Nivolumab
MedImmune BMS
Pembrolizumab MK3475
Merck — MSD
Pidilizumab CT-011 Atezolizumab MPDL3280A Durvalumab MEDI-4736 Avelumab MSB0010718C
CureTech Genentech-Roche Astra-Zeneca/Medimmune Pfizer/Merck Serono
PD-L1
Development stage FDA approved (melanoma) Phase I–III multiple tumors Phase I–III multiple tumors FDA approved (melanoma, NSCLC, RCC) Phase III multiple tumors (NSCLC, melanoma, RCC, HNSCC, GBM, gastric) FDA approved (melanoma, NSCLC) Phase III multiple tumors (HNSCC, NSCLC, melanoma, bladder, gastric/GE) Phase II multiple tumors (pancreatic, CRC, RCC, prostate, CNS) Phase III multiple tumors (NSCLC, bladder, RCC, TNBC) Phase III multiple tumors (NSCLC, HNSCC) Phase III (NSCLC)
Abbreviations: BMS: Bristol-Myers Squibb, CNS: Central Nervous System, CRC: Colorectal Cancer, FDA: US Food and Drug Administration, GBM: Glioblastoma multiforme, GE: gastro-esophageal, HNSCC: head and neck squamous cell carcinoma, MSD: Merck Sharp and Dohme, NSCLC: non-small cell lung cancer, RCC: renal cell carcinoma, TNBC: triple negative breast cancer.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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significant difference between ICB and controls (HR, 0.73; 95% CI, 0.66–0.81; P < 0.001). For 1244 older patients, ICB also significantly improved OS (HR, 0.72; 95% CI, 0.58–0.90; P = 0.004) in comparison with controls. This meta-analysis revealed that there was no statistically significant difference between subgroups of younger and older patients concerning the pooled HR for OS (P = 0.93). We detail below elderly efficacy data in some of the key reported phase 3 trials of CTLA4 or PD1/PD-L1 targeting agents.
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in a phase III study.31 655 were included, 328 in tremelimumab group and 327 in chemotherapy group. Unfortunately, there was no difference in OS in the two groups, 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = 0.127). In this study, 200 (31%) patients were aged over 65 years, 110 in tremelimumab group and 90 in chemotherapy group. There was no difference in overall survival between these groups in the elderly population (HR = 0.87, P = 0.384).
3.1. Ipilimumab Ipilimumab is a fully humanized monoclonal antibody directed against CTLA4. This therapeutic agent was the first immune checkpoint inhibitor to be approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. In a phase 3 trial, ipilimumab, with or without a glycoprotein 100 (gp100) peptide vaccine, was compared with gp100 alone in patients with previously treated metastatic melanoma.29 676 patients were included in the study; 403 were randomly assigned to receive ipilimumab, at a dose of 3 mg per kilogram of body weight, plus gp100, 137 to receive ipilimumab alone, and 136 to receive gp100 alone. Ipilimumab was administered once every 3 weeks for four treatments. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P < 0.001). The median overall survival (OS) with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Among these 676 patients on this trial, 196 (29%) were aged over 65 years. 112 patients were randomized in the group with Ipilimumab and gp100, 42 in the group with gp100 alone and 42 in the group with Ipilimumab alone. Analyses of OS in these subgroups showed that the effect of ipilimumab was independent of age. In the elderly population, a 31% reduction in the risk of death was noted with ipilimumab plus gp100, as compared with gp100 alone (hazard ratio, 0.69 (0.47–1.01)), and a 39% reduction in risk of death was seen with ipilimumab alone as compared with gp100 alone (hazard ratio, 0.61 (0.38–0.99)). Sileni et al. assessed the efficacy and safety of ipilimumab at its approved dose of 3 mg/kg in elderly patients within an expanded access program.30 193 patients over 70 years were included and among these patients, 27 were aged over 80 years. The immune related disease control rate (irDCR) was 38%, with 2% of irCR (complete response), 13% with irPR (partial response) and 23% with irSD (stable disease). The median duration of irDC was 11.5 months (95% CI 9.3–13.7). There was no difference in median OS between ≥70 years (8.9 months (95% CI 7.2–10.6)) and < 70 years (7.0 months (95% CI 6.1–7.9)) P = 0.17.
3.2. Tremelimumab Tremelimumab is a fully human IgG2 monoclonal antibody directed against CTLA4. Ribas et al. assessed the efficacy and safety of tremelimumab (15 mg/kg once every 90 days) versus chemotherapy in patients with treatment-naive, unresectable stage IIIc or IV melanoma,
4. Anti-PD1 agents: nivolumab and pembrolizumab 4.1. Nivolumab Nivolumab (BMS 936558, MDX 1106, ONO-4538), is a fully human IgG4 monoclonal antibody against the PD1 receptor, blocking its binding with its ligands (PD-L1 and PD-L2). In a phase III study, Borghaei et al. assessed the efficacy and tolerance of nivolumab in non-small cell lung cancer (NSCLC) patients, in second line of treatment after platinumbased doublet chemotherapy.32 582 patients were included, 287 were randomly assessed to receive nivolumab (3 mg/kg every 2 weeks) and 268 received docetaxel (5 mg/m2 every 3 weeks). Nivolumab has shown an improvement in OS compared to docetaxel with a median of OS at 12.2 months (95% CI, 9.7 to 15.0) in the nivolumab group versus 9.4 months (95% CI, 8.1 to 10.7) in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P = 0.002). At 1 year, the OS rate was 51% (95% CI, 45 to 56) in nivolumab group versus 39% (95% CI, 33 to 45) in the docetaxel group. In this trial, 200 (34%) patients were aged between 65 and 75 years old and a set of 43 (7%) were aged over 75 years. A 37% reduction of the risk of death was observed in the nivolumab group, compared to docetaxel group (hazard ratio, 0.63 (0.45–0.89)) in ≥65 to <75 years group. A 10% reduction in the risk of death was noted with nivolumab, as compared with docetaxel (hazard ratio, 0.90 (0.43–1.87)) in ≥ 75 years group. Motzer et al., in a randomized phase III trial in advanced renal cell carcinoma (RCC), reported a 27% reduction risk of death with nivolumab as compared with everolimus.33 In this study, 324 patients (39%) were aged over 65 years old. This benefit was showed in patients aged between 65 and 75 years old with a 36% reduction of the risk of death with nivolumab compared with everolimus (hazard ratio, 0.64 (0.45–0.91)). However, this benefit was not observed in the group over 75 years old (hazard ratio, 1.23 (0.66–2.31)), potentially due to lack of power in this subgroup.
4.2. Pembrolizumab Pembrolizumab is a humanized IgG4 antibody against PD1. In a phase III study, Robert et al., compared pembrolizumab (10 mg/kg, every 2 weeks or every 3 weeks) to four doses of ipilimumab (at 3 mg/kg every 3 weeks) in patients with advanced melanoma.34 834 patients were included, 279 were randomly assigned to receive pembrolizumab every 2 weeks, 277 to receive pembrolizumab every 3 weeks, and 278 to receive ipilimumab. OS rates at 1 year were 74.1% for patients receiving pembrolizumab every 2 weeks (hazard ratio for
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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death as compared with the ipilimumab group, 0.63; 95% CI, 0.47 to 0.83; P < 0.0005), 68.4% for the pembrolizumab group every 3 weeks (hazard ratio for death as compared with the ipilimumab group, 0.69; 95% CI, 0.52 to 0.90; P = 0.004), and 58.2% for the ipilimumab group. It was a one year estimate of survival. In this study, 238 (29%) patients were aged over 65 years.
5. Anti-PD-L1 agents: Atezolizumab and Durvalumab Atezolizumab (MPDL3280A, humanized IgG4) and Durvalumab (MEDI 4736, fully human IgG1) are human antibodies targeting PD-L1 (IgG4 and IgG1 respectively). These two agents have shown promising efficacy in multiple cancer subtypes, however no data is currently available concerning efficacy in older patients.35,36 As reported above, the current data is very promising, showing similar benefit of anti-CTLA4 and anti PD-1 therapeutics in older patients as compared to the overall population. Nevertheless, these preliminary results are limited to subgroup analysis and dedicated studies are therefore needed to confirm efficacy of ICBs in older patients with cancer. Moreover, to avoid bias due to studies heterogeneity, future meta-analysis studies should focus on approved ICB individually and be limited to specific tumor types.
6. ICB toxicity profile: immune-related adverse events (irAEs) ICB may be responsible for specific toxicities called “immunerelated adverse events” (irAEs). These irAEs are related to the infiltration of normal tissues by activated T cells responsible for autoimmunity. Since ICs have a key physiological role and are not only expressed by tumor cells, blocking IC can potentially amplify any immune response present in the patient and nearly all organs can be affected (Fig. 1). As reported in the literature,3–8,37 immune toxicities can affect the skin (maculopapular rash, vitiligo, psoriasis, Lyell syndrome, DRESS), the gastrointestinal tract (enterocolitis, gastritis, pancreatitis, coeliac disease), the endocrine glands (hypo- or hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes), the lung (pneumonitis, pleural effusion, sarcoidosis), the nervous system (peripheral neuropathy, aseptic meningitis, Guillain–Barré syndrome, encephalopathy, myelitis, meningo– radiculo-neuritis, myasthenia), the liver (hepatitis), the kidney (granulomatous interstitial nephritis, lupus-like glomerulonephritis), hematological cells (hemolytic anemia, thrombocytopenia, neutropenia, pancytopenia), the musculo-articular system (arthritis, myopathies), the heart (pericarditis, cardiomyopathy) and/or the eyes (uveitis, conjunctivitis, blepharitis, retinitis, choroiditis, orbital myositis). Fortunately, most of these serious immune-related adverse events are individually rare(<1%).3–5
However, this low frequency leads to difficulties in diagnosis and treatment due to lack of experience. The spectrum of toxicities observed with anti CTLA4 or anti PD1/PD-L1 is similar but the frequencies differ.34,35,38,39 Indeed, anti-CTLA4 is more toxic than anti-PD1/PD-L1: The rate of grade 3–4 toxicities with anti-CTLA4 is around 20–30% versus 10–15% for anti PD-1. For anti-CTLA 4, the most commonly observed toxicities (>10%) are diarrhea, rash, pruritus, fatigue, nausea, vomiting, anorexia and abdominal pain.3,6 For anti-PD1 the most commonly observed toxicities (>10%) are fatigue, rash, pruritus, diarrhea, nausea and arthralgia.4,5,7,8 The main ICB life-threatening toxicities are dysimmune colitis (more common for anti-CTLA4) and interstitial pneumonitis (for the anti-PD1). Other severe toxicities were reported, including infusion reactions, Guillain–Barré syndrome, type 1 diabetes with ketoacidosis, Stevens Johnson syndromes or autoimmune anemia and thrombocytopenia with bleeding complications. Interestingly, it seems that the detection and early treatment of irAEs could limit their severity. Most irAEs are mild and can be treated symptomatically. Depending on their severity, irAEs require close monitoring, interruption or discontinuation of the ICB, introduction of corticosteroid therapy, and in some cases more immunosuppressive medications such as of anti-TNF therapy (infliximab). Several guidelines have been proposed for the management of these irAEs.40–43 It has to be noted that the current recommendations are only based on experts' consensus since no prospective study has been done to date to evaluate the different managements. The kinetics of onset and resolution of these toxicities is particularly different from what is observed with conventional anti-cancer treatments. Despite the fact that the majority of irAEs usually occur within the first 4 months of treatment,44 immune toxicities can also occur at any time during treatment: at the beginning, during treatment course, but also several months after discontinuation. This feature of irAEs supports a careful monitoring throughout the treatment and after termination. In the absence of sufficient experience, it is now accepted that this monitoring should continue for at least one year after stopping immunotherapy.
6.1. ICB combinations are associated with higher toxicities ICB combinations or associated with targeted therapy or conventional chemotherapy have systematically shown an increased toxicity. The combination of ipilimumab (anti-CTLA4) with nivolumab (anti-PD1) is responsible for 55% grade 3–4 adverse events.38 The combination of ipilimumab with conventional chemotherapy in lung cancer causes 58% of grades 3–4 toxicities (against 52% in the sequential arm and 42% in the chemotherapy alone arm).45 Finally, ipilimumab combination with vemurafenib in melanoma is responsible for asymptomatic but severe liver toxicity with an early elevation of transaminases
Fig. 1 – Spectrum of immune-related adverse events (irAEs). From: Champiat, S., Lambotte, O., Barreau, E., Belkhir, R., Berdelou, A., Carbonnel, F., et al. (2015). Management of Immune Checkpoint Blockade Dysimmune Toxicities: a collaborative position paper. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, mdv623. http://doi.org/10.1093/annonc/mdv623. Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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or bilirubin within 3 weeks after initiation of ipilimumab.46 Given the toxicity observed in the early patients, this phase I trial was stopped.
6.2. Do irAEs differ in older patients? Immune-related side effects may be more challenging in older patients due to reduced functional reserve and age-associated comorbidities.1,2 Furthermore the “immunosenescence” phenomenon,47,48 which is the term given to age-associated impairments of the immune system, could affect the efficacy and/or the toxicity of immune checkpoint blockade. In fact, during aging, the expression patterns of T cell co-stimulatory or co-inhibitory proteins change considerably: the expression of inhibitory receptors such as PD-1 or LAG-3 is enhanced, associated with a decrease of the costimulatory molecules. Paradoxically, immunosenescence is also coupled with higher concentrations of inflammatory cytokines, called “inflammaging”. Finally, older patients are known to have a higher prevalence of autoantibodies49,50 and one can expect that ICB may reveal subclinical autoimmune diseases. Using ipilimumab in elderly melanoma patients, Sileni reported that patients over 70 years old presented irAE with a similar frequency compared to overall population.30 A retrospective analysis of irAEs in melanoma patients <65 compared to those > 65 treated with nivolumab was recently reported.51 Data pooled 148 patients treated with nivolumab plus peptide vaccine or nivolumab alone every two weeks for at least 12 weeks. Frequency, grade, and characteristics of irAEs were analyzed among patients > 65 and < 65 years of age. This study showed no statistically significant difference in incidence of irAEs and the irAE profile was similar in the two groups. Thus, despite speculation about the specificities of
older adult immunity, the current safety data appears to be similar to the population at large. Across the different approved ICBs, no overall differences in safety were reported in elderly patients (≥65 y.o.) and no dose adjustment is recommended.3–8 The currently approved ICBs have not been evaluated in patients with severe renal or hepatic impairment. Nevertheless, no dose adjustment is recommended for patients with mild or moderate renal impairment (i.e. ≥30 ml/min creatinine clearance) or mild hepatic impairment (i.e. total bilirubin > upper limit normal to 1.5 N). As older patients with cancer are often taking medications for other comorbidities, it is important to note that the currently approved ICB monoclonal antibodies are not metabolized by cytochrome P450 enzymes, therefore enzymatic competition is not expected. The use of corticosteroids may hypothetically interfere with ICB efficacy (even if it has not been evaluated by proper studies) and is recommended to avoid at baseline. Patients treated by anticoagulants or anti-aggregants must be carefully monitored in case of colitis symptoms (risk of gastrointestinal hemorrhage) or autoimmune thrombocytopenia.
7. Principle of clinical management of irAEs Clinical management of irAEs is new to many oncologists and expertise is still limited. Here are some key principles that have been proposed to properly manage patients treated by ICB40 (Fig. 2).
7.1. Prevent Before initiation of immunotherapy, it is recommended to detect any personal or family history of autoimmune disease
Fig. 2 – Principle of clinical management of irAEs. From: Champiat, S., Lambotte, O., Barreau, E., Belkhir, R., Berdelou, A., Carbonnel, F., et al. (2015). Management of Immune Checkpoint Blockade Dysimmune Toxicities: a collaborative position paper. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, mdv623. http://doi.org/10.1093/annonc/mdv623. Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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or chronic viral infection which pathogenesis might be potentiated by the ICB treatment. Nevertheless, a controlled autoimmune disease is not considered as a contraindication for currently approved ICBs. In such case, ICBs should be used with caution after careful consideration of the potential risk– benefit on an individual basis.3,6 To facilitate early identification of symptoms related to irAEs, it is key to inform the patient, his/her family and his/her caregivers about the nature and specificity of irAEs. It is important to ask the patient to promptly report any new symptoms or worsening of pre-existing symptoms to allow proper assessment without delay. Patients must also be informed that immune-adverse reactions may occur at any time: at the beginning, during or after treatment discontinuation.
7.2. Anticipate Since patients with cancer can present with toxicity sequelae from previous treatments, physical examination, laboratory tests and imaging performed at baseline must be used as a reference for any new abnormality occurring during immunotherapy. Any baseline comorbidity should be properly evaluated before initiation and during ICB treatment. Minimal testing should include CBC, renal function, serum electrolytes, liver function and regular thyroid evaluation (TSH). Chest imaging should be systematically performed at baseline as a reference in case a pulmonary toxicity occurs.
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– Organ-specialist advice to assess the interest of other immunosuppressive agents (such as anti-TNF for severe colitis), especially for severe, persistent or relapsing toxicities It is important to note that corticotherapy is not systematic in the treatment of irAEs: most grade 1 irAEs can be managed with symptomatic treatment only. Also, ICB dose reduction is currently not recommended for the 3 approved ICBs.
7.5. Monitor irAE resolution can highly vary across the different types of toxicities: gastrointestinal, hepatic and renal toxicities usually quickly improve when immunosuppressants are started, on the other side, rash and endocrine irAEs are more chronic. Endocrine insufficiencies often require long-term hormonal substitution.38,52,53 In case a corticotherapy is started, steroids should be gradually tapered (usually over a period of ≥1 month) to avoid recurrence or worsening of the irAE. Finally the use of prolonged immunosuppressive treatments requires proper monitoring and prophylactic treatment to avoid life-threatening opportunistic infections.54 In older adults, tolerance of irAEs should be carefully monitored as associated comorbidities may decompensate more easily. Moreover the use of some symptomatic treatments (such as antihistamine for pruritis) or corticosteroids may expose older patients to iatrogenic events such as diabetes worsening, mental status disturbance, hypertension and delirium.
7.3. Detect New symptoms or increase of pre-existing symptoms should be systematically suspected to be an irAE. However irAE frequency is relatively low compared to other etiologies such as disease progression or intercurrent infection and these must be first ruled out. Nevertheless, dysimmune toxicities should always be considered and lead to proper investigations. Baseline assessment is then essential because it will serve as a reference. In clinical practice one must pay particular attention to the occurrence of respiratory (cough, dyspnea), gastrointestinal (diarrhea) or skin (rash, pruritus) symptoms. Non-specific general signs must suggest endocrine toxicity (especially thyroid dysfunction). Laboratory tests particularly will look at hematological toxicity (anemia, thrombocytopenia), hepatic (transaminase elevation) and kidney (increased serum creatinine) toxicities. TSH should be regularly checked (every 2– 3 months). Since irAEs can be delayed, patients' clinical and biological monitoring should be maintained after therapy discontinuation (every 3–6 months).
7.4. Treat Suspicion or diagnosis of an irAE always requires close monitoring to detect any worsening or relapse. Facing the diagnosis of an irAEs, several elements must be discussed: – – – –
Patient information about self-monitoring elements Symptomatic treatment Suspension or termination of immunotherapy agent Corticosteroid therapy
8. Conclusion ICBs such as anti-CTLA4 and anti PD1/PD-L1 are already part of the approved treatments for patients with advanced melanoma, NSCLC and RCC. As most of ICB studies have involved a low number of older patients it remains difficult to confirm the impact of these new therapeutics in elderly. One could expect that clinical specificity of older patients (comorbidities, co-medications, reduced functional reserve) and immunosenescence may affect ICB efficacy and tolerance in this population. However, ICB preliminary data presented in this review are very encouraging and suggest that older adults will benefit from the ICB revolution in oncology without increased toxicity. ICB toxicities are new to clinicians as they are distinct from those associated with traditional chemotherapeutic agents or molecularly targeted therapies. The use of immunotherapy agents will likely be widely expanded in the near term and it is critical that healthcare practitioners become more familiar with immune-related toxicities. The current experience with irAEs is limited and the current management guidelines are based on experts' consensus. Collaborative initiatives will be needed to evaluate and standardize the management of the different irAEs. Finally, as malignancies are often diagnosed in older patients, dedicated studies in elderly are necessary to properly and safely use these immunotherapeutics.
Disclosures and conflict of interest statements The authors have no conflicts of interest to report.
Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007
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Author contributions All of the authors have participated to the writing of the manuscript and approved its content. REFERENCES
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Please cite this article as: Helissey C, et al, The development of immunotherapy in older adults: New treatments, new toxicities?, J Geriatr Oncol (2016), http://dx.doi.org/10.1016/j.jgo.2016.05.007