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Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours
European Journal of Cancer 95 (2018) 68e74
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours H. Herin a, S. Aspeslagh a, E. Castanon a, V. Dyevre b, A. Marabelle a, A. Varga a, S. Postel Vinay a, J.M. Michot a, V. Ribrag a, A. Gazzah a, R. Bahleda a, O. Mir a, C. Massard a, A. Hollebecque a, J.C. Soria a, C. Baldini a,* a b
Gustave Roussy, Universite´ Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France Gustave Roussy, Universite´ Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, F-94805, France
Received 28 February 2018; accepted 8 March 2018
KEYWORDS Phase I trials; Immunotherapy; Older patients
Abstract Background: The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. Methods: All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Caseecontrol analysis was performed in OPs (patients 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. Results: Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade IIIeIV IrAEs. Cumulative incidence of grade IeII IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade IIIeIV IrAEs (p Z 0.50). Older age was not associated with lower dose intensity of treatment (p Z 0.14). No significant difference was observed between
* Corresponding author: Fax: þ33 (0)142116444. E-mail address: [email protected] (C. Baldini). https://doi.org/10.1016/j.ejca.2018.03.002 0959-8049/ª 2018 Elsevier Ltd. All rights reserved.
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OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94e2.11] p Z 0.09) or median overall survival (HR 0.92, 95% CI [0.61e1.39] p Z 0.77). Conclusion: Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials. ª 2018 Elsevier Ltd. All rights reserved.
1. Introduction Ageing is associated with an increase of cancer incidence [1]. Since the last century, the number of elderly people worldwide has raised constantly due to increasing life expectancy. In 2050, 30% of the European population is expected to be older than 60 years [2]. In 2012, in France, people older than 75 years accounted for 32% of new cancer cases, reflecting the need of finding an optimal treatment in this population [3]. However older patients (OPs) are still underrepresented in clinical trials [4]. Restrictive inclusion criteria, comorbidities, polymedication, physician’s perception of OPs, fear of toxicity or patient’s refusal are the main reasons for limiting the inclusion of OPs in clinical trials [5]. New evidence and new treatment approach are warranted in this population to improve cancer care. In the past years, restoring a patient’s own immunity against cancer with immunotherapy has profoundly changed the management of patients with cancer [7,8]. Various monoclonal antibodies have been developed to target immune checkpoints [9].Their blockade can improve antitumour immune responses by reinvigorating an efficient antitumour T-cell response. The most promising immune checkpoint inhibitors (ICIs) currently are directed against cytotoxic T-lymphocyteeassociated protein 4 (CTLA4), programmed death 1 (PD1) and programmed death ligand 1 (PDL-1). Some are approved in various cancer types where the proportion of elderly patients is important, such as nonesmall cell lung cancer (NSCLC), bladder carcinoma, head and neck cancer, melanoma and renal cell carcinoma [10e14], and new indications are arising [15,16]. Nevertheless, at the moment, there is few evidence of efficacy and tolerance of these drugs in the geriatric population [17]. At the same time, a decline of both adaptive and innate immunity is observed with increasing age [18]. This phenomenon, called immunosenescence (IS), is responsible for poor response to vaccination and increased susceptibility to infections [19]. In addition, increased prevalence of some autoimmune diseases is linked with an increase of auto-antibodies observed in OPs [20]. Especially in this population, modification of the immune cell phenotype, immune microenvironment and intracellular communication are the main reasons for dysfunctional immune responses [21]. Besides, IS is also associated with a state of chronic low-grade
inflammation called inflammaging, responsible for altered level of cytokines. All these reasons urged us to analyse efficacy and toxicity of ICI therapy. Therefore, the aim of this study is to compare safety profile and treatment outcome between OPs and YPs in early immunotherapy clinical trials. 2. Patients and methods 2.1. Patients We retrospectively reviewed all cases of patients with advanced solid tumour, enrolled in immunotherapy phase I trials, between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy Cancer Centre. We performed a caseecontrol analysis and selected all patients 70 years (OP) included in these trials. Patients <70 years (YP) were used as the control group. The two groups were matched according to trial and dose treatment. Cases were matched to up to five controls. Controls were randomly assigned inside trials and level doses. We recorded patients, treatment characteristics and clinical outcome until the last follow up. The eligibility criteria for the phase I clinical trial were as follows: age 18, Eastern Cooperative Group (ECOG) performance status (PS), measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Other eligibility criteria varied according to each trial. All patients signed a written informed consent before trial enrolment. 2.2. Statistics Descriptive statistics were used to summarise patient characteristics. The following variables were collected prospectively by the trial investigators: gender, age at inclusion, Charlson index, tumoural type, medical history of autoimmune disease, number of comedications, number of prior lines of therapy, ECOG status, body mass index, number of metastatic sites, type of metastasis, albumin level, lactate dehydrogenase (LDH) level, renal function (clearance), toxicity and treatment characteristics. Charlson index was estimated without the count of age and cancer co-morbidity. The Royal Marsden Hospital (RMH) score, a survival prognostic score for patients included in the early clinical trial, was also calculated [22]. A p-value less than 0.05 was
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considered statistically significant. Toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE), version per protocol. We compared grade and type of immune-related adverse event (IrAEs). Cumulative incidence of IrAEs was calculated according to Fine and Gray method and compared between grades of IrAEs using Gray non-parametric test. For each patient, we recorded the observed dose under the number of cycles received and the theoretical dose. The relative dose intensity of treatment was calculated and compared using a marginal model (GEE). Treatment response was assessed by our radiologist using RECIST 1.1 criteria. Overall response rate was compared using conditional logistic regression. The disease control rate was defined as a response or stable disease obtained for at least 6 months and was compared using a Wald test. Overall survival (OS) was defined as the time from the start date of treatment until death from any cause or the last follow up. Progression-free survival (PFS) was defined as the period from the start date of the trial until the date of the end of treatment. We estimated and compared OS and PFS by KaplaneMeier methods and log rank test. Analysis was conducted using R 3.3.2 and Stata 14.1. 3. Results 3.1. Patients characteristics Two hundred twenty patients were included, 46 (20%) OPs and 174 (80%) YPs. The median age of patients was 75 [70e88] years in the older group and 55 [22e69] years in the younger group. Patients had a good performance status with 13% (6/46) of the YPs and 36% (62/174) of the OPs having ECOG 0 and 87% (40/46) of the YPs and 62% (108/174) of the OPs having ECOG 1. Polymedication was present especially in OPs with 57% having more than five medications versus 38% in YPs. The most represented tumour types were bladder carcinoma (22%), NSCLC (19%), gastrointestinal cancer (14%), gynaecological cancer (12%), head and neck carcinoma (10%), breast cancer (7%) and renal cell carcinoma (6%). Fifty-nine percent of patients had an RMH score greater than 2, which was similar in both the groups (Table 1). Considering biological characteristics, 33% of OPs had an albumin level <35 g/l, and 35% of OPs had a creatinine clearance according to Modification of Diet in Renal Disease < 60 mL/min (Table 2). 3.2. Clinical trials During the study period, 31 trials testing several combinations of immunotherapy were conducted at our centre, and 14 trials enrolled OPs. The proportion of
Table 1 Clinical characteristic of study population. Characteristics
OP
YP
Total
Number (%)
Number (%)
Number (%)
71 (41) 103 (59)
90 (41) 130 (59)
62 (36) 108 (62) 4 (2)
68 (31) 148 (67) 4 (2)
134 (77) 40 (33)
158 (72) 62 (38)
9 (5) 165 (95)
13 (6) 207 (94)
107 (61) 67 (39)
127 (58) 93 (42)
13 39 44 78
17 51 60 92
Sex Women 19 (41) Men 27 (59) PS 0 6 (13) 1 40 (87) 2 0 Charlson index 0 24 (52) 1 22 (48) Auto immune disease history Yes 4 (9) No 42 (91) Co medication number <5 20 (43) 5 26 (57) Prior lines number None 4 (9) 1 12 (26) 2 16 (35) 3 14 (30) Metastatic site number 0 0 1 17 (37) 2 16 (35) 3 13 (28) Body mass index 18.5 1 (2) 18.5e25 31 (68) 25 14 (30) RMH 0e1 20 (44) 2e3 25 (56)
(7) (23) (25) (45)
(8) (23) (27) (42)
8 (5) 46 (26) 71 (41) 49 (28)
8 (4) 63 (28) 87 (40) 64 (28)
15 (9) 92 (53) 66 (38)
16 (7) 123 (56) 80 (37)
70 (40) 104 (60)
90 (41) 129 (59)
Abbreviations: OP: older patients; YP: younger patients; RMH: Royal Marsden Score; PS, performance status.
OPs included in phase I trial during this period of time was 46 of 240 (19%). Among the 14 trials, seven were investigating an anti-PD1/PDL-1 monotherapy, six a combination of anti-PD1/PDL-1 with other immunomodulatory monoclonal antibodies and one a combination of anti-PD1 with a targeted therapy. Patients received a median of 5 (1e55) cycles of therapy. No dose reduction of immunotherapy agent was observed. There was no difference in relative dose intensity between YPs and OPs (p Z 0.14) (Fig. 1). 3.3. Toxicity profile Grade I IrAEs were experienced by 53% (117/220) of patients, 72% (33/46) of OPs and 48% (84/174) of YPs. A quarter of patients presented grade II IrAEs, 41% (19/ 46) of OPs and 20% (35/174) of YPs (Fig. 2). Cumulative incidence of grade I (p Z 0.039), grade II (p Z 0.035) and grade IeII (p < 0.001) IrAEs was significantly different between OPs and YPs. Grade IIIeIV IrAES occurred in 22% (10/46) of OPs and 13%
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Table 2 Biological characteristic of study population. Characteristics
OP Median (range)
LDH 195 (118e604) 250 >250 Albumin 37.5 (22e45) <35 g/l 35 g/l Creatinine clearance 90 60e89 45e59 <45
YP Number (%)
Total
Median (range)
Number (%)
203 (69e8147) 31 (69) 14 (31)
Median (range)
Number (%)
202 (69e8147) 123 (71) 51 (29)
37 (22e50)
154 (70) 65 (30) 37 (22e50)
15 (33) 31 (67)
49 (28) 125 (72)
64 (29) 156 (71)
13 (28) 17 (37) 11 (24) 5 (11)
88 (50) 69 (40) 12 (7) 5 (3)
101 (46) 86 (39) 23 (10) 10 (5)
Abbreviations: OP: older patients; YP: younger patients; LDH: lactate dehydrogenase.
dermatomyositis, neuropathy, colitis and fever. One dose-limiting toxicity was reported in the YP group. Ten patients stopped treatment because of toxicity (6 YPs and 4 OPs). 3.4. Response rate and survival
Fig. 1. Relative dose intensity (RDI) in OPs and YPs (OP: older patient; YP: younger patient).
Two hundred thirteen patients were evaluable for efficacy. The response rate was 14% for OPs and 18.5% for YPs (p Z 0.52). Disease control rate was 29%, with disease control obtained for 46 YPs (26%) and 18 OPs (39%). Main reasons for trial discontinuation were progressive disease for 159 patients (89%), toxicity for 10 patients (5.6%), death caused by drug not related to the study for four patients (2.2%), sponsor’s decision for two patients and an intercurrent medical event for three patients. Forty-two patients were still on trial at the time of the analysis. No difference was observed in median PFS between the two groups with 5.3 months (95% confidence interval [CI] 2.9e10.8) for OPs and 3.1 months (95% CI 2.6e4) for YPs (hazard ratio [HR] 1.41, 95% CI 0.94e2.11; p Z 0.09) (Fig. 3). Median OS was 7.1 months (95% CI 5.8e15.8) in OPs and 9.8 months in YPs (95% CI 7.1e13) (HR 0.92, 95% CI 0.61e1.39; p Z 0.77) (Figs. 4 and 5). 4. Discussion
Fig. 2. Description of IrAEs grade in OPs and YPs (IrAEs: Immune-related Adverse Events; OP: older patient; YP: younger patient).
(23/174) of YPs without statistical significance (p Z 0.12). There was no difference in cumulative incidence of grade IIIeIV IrAEs noticed between the two groups (p Z 0.50) (Fig. 2). Median time before first event was 16 d (7e41) for OPs and 36 d (14e81) for YPs. Grade III/IV IrAEs were skin rash, arthralgia, hepatic cytolysis, asymptomatic lipase increase,
Our study is the first to investigate tolerability and efficacy of immunotherapy in OPs in phase I trials. In our analysis, we observed more grade IeII IrAEs in OPs than in YPs, but no statistical significance in severe toxicity (grade IIIeIV) and no difference in cumulative incidence of grade IIIeIV IrAEs were observed. ICIs are usually associated with lower rates of AEs of any grade than conventional cancer therapy [23]. However, current data available in the literature regarding toxicity in OPs treated with ICIs are conflicting. Subset analysis in phase II/III trials, including advanced NSCLC, melanoma and renal cell carcinoma,
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Fig. 3. Cumulative incidence of grade I, 2II and III/IV IrAEs in OPs and YPs (IrAEs: Immune-related Adverse Events; OP: older patient; YP: younger patient).
confirmed that nivolumab (anti-PD1) is well tolerated in OPs, but there seems to be a trend of increased grade IIIeV toxicity in patients older than 70 years [24e26]. Regarding anti-CTLA4 in monotherapy, Chiarion et al. analysed the subgroup of patients older than 70 years with metastatic melanoma in an expanded access program for ipilimumab and reported the same incidence
Fig. 4. Progression-free survival according to age group.
Fig. 5. Overall survival according to age group.
of grade IIIeIV IrAEs compared with the overall population [27]. However, combination therapies with anti-CTLA4 appeared to be more toxic. Friedman et al. reported an increase of high-grade toxicity in patients with melanoma older than 80 years with the combination of ipilimumab and nivolumab [28]. In our study, we had no trials testing anti-CTLA4 in combination. IrAEs usually occurred during the first 2 months of treatment [29], but remarkably, they appear earlier in OPs in our study (16 d versus 36 d), which might be related to an increased presence of autoimmune antibodies in OPs at baseline [20,30]. Increased incidence of grade IeII toxicity in our study and early occurrence of these toxicities can have consequences in OPs. For example, diarrhoea grade II can lead to dehydration and hospitalisation in this population. Thus, IrAES even of low grade should be monitored closely. Presently, there are no specific guidelines to manage IrAES in OPs compared with YPs, but the impact of some grade II toxicities and the use of corticosteroids in this population might lead to adapted guidelines. Notably, no dose adjustments are recommended with ICIs according to comorbidities or toxicity [17]. We also evaluated efficacy of immunotherapy in OPs, and no differences were observed between OPs and YPs. Our results are consistent with previous published works. In first line patients with NSCLC treated with pembrolizumab (anti PD1), Reck et al. observed a better hazard ratio for disease progression or death in patients 65 years than those < 65 years (HR 0.45, 95% CI 0.29e0.70) versus HR 0.61 (95% CI, 0.40e0.95) [11]. In checkmate 017 and 057, survival outcomes of nivolumab in second line, respectively, for squamous cell and nonesquamous cell NSCLC were comparable between OPs and YPs. However, the HR for survival of the subset of patient 75 years in both studies were non-significant 1.85 (95% CI, 0.76e4.51) and 0.90 (95% CI, 0.43e1.87) [31,32]. In renal cell carcinoma, nivolumab did not show benefit in the subgroup of patients 75 years with HR 1.23 (95% CI, 0.66e2.31) [12]. Finally, in a meta-analysis on 3322 patients, from six phase III randomised clinical trials of ICIs, Nishijima et al. compared OPs and YPs with an age cut-off of 65e70. In the subset of patient older than 75 years treated with anti-PD1, there was no benefit on OS (HR Z 0.86 [0.41e1.83]; p Z 0.70) [33]. Therefore, the benefit of immunotherapy in patients older than 75 years is still controversial and needs more evidence [34]. Furthermore, new patterns of response have been described and are associated with older age. ‘Hyperprogressive disease’ has been described in 10% of patients and more frequently in patients older than 65 years (19% versus 5%) [35e37]. The influence of immunosenescence and particularly T cell modification on the response to ICIs needs to be clarified. Ageing is impacting composition, physiological function and
H. Herin et al. / European Journal of Cancer 95 (2018) 68e74
competence of normal immunity [38]. Mechanisms of ‘hyperprogression’ are not yet understood but could be explained in OPs by the modification in subpopulation of immune cells, inflammaging process associated with a cytokine pro-inflammatory secretion profile or alteration of costimulatory receptors in T-cell population [21]. In preclinical studies in mice, introduction of immunotherapy was associated with an increase of proinflammatory cytokines such as interleukin-6, tumour necrosis factor-a or interferon-g, responsible for lethal toxicities in multiple organs. Thus, stimulation by immunotherapy of tumoural microenvironment could result in more toxicity [39,40]. The main limitations of this study are the single-site design and the small number of patients older than 70 years analysed. Owing to the retrospective data collection, we did not have any information about geriatric assessment or screening tools such as G8. Moreover, our recruitment is biased; OPs included in phase I trials are fit patients with good ECOG and have no impaired organ function due to the trial’s restrictive criteria. They are not representative of global geriatric population, and our results are therefore not applicable to all OPs. Indeed, Wong et al. analysed 91 patients with advanced melanoma treated by anti PD1 and showed that patients with an ECOG PS of 2e3 have a lower OS and a reduced response compared with those with an ECOG PS of 0e2 (19.5 months versus 1.8 months, HR 5.5; 95% CI [9.1e50.3], p Z 0.0001) [41]. OPs with bad performance status might not have a real benefit with immunebased therapies. 5. Conclusion Our analysis seems to be in favour of ICIs as a practicable option of treatment for elderly patients. The grade IIIeV toxicity rate and efficacy profiles appear similar to the ones in YPs. Age should not be a deciding factor when considering ICIs. Specific guidelines should be set up, and dedicated studies in this population are warranted. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors. Declarations of interest None. Conflict of interest statement Sandrine Aspeslagh received speakers fee from BMS, Astra Zeneca and Roche.Aurelien Marabelle
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received honoraria/consultancy fees from Medimmune, Lilly, Amgen, BMS, Merck Serono, Sanofi Genzyme, Janssen, Astellas, Genentech, Orion and Ipsen. Sophie Postel Vinay received honoraria from Astra Zeneca. Aurelien Marabelle received honoraria/consultancy fees from Medimmune, Lilly, Amgen, BMS, Merck Serono, Sanofi Genzyme, Janssen, Astellas, Genentech, Orion and Ipsen. Sophie Postel Vinay received honoraria from Astra Zeneca. Antoine Hollebecque received honoraria from Merck Serono, had an advisory role for AMGEN and Lilly and received travel and accommodation expenses from Amgen and Servier. Massard received honoraria/consultancy fees from Sanofi Genzyme and JanssenAstellasGenentechOrionMedimmune and Ipsen, and Christophe Massard received honoraria/consultancy fees from Sanofi Genzyme, Janssen, Astellas, Genentech, Orion, Medimmune and Ipsen. Jean-Charles Soria is employed in Medimmune and receives honoraria from Astra Zeneca, Astex, Clovis, GSK, Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pharmamar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. The rest of the authors have no conflicts of interest to declare.
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treatment of advanced melanoma (mel) in patients (pts) age 80 and older (80þ). ASCO Meeting Abstracts 2016;34:10009. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017 Mar;35(7):785e92. Candore G, Grimaldi MP, Listi F, Ferlazzo V, ColonnaRomano G, Motta M, et al. Prevalence of non organ-specific autoantibodies in healthy centenarians. Arch Gerontol Geriatr Suppl 2002;8:75e80. Brahmer J, Reckamp KL, Baas P, Crino` L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015 Jul 9;373(2):123e35. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015 Oct 22; 373(17):1627e39. Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev 2016 Apr;45:30e7. Landre T, Taleb C, Nicolas P, Des Guetz G. Is there a clinical benefit of anti- PD-1 in patients older than 75 years with previously treated solid tumour? J Clin Oncol 2016;34. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 2017 Apr 15;23(8):1920e8. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017 Aug 1;23(15):4242e50. Saaˆda-Bouzid E, Defaucheux C, Karabajakian A, Coloma VP, Servois V, Paoletti X, et al. Hyperprogression during anti-PD1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 2017 Jul 1; 28(7):1605e11. DelaRosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, et al. Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 2006 Dec;7(5e6): 471e81. Bouchlaka MN, Sckisel GD, Chen M, Mirsoian A, Zamora AE, Maverakis E, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med 2013 Oct 21;210(11):2223e37. Bouchlaka MN, Murphy WJ. Impact of aging in cancer immunotherapy: the importance of using accurate preclinical models. OncoImmunology 2013 Dec 1;2(12):e27186. Wong A, Williams M, Milne D, Morris K, Lau P, Spruyt O, et al. Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advanced melanoma. Asia Pac J Clin Oncol 2017 Dec;13(6):385e90.
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Original Research
Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours H. Herin a, S. Aspeslagh a, E. Castanon a, V. Dyevre b, A. Marabelle a, A. Varga a, S. Postel Vinay a, J.M. Michot a, V. Ribrag a, A. Gazzah a, R. Bahleda a, O. Mir a, C. Massard a, A. Hollebecque a, J.C. Soria a, C. Baldini a,* a b
Gustave Roussy, Universite´ Paris-Saclay, Drug Development Department (DITEP), Villejuif, F-94805, France Gustave Roussy, Universite´ Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, F-94805, France
Received 28 February 2018; accepted 8 March 2018
KEYWORDS Phase I trials; Immunotherapy; Older patients
Abstract Background: The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. Methods: All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Caseecontrol analysis was performed in OPs (patients 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. Results: Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade IIIeIV IrAEs. Cumulative incidence of grade IeII IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade IIIeIV IrAEs (p Z 0.50). Older age was not associated with lower dose intensity of treatment (p Z 0.14). No significant difference was observed between
* Corresponding author: Fax: þ33 (0)142116444. E-mail address: [email protected] (C. Baldini). https://doi.org/10.1016/j.ejca.2018.03.002 0959-8049/ª 2018 Elsevier Ltd. All rights reserved.
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OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94e2.11] p Z 0.09) or median overall survival (HR 0.92, 95% CI [0.61e1.39] p Z 0.77). Conclusion: Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials. ª 2018 Elsevier Ltd. All rights reserved.
1. Introduction Ageing is associated with an increase of cancer incidence [1]. Since the last century, the number of elderly people worldwide has raised constantly due to increasing life expectancy. In 2050, 30% of the European population is expected to be older than 60 years [2]. In 2012, in France, people older than 75 years accounted for 32% of new cancer cases, reflecting the need of finding an optimal treatment in this population [3]. However older patients (OPs) are still underrepresented in clinical trials [4]. Restrictive inclusion criteria, comorbidities, polymedication, physician’s perception of OPs, fear of toxicity or patient’s refusal are the main reasons for limiting the inclusion of OPs in clinical trials [5]. New evidence and new treatment approach are warranted in this population to improve cancer care. In the past years, restoring a patient’s own immunity against cancer with immunotherapy has profoundly changed the management of patients with cancer [7,8]. Various monoclonal antibodies have been developed to target immune checkpoints [9].Their blockade can improve antitumour immune responses by reinvigorating an efficient antitumour T-cell response. The most promising immune checkpoint inhibitors (ICIs) currently are directed against cytotoxic T-lymphocyteeassociated protein 4 (CTLA4), programmed death 1 (PD1) and programmed death ligand 1 (PDL-1). Some are approved in various cancer types where the proportion of elderly patients is important, such as nonesmall cell lung cancer (NSCLC), bladder carcinoma, head and neck cancer, melanoma and renal cell carcinoma [10e14], and new indications are arising [15,16]. Nevertheless, at the moment, there is few evidence of efficacy and tolerance of these drugs in the geriatric population [17]. At the same time, a decline of both adaptive and innate immunity is observed with increasing age [18]. This phenomenon, called immunosenescence (IS), is responsible for poor response to vaccination and increased susceptibility to infections [19]. In addition, increased prevalence of some autoimmune diseases is linked with an increase of auto-antibodies observed in OPs [20]. Especially in this population, modification of the immune cell phenotype, immune microenvironment and intracellular communication are the main reasons for dysfunctional immune responses [21]. Besides, IS is also associated with a state of chronic low-grade
inflammation called inflammaging, responsible for altered level of cytokines. All these reasons urged us to analyse efficacy and toxicity of ICI therapy. Therefore, the aim of this study is to compare safety profile and treatment outcome between OPs and YPs in early immunotherapy clinical trials. 2. Patients and methods 2.1. Patients We retrospectively reviewed all cases of patients with advanced solid tumour, enrolled in immunotherapy phase I trials, between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy Cancer Centre. We performed a caseecontrol analysis and selected all patients 70 years (OP) included in these trials. Patients <70 years (YP) were used as the control group. The two groups were matched according to trial and dose treatment. Cases were matched to up to five controls. Controls were randomly assigned inside trials and level doses. We recorded patients, treatment characteristics and clinical outcome until the last follow up. The eligibility criteria for the phase I clinical trial were as follows: age 18, Eastern Cooperative Group (ECOG) performance status (PS), measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Other eligibility criteria varied according to each trial. All patients signed a written informed consent before trial enrolment. 2.2. Statistics Descriptive statistics were used to summarise patient characteristics. The following variables were collected prospectively by the trial investigators: gender, age at inclusion, Charlson index, tumoural type, medical history of autoimmune disease, number of comedications, number of prior lines of therapy, ECOG status, body mass index, number of metastatic sites, type of metastasis, albumin level, lactate dehydrogenase (LDH) level, renal function (clearance), toxicity and treatment characteristics. Charlson index was estimated without the count of age and cancer co-morbidity. The Royal Marsden Hospital (RMH) score, a survival prognostic score for patients included in the early clinical trial, was also calculated [22]. A p-value less than 0.05 was
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considered statistically significant. Toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE), version per protocol. We compared grade and type of immune-related adverse event (IrAEs). Cumulative incidence of IrAEs was calculated according to Fine and Gray method and compared between grades of IrAEs using Gray non-parametric test. For each patient, we recorded the observed dose under the number of cycles received and the theoretical dose. The relative dose intensity of treatment was calculated and compared using a marginal model (GEE). Treatment response was assessed by our radiologist using RECIST 1.1 criteria. Overall response rate was compared using conditional logistic regression. The disease control rate was defined as a response or stable disease obtained for at least 6 months and was compared using a Wald test. Overall survival (OS) was defined as the time from the start date of treatment until death from any cause or the last follow up. Progression-free survival (PFS) was defined as the period from the start date of the trial until the date of the end of treatment. We estimated and compared OS and PFS by KaplaneMeier methods and log rank test. Analysis was conducted using R 3.3.2 and Stata 14.1. 3. Results 3.1. Patients characteristics Two hundred twenty patients were included, 46 (20%) OPs and 174 (80%) YPs. The median age of patients was 75 [70e88] years in the older group and 55 [22e69] years in the younger group. Patients had a good performance status with 13% (6/46) of the YPs and 36% (62/174) of the OPs having ECOG 0 and 87% (40/46) of the YPs and 62% (108/174) of the OPs having ECOG 1. Polymedication was present especially in OPs with 57% having more than five medications versus 38% in YPs. The most represented tumour types were bladder carcinoma (22%), NSCLC (19%), gastrointestinal cancer (14%), gynaecological cancer (12%), head and neck carcinoma (10%), breast cancer (7%) and renal cell carcinoma (6%). Fifty-nine percent of patients had an RMH score greater than 2, which was similar in both the groups (Table 1). Considering biological characteristics, 33% of OPs had an albumin level <35 g/l, and 35% of OPs had a creatinine clearance according to Modification of Diet in Renal Disease < 60 mL/min (Table 2). 3.2. Clinical trials During the study period, 31 trials testing several combinations of immunotherapy were conducted at our centre, and 14 trials enrolled OPs. The proportion of
Table 1 Clinical characteristic of study population. Characteristics
OP
YP
Total
Number (%)
Number (%)
Number (%)
71 (41) 103 (59)
90 (41) 130 (59)
62 (36) 108 (62) 4 (2)
68 (31) 148 (67) 4 (2)
134 (77) 40 (33)
158 (72) 62 (38)
9 (5) 165 (95)
13 (6) 207 (94)
107 (61) 67 (39)
127 (58) 93 (42)
13 39 44 78
17 51 60 92
Sex Women 19 (41) Men 27 (59) PS 0 6 (13) 1 40 (87) 2 0 Charlson index 0 24 (52) 1 22 (48) Auto immune disease history Yes 4 (9) No 42 (91) Co medication number <5 20 (43) 5 26 (57) Prior lines number None 4 (9) 1 12 (26) 2 16 (35) 3 14 (30) Metastatic site number 0 0 1 17 (37) 2 16 (35) 3 13 (28) Body mass index 18.5 1 (2) 18.5e25 31 (68) 25 14 (30) RMH 0e1 20 (44) 2e3 25 (56)
(7) (23) (25) (45)
(8) (23) (27) (42)
8 (5) 46 (26) 71 (41) 49 (28)
8 (4) 63 (28) 87 (40) 64 (28)
15 (9) 92 (53) 66 (38)
16 (7) 123 (56) 80 (37)
70 (40) 104 (60)
90 (41) 129 (59)
Abbreviations: OP: older patients; YP: younger patients; RMH: Royal Marsden Score; PS, performance status.
OPs included in phase I trial during this period of time was 46 of 240 (19%). Among the 14 trials, seven were investigating an anti-PD1/PDL-1 monotherapy, six a combination of anti-PD1/PDL-1 with other immunomodulatory monoclonal antibodies and one a combination of anti-PD1 with a targeted therapy. Patients received a median of 5 (1e55) cycles of therapy. No dose reduction of immunotherapy agent was observed. There was no difference in relative dose intensity between YPs and OPs (p Z 0.14) (Fig. 1). 3.3. Toxicity profile Grade I IrAEs were experienced by 53% (117/220) of patients, 72% (33/46) of OPs and 48% (84/174) of YPs. A quarter of patients presented grade II IrAEs, 41% (19/ 46) of OPs and 20% (35/174) of YPs (Fig. 2). Cumulative incidence of grade I (p Z 0.039), grade II (p Z 0.035) and grade IeII (p < 0.001) IrAEs was significantly different between OPs and YPs. Grade IIIeIV IrAES occurred in 22% (10/46) of OPs and 13%
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Table 2 Biological characteristic of study population. Characteristics
OP Median (range)
LDH 195 (118e604) 250 >250 Albumin 37.5 (22e45) <35 g/l 35 g/l Creatinine clearance 90 60e89 45e59 <45
YP Number (%)
Total
Median (range)
Number (%)
203 (69e8147) 31 (69) 14 (31)
Median (range)
Number (%)
202 (69e8147) 123 (71) 51 (29)
37 (22e50)
154 (70) 65 (30) 37 (22e50)
15 (33) 31 (67)
49 (28) 125 (72)
64 (29) 156 (71)
13 (28) 17 (37) 11 (24) 5 (11)
88 (50) 69 (40) 12 (7) 5 (3)
101 (46) 86 (39) 23 (10) 10 (5)
Abbreviations: OP: older patients; YP: younger patients; LDH: lactate dehydrogenase.
dermatomyositis, neuropathy, colitis and fever. One dose-limiting toxicity was reported in the YP group. Ten patients stopped treatment because of toxicity (6 YPs and 4 OPs). 3.4. Response rate and survival
Fig. 1. Relative dose intensity (RDI) in OPs and YPs (OP: older patient; YP: younger patient).
Two hundred thirteen patients were evaluable for efficacy. The response rate was 14% for OPs and 18.5% for YPs (p Z 0.52). Disease control rate was 29%, with disease control obtained for 46 YPs (26%) and 18 OPs (39%). Main reasons for trial discontinuation were progressive disease for 159 patients (89%), toxicity for 10 patients (5.6%), death caused by drug not related to the study for four patients (2.2%), sponsor’s decision for two patients and an intercurrent medical event for three patients. Forty-two patients were still on trial at the time of the analysis. No difference was observed in median PFS between the two groups with 5.3 months (95% confidence interval [CI] 2.9e10.8) for OPs and 3.1 months (95% CI 2.6e4) for YPs (hazard ratio [HR] 1.41, 95% CI 0.94e2.11; p Z 0.09) (Fig. 3). Median OS was 7.1 months (95% CI 5.8e15.8) in OPs and 9.8 months in YPs (95% CI 7.1e13) (HR 0.92, 95% CI 0.61e1.39; p Z 0.77) (Figs. 4 and 5). 4. Discussion
Fig. 2. Description of IrAEs grade in OPs and YPs (IrAEs: Immune-related Adverse Events; OP: older patient; YP: younger patient).
(23/174) of YPs without statistical significance (p Z 0.12). There was no difference in cumulative incidence of grade IIIeIV IrAEs noticed between the two groups (p Z 0.50) (Fig. 2). Median time before first event was 16 d (7e41) for OPs and 36 d (14e81) for YPs. Grade III/IV IrAEs were skin rash, arthralgia, hepatic cytolysis, asymptomatic lipase increase,
Our study is the first to investigate tolerability and efficacy of immunotherapy in OPs in phase I trials. In our analysis, we observed more grade IeII IrAEs in OPs than in YPs, but no statistical significance in severe toxicity (grade IIIeIV) and no difference in cumulative incidence of grade IIIeIV IrAEs were observed. ICIs are usually associated with lower rates of AEs of any grade than conventional cancer therapy [23]. However, current data available in the literature regarding toxicity in OPs treated with ICIs are conflicting. Subset analysis in phase II/III trials, including advanced NSCLC, melanoma and renal cell carcinoma,
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Fig. 3. Cumulative incidence of grade I, 2II and III/IV IrAEs in OPs and YPs (IrAEs: Immune-related Adverse Events; OP: older patient; YP: younger patient).
confirmed that nivolumab (anti-PD1) is well tolerated in OPs, but there seems to be a trend of increased grade IIIeV toxicity in patients older than 70 years [24e26]. Regarding anti-CTLA4 in monotherapy, Chiarion et al. analysed the subgroup of patients older than 70 years with metastatic melanoma in an expanded access program for ipilimumab and reported the same incidence
Fig. 4. Progression-free survival according to age group.
Fig. 5. Overall survival according to age group.
of grade IIIeIV IrAEs compared with the overall population [27]. However, combination therapies with anti-CTLA4 appeared to be more toxic. Friedman et al. reported an increase of high-grade toxicity in patients with melanoma older than 80 years with the combination of ipilimumab and nivolumab [28]. In our study, we had no trials testing anti-CTLA4 in combination. IrAEs usually occurred during the first 2 months of treatment [29], but remarkably, they appear earlier in OPs in our study (16 d versus 36 d), which might be related to an increased presence of autoimmune antibodies in OPs at baseline [20,30]. Increased incidence of grade IeII toxicity in our study and early occurrence of these toxicities can have consequences in OPs. For example, diarrhoea grade II can lead to dehydration and hospitalisation in this population. Thus, IrAES even of low grade should be monitored closely. Presently, there are no specific guidelines to manage IrAES in OPs compared with YPs, but the impact of some grade II toxicities and the use of corticosteroids in this population might lead to adapted guidelines. Notably, no dose adjustments are recommended with ICIs according to comorbidities or toxicity [17]. We also evaluated efficacy of immunotherapy in OPs, and no differences were observed between OPs and YPs. Our results are consistent with previous published works. In first line patients with NSCLC treated with pembrolizumab (anti PD1), Reck et al. observed a better hazard ratio for disease progression or death in patients 65 years than those < 65 years (HR 0.45, 95% CI 0.29e0.70) versus HR 0.61 (95% CI, 0.40e0.95) [11]. In checkmate 017 and 057, survival outcomes of nivolumab in second line, respectively, for squamous cell and nonesquamous cell NSCLC were comparable between OPs and YPs. However, the HR for survival of the subset of patient 75 years in both studies were non-significant 1.85 (95% CI, 0.76e4.51) and 0.90 (95% CI, 0.43e1.87) [31,32]. In renal cell carcinoma, nivolumab did not show benefit in the subgroup of patients 75 years with HR 1.23 (95% CI, 0.66e2.31) [12]. Finally, in a meta-analysis on 3322 patients, from six phase III randomised clinical trials of ICIs, Nishijima et al. compared OPs and YPs with an age cut-off of 65e70. In the subset of patient older than 75 years treated with anti-PD1, there was no benefit on OS (HR Z 0.86 [0.41e1.83]; p Z 0.70) [33]. Therefore, the benefit of immunotherapy in patients older than 75 years is still controversial and needs more evidence [34]. Furthermore, new patterns of response have been described and are associated with older age. ‘Hyperprogressive disease’ has been described in 10% of patients and more frequently in patients older than 65 years (19% versus 5%) [35e37]. The influence of immunosenescence and particularly T cell modification on the response to ICIs needs to be clarified. Ageing is impacting composition, physiological function and
H. Herin et al. / European Journal of Cancer 95 (2018) 68e74
competence of normal immunity [38]. Mechanisms of ‘hyperprogression’ are not yet understood but could be explained in OPs by the modification in subpopulation of immune cells, inflammaging process associated with a cytokine pro-inflammatory secretion profile or alteration of costimulatory receptors in T-cell population [21]. In preclinical studies in mice, introduction of immunotherapy was associated with an increase of proinflammatory cytokines such as interleukin-6, tumour necrosis factor-a or interferon-g, responsible for lethal toxicities in multiple organs. Thus, stimulation by immunotherapy of tumoural microenvironment could result in more toxicity [39,40]. The main limitations of this study are the single-site design and the small number of patients older than 70 years analysed. Owing to the retrospective data collection, we did not have any information about geriatric assessment or screening tools such as G8. Moreover, our recruitment is biased; OPs included in phase I trials are fit patients with good ECOG and have no impaired organ function due to the trial’s restrictive criteria. They are not representative of global geriatric population, and our results are therefore not applicable to all OPs. Indeed, Wong et al. analysed 91 patients with advanced melanoma treated by anti PD1 and showed that patients with an ECOG PS of 2e3 have a lower OS and a reduced response compared with those with an ECOG PS of 0e2 (19.5 months versus 1.8 months, HR 5.5; 95% CI [9.1e50.3], p Z 0.0001) [41]. OPs with bad performance status might not have a real benefit with immunebased therapies. 5. Conclusion Our analysis seems to be in favour of ICIs as a practicable option of treatment for elderly patients. The grade IIIeV toxicity rate and efficacy profiles appear similar to the ones in YPs. Age should not be a deciding factor when considering ICIs. Specific guidelines should be set up, and dedicated studies in this population are warranted. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors. Declarations of interest None. Conflict of interest statement Sandrine Aspeslagh received speakers fee from BMS, Astra Zeneca and Roche.Aurelien Marabelle
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received honoraria/consultancy fees from Medimmune, Lilly, Amgen, BMS, Merck Serono, Sanofi Genzyme, Janssen, Astellas, Genentech, Orion and Ipsen. Sophie Postel Vinay received honoraria from Astra Zeneca. Aurelien Marabelle received honoraria/consultancy fees from Medimmune, Lilly, Amgen, BMS, Merck Serono, Sanofi Genzyme, Janssen, Astellas, Genentech, Orion and Ipsen. Sophie Postel Vinay received honoraria from Astra Zeneca. Antoine Hollebecque received honoraria from Merck Serono, had an advisory role for AMGEN and Lilly and received travel and accommodation expenses from Amgen and Servier. Massard received honoraria/consultancy fees from Sanofi Genzyme and JanssenAstellasGenentechOrionMedimmune and Ipsen, and Christophe Massard received honoraria/consultancy fees from Sanofi Genzyme, Janssen, Astellas, Genentech, Orion, Medimmune and Ipsen. Jean-Charles Soria is employed in Medimmune and receives honoraria from Astra Zeneca, Astex, Clovis, GSK, Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pharmamar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. The rest of the authors have no conflicts of interest to declare.
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