- Email: [email protected]
Immunotherapy targeting immune check-point(s) in brain metastases
G Model CGFR 1004 No. of Pages 6
Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Short Review
Immunotherapy targeting immune check-point(s) in brain metastases Anna Maria Di Giacomo* , Monica Valente, Alessia Covre, Riccardo Danielli, Michele Maio Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
A R T I C L E I N F O
Article history: Received 10 July 2017 Accepted 11 July 2017 Available online xxx Keywords: Cancer immunotherapy Brain metastases Melanoma CTLA-4 PD-1/PD-L1 Glioblastoma multiforme
A B S T R A C T
Immunotherapy with monoclonal antibodies (mAb) directed to different immune check-point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Brain metastases pose a huge thread to treating physicians and, irrespective of treatment, the survival of cancer patients with intracranial disease remains extremely poor and frequently associates with quality of life impairing neurologic complications, making it one of the most daunting problems in oncology. Among solid tumors the highest incidence of brain metastases has been reported in lung (40%–50%), breast (15%–25%) and melanoma (40– 50%) patients [1,2]. The median survival for subjects with untreated brain metastases is 2 months but it can be extended to 12–15 months with a multi-disciplinary approach including surgery, radiotherapy and/or chemotherapy [3]. A very dismal prognosis characterizes also malignant primary brain tumors whose incidence accounted for 3.4 cases per 100,000 inhabitants in 2012 [4]; glioblastoma multiforme (GBM) being the most common (46%) and deadliest, with a 5-year survival rate of less than 5% [5]. Currently, there is no cure for GBM and the best first-line treatment still includes a combination of debulking surgery, chemotherapy and radiotherapy [6].
* Corresponding author at: Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Viale Bracci 14, 53100 Siena, Italy. E-mail address: [email protected] (A.M. Di Giacomo).
Due to the supposed role of the blood-brain barrier in preventing therapeutic agents from reaching the brain and to their worse prognosis, patients with brain metastases have been generally excluded from clinical trials designed to test the efficacy of novel therapeutic agents in the extracranial setting. A very similar situation has occurred also for the majority of clinical trials testing the efficacy of novel immunotherapeutic mAb targeting immune check-point(s). However, the success of this therapeutic approach in the extra-cranial disease has most recently fostered retrospective analyses and prospective clinical trials designed to explore its efficacy in brain metastases and, subsequently, in primary brain tumors. In this manuscript we review the most recent clinical evidence on the safety and efficacy of immune check-point(s) directed mAb in patients with brain metastases and primary central nervous system tumors. 2. Immune-checkpoints The physiologic homeostasis of immune responses is controlled both by co-stimulatory (agonistic) and co-inhibitory (antagonistic) signals delivered by cell surface receptors belonging mainly to the immunoglobulin-like superfamily or to the tumor necrosis factor receptor superfamily [7]. Therefore, therapeutic mAb to agonistic or antagonistic immune check-points have been generated due to their potential to enhance anti-tumor immunity. Among costimulatory receptors in clinical development are OX40 and CD137,
http://dx.doi.org/10.1016/j.cytogfr.2017.07.002 1359-6101/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
2
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
Fig. 1. T-cell Checkpoint and Co-stimulatory Pathways. T cell response to antigen (which is mediated by peptide–major histocompatibility complex (MHC) molecule complexes that are recognized by the T cell receptor (TCR)) is regulated by various ligand–receptor interactions between T cells and antigen-presenting cells. Many of the ligands bind to multiple receptors, some of which deliver costimulatory signals and others inhibitory signals. Among co-stimulatory signals are the binding between: Cluster of differentiation 40 (CD40) and its ligand (CD40L); members of the tumor necrosis factor receptor family (CD137 and OX40) and their ligands (CD137L and OX40L); as well as the ligand between Cluster of differentiation 28 (CD28) with its receptors CD80 (B7.1) and CD86 (B7.2). Among inhibitory signals are the binding between cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) with its receptors CD80 (B7.1) and CD86 (B7.2); Programmed death- 1 (PD-1) and CD40 with programmed death-ligand 1 and 2 (PD-L1; PD-L2); lymphocyte activation gene 3 (LAG-3) with MHC class II.
while CTLA-4 and PD-1 are among the co-inhibitory ones [7] (Fig. 1). Treatment with mAb to CTLA-4 or to PD-1/PD-L1, as well as their combination has already shown significant clinical activity across a wide range of tumor types [8,9], being under clinical development in the majority of solid and hemopoietic malignancies.
expanded access program (EAP) with ipilimumab in which a 20% 1year OS was observed in 146 melanoma patients with stable, asymptomatic, brain metastases [13].
3. Check-point monotherapy of brain metastases
Providing support to the notion that patients with brain metastases can benefit from treatment with anti-check-point mAb, the activity of anti-PD-1 mAb monotherapy with nivolumab or pembrolizumab in subjects with intra-cranial disease was recently reported. The two-arm phase II trial of pembrolizumab in melanoma or Non-Small Cell Lung Cancer (NSCLC) patients with untreated brain metastases enrolled 32 subjects (18 melanoma and 18 NSCLC) with at least 1 asymptomatic, untreated or progressive brain lesion with a diameter ranging from 5 to 20 mm. Durable intracranial objective responses were achieved in 4 and 6 melanoma and NSCLC patients, respectively [14]. A more recent retrospective analysis of 66 melanoma patients with brain metastases treated with nivolumab or pembrolizumab reported an intracranial overall response rate (ORR) and a DCR in 21% and 56% subjects, respectively. The median OS was 9.9 months (95% CI 6.93–17.74). Patients with symptomatic brain metastases had a shorter progression free survival (PFS) compared to the asymptomatic ones (2.7 vs 7.4 months, p = 0.035), and a shorter OS (5.7 vs 13.0 months, p = 0.068) [15].
3.1. Anti-CTLA-4 Initial clinical evidence providing proof of activity in brain metastases were generated with the anti-CTLA-4 mAb ipilimumab utilized as single agent in metastatic melanoma patients. A retrospective analysis of the phase II trial CheckMate CA189007 demonstrated that among the 115 treated subjects, 5 out of the 12 patients with stable brain metastases achieved a clinical benefit, with 3 of them surviving at 4 years [10,11]. Based on this observation, a subsequent phase II trial investigated the efficacy of ipilimumab in melanoma patients with asymptomatic (n = 51, cohort A) or symptomatic (n = 21, cohort B) brain metastases. Disease control rate (DCR) at 12 weeks was 26% and 10% in cohorts A and B, respectively. Median OS was 7 months (range 0.4–31 + ) for cohort A and 4 months (0.5–25 + ) for cohort B, while survival rates at 24 months were 26%, and 10%, respectively [12]. These very initial findings were subsequently confirmed in a large Italian
3.2. Anti-PD-1
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
To further explore the efficacy and safety of the anti-PD-1 nivolumab in lung cancer patients with previously treated or untreated asymptomatic brain metastases, a pooled analysis from three studies, CheckMate 017 [16], CheckMate 063 [17], and CheckMate 057 [18] was recently performed [19]. Among patients with pre-treated brain metastases, the median OS was longer in the nivolumab group (8.4 months; 95% CI, 4.99–11.6) as compared to the chemotherapy (docetaxel) group (6.2 months; 95% CI, 4.4– 9.23); however, the frequency and time to new brain lesions were similar across both treatment groups. The foreseeable role of antiPD-1 immunotherapy in NSCLC brain metastases seems to be supported also from real-world evidence [20]. Three hundred seventy-one patients with squamous NSCLC were enrolled in a large Italian EAP at 96 Centers; among the 38 (10%) subjects with asymptomatic, stable, brain metastases the DCR was 47% while the ORR was 19%. The median OS and the 1-year OS rate were 5.8 months (95% CI, 1.8–9.8) and 35%, for patients with brain metastases, and 7.9 months (95% CI, 6.2–9.6) and 39% for all patients, respectively. These comprehensive evidence, though partly deriving from retrospective analyses, suggest for a promising activity of monotherapy with anti-CTLA-4 and anti-PD1 mAbs in brain metastases, proving ground to develop combination therapies in prospective clinical trials. 4. Check-point combinations in brain metastases 4.1. The italian network for tumor biotherapy (NIBIT) studies The NIBIT-M1 study, an open-label, multicenter, phase II trial, was designed to investigate the safety and efficacy of ipilimumab combined with the alkylating agent fotemustine in metastatic melanoma patients. Being fotemustine standard-of-care for melanoma patients with brain metastases, the NIBIT-M1 study allowed also the enrollment of subjects with asymptomatic, untreated brain metastases. Among the 86 treated patients 20 had asymptomatic brain metastases; the immune-related (ir)-DCR was 50%, for patients with brain metastases, and 46.5% for the whole population. The 1-year survival rate was 54.2%, for patients with
3
brain metastases, and 52.6%, for all treated subjects [21]. Noteworthy, a 3-year milestone analysis showed a median OS of 12.7 months (95% CI 2.7–22.7) for patients with brain metastases and 12.9 months (95% CI 7.1–18.7) for the whole population; both groups had a similar 3-years survival rate (27.8% vs 28.5%) [22]. Based on the intriguing activity of ipilimumab combined with fotemustine in melanoma brain metastases, of nivolumab monotherapy in intracranial disease, and on up-coming evidence showing an additive clinical efficacy of ipilimumab combined with nivolumab in melanoma patients, the ongoing NIBIT-M2 study was designed and sponsored by the NIBIT Foundation [23]. The NIBIT-M2 is a randomized, multicenter, phase 3, open-label study, designed to assess the OS of previously untreated metastatic melanoma patients with asymptomatic brain metastases treated with fotemustine vs its combination with ipilimumab or vs the combination of ipilimumab and nivolumab (Fig. 2). To date 81 of the 168 planned patients have been enrolled in the NIBIT-M2 study. 4.2. Anti-CTLA-4 and anti-PD-1 combinations Most recent results from two phase II studies provide further insights to the activity of immunotherapy with anti-check-points mAb in melanoma patients with brain metastases. The phase II trial CheckMate 204 enrolled melanoma patients with asymptomatic brain lesions (from 0.5 to 3.0 cm in diameter) that were treated with ipilimumab combined to nivolumab; initial results from the first 75 evaluable patients showed a 55% durable intracranial ORR, a 21% complete response (CR), and a 60% DCR. On note, the safety profile of treatment was consistent with earlier experiences with 52% of patients undergoing Grade (G) 3–4 adverse events (AEs) [24]. The phase II, multi-cohort Anti-PD1 Brain Collaboration (ABC) trial enrolled melanoma patients with asymptomatic or symptomatic brain metastases; subjects with no prior local brain treatment were randomly assigned to receive nivolumab combined to ipilimumab (Cohort A) or nivolumab alone (Cohort B); symptomatic patients who had failed local brain therapy and/or had leptomeningeal spreading of disease received nivolumab alone (Cohort C). The intracranial ORR was 42%, 20% and 6% in Cohorts A,
Fig. 2. NIBIT-M2 study design.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
4
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
B, and C, respectively. Noteworthy, among patients enrolled in Cohort A, those with treatment-naïve brain disease achieved a 50% OR; instead, the latter was 16% for subjects previously treated with BRAF and MEK inhibitors. Consistent with the safety results from the CheckMate 204 study treatment with nivolumab combined to ipilimumab induced 46% G 3–4 AEs [25]. 5. Check-point immunotherapy of primary brain tumors Preclinical studies in mouse models suggested for a therapeutic potential of anti-CTLA-4 and anti-PD-1/PD-L1 mAb in primary brain tumors [26–29]. These findings, combined with up-coming
clinical evidence in brain metastases (see above) prompted investigating the efficacy of anti-immune check-point(s) therapy also in primary brain tumors, with major emphasis on GBM. Results from Cohort 2 of the phase III study CheckMate 143 comparing the efficacy of nivolumab to the anti-vascular endothelial growth factor A mAb bevacizumab in patients with recurrent GBM did not reach the primary study endpoint. The OS was 9.8 months (95% CI 8.2–11.8) and 10 months (95% CI 9.0–11.8) in patients treated with nivolumab and bevacizumab, respectively; objective clinical responses were also higher in bevacizumabtreated patients (23% vs 8%), though their median duration was higher in the nivolumab arm (11.1 vs 5.3 months) [30].
Table 1 Summary of current CTLA-4, PD1/PD-L1 blockade agents in clinical trials in primary central nervous system neoplasms. This information of clinical trials came from the website of clinicaltrials.gov (The last search conducted on July 7, 2017). Target
Clinical trial identifier
Trial Name
Phase
Status
CTLA-4
NCT02311920
Ipilimumab and/or Nivolumab in Combination With Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients (CheckMate 143) Tremelimumab and Durvalumab in Combination or Alone in Treating Patients With Recurrent Malignant Glioma A Study Evaluating the Association of Hypofractionated Stereotactic Radiation Therapy and Durvalumab for Patients With Recurrent Glioblastoma (STERIMGLI) Phase 2 Study of MEDI4736 in Patients With Glioblastoma
I
Recruiting
III
Completed
II I/II
Recruiting Recruiting
II II I I I/II
Active, no recruiting Completed Recruiting Recruiting Recruiting
I I/II
Recruiting Recruiting
I/II
Recruiting
II
Recruiting
III
Recruiting
II I
Not yet recruiting Recruiting
I
Recruiting
Not provided I/II Not provided II
Recruiting
NCT02017717 NCT02794883 NCT02866747 NCT02336165 PD-1
NCT02550249 NCT02829931 NCT02529072 NCT02423343 NCT02526017 NCT02327078 NCT02335918 NCT02667587 NCT02617589 NCT03014804 NCT02658981 NCT02313272 NCT02658279 NCT02311582 NCT02359565 NCT03018288 NCT02798406 NCT02337686 NCT02337491 NCT02852655 NCT02530502 NCT02430363 NCT01952769
NCT03058289 AntiNCT02937844 PDL-1 NCT02866747 NCT02336165 NCT01375842
Neoadjuvant Nivolumab in Glioblastoma (Neo-nivo) Hypofractionated Stereotactic Irradiation With Nivolumab in Patients With Recurrent High Grade Gliomas Nivolumab With DC Vaccines for Recurrent Brain Tumors (AVERT) A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, or Hepatocellular Carcinoma Study of FPA008 in Combination With Nivolumab in Patients With Selected Advanced Cancers (FPA008-003) A Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204) A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors An Investigational Immuno-therapy Study of Temozolomide Plus Radiation Therapy With Nivolumab or Placebo, for Newly Diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate548) An Investigational Immuno-therapy Study of Nivolumab Compared to Temozolomide, Each Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate 498) Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma Anti-LAG-3 or Urelumab Alone and in Combination With Nivolumab in Treating Patients With Recurrent Glioblastoma Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype MK-3475 in Combination With MRI-guided Laser Ablation in Recurrent Malignant Gliomas Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, or Hypermutated Brain Tumors Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM) Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) Pharmacodynamic Study of Pembrolizumab in Patients With Recurrent Glioblastoma Pembrolizumab +/ Bevacizumab for Recurrent GBM
II II II
Recruiting Recruiting Recruiting Recruiting Recruiting Active, no recruiting Recruiting
A Pilot Surgical Trial To Evaluate Early Immunologic Pharmacodynamic Parameters For The PD-1 Checkpoint Inhibitor, Pembrolizumab (MK-3475), In Patients With Surgically Accessible Recurrent/Progressive Glioblastoma Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed Glioblastoma Evaluation Of The Treatment Effectiveness Of Glioblastoma/Gliosarcoma Through The Suppression Of The PI3K/Akt Pathway In Compared With MK-3475 Anti PD1 Antibody in Diffuse Intrinsic Pontine Glioma
Not provided I/II Active, no recruiting Recruiting I/II
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6 (IT-01) Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme
I/II I
I/II
A Study Evaluating the Association of Hypofractionated Stereotactic Radiation Therapy and Durvalumab for Patients I/II With Recurrent Glioblastoma (STERIMGLI) Phase 2 Study of MEDI4736 in Patients With Glioblastoma II A Phase 1 Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL1] Antibody) to Evaluate I Safety, Tolerability and Pharmacokinetics in Participants With Locally Advanced or Metastatic Solid Tumors
Active, no recruiting Recruiting Recruiting Recruiting Active, no recruiting Active, no recruiting
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
5
Table 2 Summary of current CTLA-4, PD1/PD-L1 blockade agents in clinical trials in brain metastases. This information of clinical trials came from the website of clinicaltrials.gov (The last search conducted on July 7, 2017). Clinical trial identifier
Trial Name
NCT02460068 NCT02621515 NCT02097732
A Study of Fotemustine(FTM) vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis (NIBIT-M2) III Nivo/Ipi Combination Therapy in Symptomatic Brain Metastases (CA209-322) II Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery II
NCT02374242
Anti-PD 1 Brain Collaboration for Patients With Melanoma Brain Metastases (ABC)
II
NCT02886585 NCT02085070 NCT02681549 NCT03175432 NCT02834013 NCT02716948 NCT02696993
II II II II II I I/II
NCT02681549 NCT02669914 NCT02107755
Pembrolizumab In Central Nervous System Metastases MK-3475 in Melanoma and NSCLC Patients With Brain Metastases Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer Study of BEvacizumab in Combination With ATezolizumab in Patients With Untreated Melanoma Brain Metastases Nivolumab and Ipilimumab in Treating Patients With Rare Tumors SRS and Nivolumab in Treating Patients With Newly Diagnosed Melanoma Metastases in the Brain or Spine Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial Metastases From Non-Small Cell Lung Cancer Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer MEDI4736 (Durvalumab) in Patients With Brain Metastasis From Epithelial-derived Tumors Stereotactic Radiation Therapy and Ipilimumab in Treating Patients With Metastatic Melanoma
NCT01703507
Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma
I
NCT02115139
GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases
II
NCT02320058
An Investigational Immuno-therapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread II to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself
The ongoing randomized phase II (CheckMate 548) and III (CheckMate 498) studies are investigating the efficacy of nivolumab combined with brain radiotherapy, with or without concurrent temozolomide, in untreated, O(6)-methylguanine-DNA methyltransferase promoter methylated or un-methylated GBM patients. Studies investigating immune check-point(s) therapy in GBM are undoubtedly in their infancy, the results from several ongoing trials will likely help shedding light on the efficacy of this novel immune-therapeutic approach also in this invariably deadly disease (Table 1). 6. Conclusions The forthcoming activity of immune check-point(s) therapy and the results from novel therapeutic combinations being explored (Table 2) may lead to a swift change in the comprehensive management of brain metastases, thus not remaining confined to standard chemo- and radio- therapy and/or surgery. Along this line, the durability of clinical responses, the increase in patient survival, the superior efficacy in asymptomatic and previously untreated subjects so far observed across tumor histologies may help to further refine the population of patients with intra-cranial disease that suits most to systemic treatment with immune checkpoint(s) mAb. At variance with brain metastases, much remains to be gained on the therapeutic potential of immune-modulating mAb in primary brain tumors, including GBM; ongoing studies will hopefully be instrumental in this specific clinical setting. Expanding on the available comprehensive clinical and preclinical observations that weaken the role of the blood-brain barrier in limiting the efficacy of systemic therapy in the control of intra-cranial disease, future combination therapy studies will undoubtedly improve the emerging efficacy of immunotherapy in primary and metastatic brain tumors. In this direction foreseeable clinical approaches should take into consideration therapeutic
Phase Status
II II II
Recruiting Recruiting Active, no recruiting Active, no recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Active, no recruiting Active, no recruiting Active, no recruiting Recruiting
strategies designed to overcome the highly immunosuppressive tumor environment that characterizes brain tumors. Conflict of interests Anna Maria Di Giacomo served as on Advisory Boards of Incyte, Pierre-Fabre. Monica Valente has no conflict of interest to declare. Alessia Covre has no conflict of interest to declare. Riccardo Danielli has no conflict of interest to declare. Michele Maio served as on Scientific or Advisory Boards of Bristol Myers Squibb, Roche-Genentech, AstraZeneca-MedImmune and Merck Sharp & Dohme. Acknowledgment This work was supported in part by grants awarded to Michele Maio from the Associazione Italiana per la Ricerca sul Cancro (2014-IG 15373) References [1] M.C. Chamberlain, C.S. Baik, V.K. Gadi, Systemic therapy of brain metastases: non-smal cell lung cancre, breast cancer, and melanoma, Neuro Oncol. 19 (2017) i1–i24. [2] M.S. Carlino, G.B. Fogarty, G.V. Long, Treatment of melanoma brain metastases: a new paradigm, Cancer J. 18 (2012) 208–212. [3] D. Bafaloukos, H. Gogas, The treatment of brain metastases in melanoma subjects, Cancer Treat. R 30 (2004) 515–520. [4] GLOBOCAN v1.0, Cancer Incidence and Mortality Worldwide, International Agency for Research on Cancer, IARC CancerBase No. 11, 2012 http://globocan. iarc.fr./, 2013 (Accessed 19 February 2014). [5] H. Ohgaki, Epidemiology of brain tumors, Methods Mol. Biol. 472 (2009) 323– 342. [6] R. Stupp, W.O. Mason, M.J. van den Bent, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N. Engl. J. Med. 352 (2005) 987–996. [7] K.S. Peggs, S.A. Quezada, J.P. Allison, Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists, Clin. Exp. Immunol. 157 (2009) 9–19. [8] F.S. Hodi, S.J. O’Day, D.F. McDermott, Improved survival with ipilimumab in patients with mwtastatic melanoma, N. Engl. J. Med. 363 (2010) 711–723.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
[9] S.L. Topalian, F.S. Hodi, J.R. Brahmer, Safety activity, and immune correlates of anti-PD-1 antibody in cancer, N. Engl. J. Med. 366 (2012) 2443–2454. [10] A. Weber, D. Amin, Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial, Melanoma Res. 21 (2011) 530–534. [11] J. Weber, J.A. Thompson, O. Hamid, A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma, Clin. Cancer Res. 15 (2009) 5591– 5598. [12] K. Margolin, M.S. Ernstoff, O. Hamid, Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial, Lancet Oncol. 13 (2012) 459–465. [13] P. Queirolo, F. Spagnolo, P.A. Ascierto, Efficacy and safety of Ipilimumab in patients withadvanced melanoma and brain metastases, J. Neurooncol. 118 (2014) 109–116. [14] S.B. Goldberg, S.N. Gettinger, A. Mahajan, Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial, Lancet Oncol. 17 (2016) 976–983. [15] S. Parakh, J.J. Park, S. Mendis, Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases, Br. J. Cancer 116 (2017) 1558–1563. [16] J. Brahmer, K.L. Reckamp, P. Baas, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 123–135. [17] N.A. Rizvi, J. Mazières, D. Planchard, Activity and safety of nivolumab, an antiPD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial, Lancet Oncol. 16 (2015) 257–265. [18] H. Borghaei, L. Paz-Ares, L. Horn, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 1627– 1639. [19] J.W. Goldman, L. Crinò, E.E. Vokes, Nivolumab in patients with advanced NSCLC and central nervous system metastases, J. Clin. Oncol. (2016) (abstr 9038). [20] P. Bidoli, R. Chiari, A. Catino, Efficacy and safety data from patients with advanced squamous NSCLC and brain metastases participing in the nivolumab Expanded Access Programme (EAP) in Italy, Ann. Oncol. 27 (2016) 416–454. [21] A.M. Di Giacomo, P.A. Ascierto, L. Pilla, A phase 2, open-label, single-arm study to investigate the combination of ipilimumab and fotemustine in patients with advanced melanoma: the NIBIT-M1 trial, Lancet Oncol. 13 (2012) 879–886. [22] A.M. Di Giacomo, P.A. Ascierto, P. Queirolo, Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study, Ann. Oncol. 26 (2015) 798–803. [23] A.M. Di Giacomo, A randomized, phase III study of fotemustine versus the combination of fotemustine and ipilimumab or the combination of ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis: the NIBIT–M2 trial, J. Clin. Oncol. 33 (2015) (abstr TPS9090.). [24] H.A. Tawabi, P.A.J. Forsyth, A.P. Algazi, Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the
[25]
[26]
[27]
[28]
[29]
[30]
brain: results of the phase II study CheckMate 204, J. Clin. Oncol. (2017) (abstr 9507). G.V. Long, V. Atkinson, A.M. Menzies, A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC), J. Clin. Oncol. (2017) (abstr 9508). J. vom Berg, M. Vrohlings, S. Haller, Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection, J. Exp. Med. 210 (2013) 2803– 2811. P. Agarwalla, Z. Barnard, P. Fecci, Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blackade effectively treats established murine intracranial tumors, J. Immunother. 35 (2012) 385–389. Z. Belcaid, J.A. Phallen, J. Zeng, Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model, PLoS One 9 (2014) e101764. D.A. Wainwright, A.L. Chang, M. Dey, Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors, Clin. Cancer Res. 20 (2014) 5290–5301. D.A. Reardon, A. Omuro, A.A. Brandes, Randomized phase 3 study evaluation the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma, CheckMate 143, Presented at 5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies May 4–7, 2017, Zurich, Switzerland, 2017.
Anna Maria Di Giacomo obtained her MD from the Tor Vergata 2nd School of Medicine, Rome, Italy, in 1997. During 1997–2001, Dr Di Giacomo held a Research position at the, Department of Pharmacology/Clinical Oncology, University of Rome Tor Vergata, Rome. In 2001, she subsequently obtained her Board Certification in Oncology. During 2001–2003, Dr Di Giacomo held a Postdoctoral Fellow position at the Department of Oncology, Fatebenefratelli Hospital, Rome. During 2003–2004, she held an Assistant position at the Division of Medical Oncology, General Hospital, Cuneo, Italy. Since 2004, Dr Di Giacomo is an Associate Director at the Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena. She is a member of three prestigious societies: the Associazione Italiana di Oncologia Medica (AIOM), the Italian Network for Tumour Biotherapy (NIBIT), and ESMO (European Society of Clinical Oncology). Dr Di Giacomo treats over 400 metastatic melanoma patients/ year and 150 primary brain tumors. She is currently Principal Investigator and CoInvestigator for more than 50 clinical trials in solid malignancies, investigating biochemotherapy, immunotherapeutic agents and molecularly targeted agents. She is the author of more than 50 scientific publications, and has been an invited speaker at more than 100 congresses. Dr Di Giacomo’s translational research interests include: epigenetics and the immunological and clinical activity of immunotherapeutic agents in the treatment of melanoma, and other solid tumors.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Short Review
Immunotherapy targeting immune check-point(s) in brain metastases Anna Maria Di Giacomo* , Monica Valente, Alessia Covre, Riccardo Danielli, Michele Maio Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
A R T I C L E I N F O
Article history: Received 10 July 2017 Accepted 11 July 2017 Available online xxx Keywords: Cancer immunotherapy Brain metastases Melanoma CTLA-4 PD-1/PD-L1 Glioblastoma multiforme
A B S T R A C T
Immunotherapy with monoclonal antibodies (mAb) directed to different immune check-point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Brain metastases pose a huge thread to treating physicians and, irrespective of treatment, the survival of cancer patients with intracranial disease remains extremely poor and frequently associates with quality of life impairing neurologic complications, making it one of the most daunting problems in oncology. Among solid tumors the highest incidence of brain metastases has been reported in lung (40%–50%), breast (15%–25%) and melanoma (40– 50%) patients [1,2]. The median survival for subjects with untreated brain metastases is 2 months but it can be extended to 12–15 months with a multi-disciplinary approach including surgery, radiotherapy and/or chemotherapy [3]. A very dismal prognosis characterizes also malignant primary brain tumors whose incidence accounted for 3.4 cases per 100,000 inhabitants in 2012 [4]; glioblastoma multiforme (GBM) being the most common (46%) and deadliest, with a 5-year survival rate of less than 5% [5]. Currently, there is no cure for GBM and the best first-line treatment still includes a combination of debulking surgery, chemotherapy and radiotherapy [6].
* Corresponding author at: Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Viale Bracci 14, 53100 Siena, Italy. E-mail address: [email protected] (A.M. Di Giacomo).
Due to the supposed role of the blood-brain barrier in preventing therapeutic agents from reaching the brain and to their worse prognosis, patients with brain metastases have been generally excluded from clinical trials designed to test the efficacy of novel therapeutic agents in the extracranial setting. A very similar situation has occurred also for the majority of clinical trials testing the efficacy of novel immunotherapeutic mAb targeting immune check-point(s). However, the success of this therapeutic approach in the extra-cranial disease has most recently fostered retrospective analyses and prospective clinical trials designed to explore its efficacy in brain metastases and, subsequently, in primary brain tumors. In this manuscript we review the most recent clinical evidence on the safety and efficacy of immune check-point(s) directed mAb in patients with brain metastases and primary central nervous system tumors. 2. Immune-checkpoints The physiologic homeostasis of immune responses is controlled both by co-stimulatory (agonistic) and co-inhibitory (antagonistic) signals delivered by cell surface receptors belonging mainly to the immunoglobulin-like superfamily or to the tumor necrosis factor receptor superfamily [7]. Therefore, therapeutic mAb to agonistic or antagonistic immune check-points have been generated due to their potential to enhance anti-tumor immunity. Among costimulatory receptors in clinical development are OX40 and CD137,
http://dx.doi.org/10.1016/j.cytogfr.2017.07.002 1359-6101/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
2
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
Fig. 1. T-cell Checkpoint and Co-stimulatory Pathways. T cell response to antigen (which is mediated by peptide–major histocompatibility complex (MHC) molecule complexes that are recognized by the T cell receptor (TCR)) is regulated by various ligand–receptor interactions between T cells and antigen-presenting cells. Many of the ligands bind to multiple receptors, some of which deliver costimulatory signals and others inhibitory signals. Among co-stimulatory signals are the binding between: Cluster of differentiation 40 (CD40) and its ligand (CD40L); members of the tumor necrosis factor receptor family (CD137 and OX40) and their ligands (CD137L and OX40L); as well as the ligand between Cluster of differentiation 28 (CD28) with its receptors CD80 (B7.1) and CD86 (B7.2). Among inhibitory signals are the binding between cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) with its receptors CD80 (B7.1) and CD86 (B7.2); Programmed death- 1 (PD-1) and CD40 with programmed death-ligand 1 and 2 (PD-L1; PD-L2); lymphocyte activation gene 3 (LAG-3) with MHC class II.
while CTLA-4 and PD-1 are among the co-inhibitory ones [7] (Fig. 1). Treatment with mAb to CTLA-4 or to PD-1/PD-L1, as well as their combination has already shown significant clinical activity across a wide range of tumor types [8,9], being under clinical development in the majority of solid and hemopoietic malignancies.
expanded access program (EAP) with ipilimumab in which a 20% 1year OS was observed in 146 melanoma patients with stable, asymptomatic, brain metastases [13].
3. Check-point monotherapy of brain metastases
Providing support to the notion that patients with brain metastases can benefit from treatment with anti-check-point mAb, the activity of anti-PD-1 mAb monotherapy with nivolumab or pembrolizumab in subjects with intra-cranial disease was recently reported. The two-arm phase II trial of pembrolizumab in melanoma or Non-Small Cell Lung Cancer (NSCLC) patients with untreated brain metastases enrolled 32 subjects (18 melanoma and 18 NSCLC) with at least 1 asymptomatic, untreated or progressive brain lesion with a diameter ranging from 5 to 20 mm. Durable intracranial objective responses were achieved in 4 and 6 melanoma and NSCLC patients, respectively [14]. A more recent retrospective analysis of 66 melanoma patients with brain metastases treated with nivolumab or pembrolizumab reported an intracranial overall response rate (ORR) and a DCR in 21% and 56% subjects, respectively. The median OS was 9.9 months (95% CI 6.93–17.74). Patients with symptomatic brain metastases had a shorter progression free survival (PFS) compared to the asymptomatic ones (2.7 vs 7.4 months, p = 0.035), and a shorter OS (5.7 vs 13.0 months, p = 0.068) [15].
3.1. Anti-CTLA-4 Initial clinical evidence providing proof of activity in brain metastases were generated with the anti-CTLA-4 mAb ipilimumab utilized as single agent in metastatic melanoma patients. A retrospective analysis of the phase II trial CheckMate CA189007 demonstrated that among the 115 treated subjects, 5 out of the 12 patients with stable brain metastases achieved a clinical benefit, with 3 of them surviving at 4 years [10,11]. Based on this observation, a subsequent phase II trial investigated the efficacy of ipilimumab in melanoma patients with asymptomatic (n = 51, cohort A) or symptomatic (n = 21, cohort B) brain metastases. Disease control rate (DCR) at 12 weeks was 26% and 10% in cohorts A and B, respectively. Median OS was 7 months (range 0.4–31 + ) for cohort A and 4 months (0.5–25 + ) for cohort B, while survival rates at 24 months were 26%, and 10%, respectively [12]. These very initial findings were subsequently confirmed in a large Italian
3.2. Anti-PD-1
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
To further explore the efficacy and safety of the anti-PD-1 nivolumab in lung cancer patients with previously treated or untreated asymptomatic brain metastases, a pooled analysis from three studies, CheckMate 017 [16], CheckMate 063 [17], and CheckMate 057 [18] was recently performed [19]. Among patients with pre-treated brain metastases, the median OS was longer in the nivolumab group (8.4 months; 95% CI, 4.99–11.6) as compared to the chemotherapy (docetaxel) group (6.2 months; 95% CI, 4.4– 9.23); however, the frequency and time to new brain lesions were similar across both treatment groups. The foreseeable role of antiPD-1 immunotherapy in NSCLC brain metastases seems to be supported also from real-world evidence [20]. Three hundred seventy-one patients with squamous NSCLC were enrolled in a large Italian EAP at 96 Centers; among the 38 (10%) subjects with asymptomatic, stable, brain metastases the DCR was 47% while the ORR was 19%. The median OS and the 1-year OS rate were 5.8 months (95% CI, 1.8–9.8) and 35%, for patients with brain metastases, and 7.9 months (95% CI, 6.2–9.6) and 39% for all patients, respectively. These comprehensive evidence, though partly deriving from retrospective analyses, suggest for a promising activity of monotherapy with anti-CTLA-4 and anti-PD1 mAbs in brain metastases, proving ground to develop combination therapies in prospective clinical trials. 4. Check-point combinations in brain metastases 4.1. The italian network for tumor biotherapy (NIBIT) studies The NIBIT-M1 study, an open-label, multicenter, phase II trial, was designed to investigate the safety and efficacy of ipilimumab combined with the alkylating agent fotemustine in metastatic melanoma patients. Being fotemustine standard-of-care for melanoma patients with brain metastases, the NIBIT-M1 study allowed also the enrollment of subjects with asymptomatic, untreated brain metastases. Among the 86 treated patients 20 had asymptomatic brain metastases; the immune-related (ir)-DCR was 50%, for patients with brain metastases, and 46.5% for the whole population. The 1-year survival rate was 54.2%, for patients with
3
brain metastases, and 52.6%, for all treated subjects [21]. Noteworthy, a 3-year milestone analysis showed a median OS of 12.7 months (95% CI 2.7–22.7) for patients with brain metastases and 12.9 months (95% CI 7.1–18.7) for the whole population; both groups had a similar 3-years survival rate (27.8% vs 28.5%) [22]. Based on the intriguing activity of ipilimumab combined with fotemustine in melanoma brain metastases, of nivolumab monotherapy in intracranial disease, and on up-coming evidence showing an additive clinical efficacy of ipilimumab combined with nivolumab in melanoma patients, the ongoing NIBIT-M2 study was designed and sponsored by the NIBIT Foundation [23]. The NIBIT-M2 is a randomized, multicenter, phase 3, open-label study, designed to assess the OS of previously untreated metastatic melanoma patients with asymptomatic brain metastases treated with fotemustine vs its combination with ipilimumab or vs the combination of ipilimumab and nivolumab (Fig. 2). To date 81 of the 168 planned patients have been enrolled in the NIBIT-M2 study. 4.2. Anti-CTLA-4 and anti-PD-1 combinations Most recent results from two phase II studies provide further insights to the activity of immunotherapy with anti-check-points mAb in melanoma patients with brain metastases. The phase II trial CheckMate 204 enrolled melanoma patients with asymptomatic brain lesions (from 0.5 to 3.0 cm in diameter) that were treated with ipilimumab combined to nivolumab; initial results from the first 75 evaluable patients showed a 55% durable intracranial ORR, a 21% complete response (CR), and a 60% DCR. On note, the safety profile of treatment was consistent with earlier experiences with 52% of patients undergoing Grade (G) 3–4 adverse events (AEs) [24]. The phase II, multi-cohort Anti-PD1 Brain Collaboration (ABC) trial enrolled melanoma patients with asymptomatic or symptomatic brain metastases; subjects with no prior local brain treatment were randomly assigned to receive nivolumab combined to ipilimumab (Cohort A) or nivolumab alone (Cohort B); symptomatic patients who had failed local brain therapy and/or had leptomeningeal spreading of disease received nivolumab alone (Cohort C). The intracranial ORR was 42%, 20% and 6% in Cohorts A,
Fig. 2. NIBIT-M2 study design.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
4
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
B, and C, respectively. Noteworthy, among patients enrolled in Cohort A, those with treatment-naïve brain disease achieved a 50% OR; instead, the latter was 16% for subjects previously treated with BRAF and MEK inhibitors. Consistent with the safety results from the CheckMate 204 study treatment with nivolumab combined to ipilimumab induced 46% G 3–4 AEs [25]. 5. Check-point immunotherapy of primary brain tumors Preclinical studies in mouse models suggested for a therapeutic potential of anti-CTLA-4 and anti-PD-1/PD-L1 mAb in primary brain tumors [26–29]. These findings, combined with up-coming
clinical evidence in brain metastases (see above) prompted investigating the efficacy of anti-immune check-point(s) therapy also in primary brain tumors, with major emphasis on GBM. Results from Cohort 2 of the phase III study CheckMate 143 comparing the efficacy of nivolumab to the anti-vascular endothelial growth factor A mAb bevacizumab in patients with recurrent GBM did not reach the primary study endpoint. The OS was 9.8 months (95% CI 8.2–11.8) and 10 months (95% CI 9.0–11.8) in patients treated with nivolumab and bevacizumab, respectively; objective clinical responses were also higher in bevacizumabtreated patients (23% vs 8%), though their median duration was higher in the nivolumab arm (11.1 vs 5.3 months) [30].
Table 1 Summary of current CTLA-4, PD1/PD-L1 blockade agents in clinical trials in primary central nervous system neoplasms. This information of clinical trials came from the website of clinicaltrials.gov (The last search conducted on July 7, 2017). Target
Clinical trial identifier
Trial Name
Phase
Status
CTLA-4
NCT02311920
Ipilimumab and/or Nivolumab in Combination With Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma A Study of the Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in Glioblastoma Patients (CheckMate 143) Tremelimumab and Durvalumab in Combination or Alone in Treating Patients With Recurrent Malignant Glioma A Study Evaluating the Association of Hypofractionated Stereotactic Radiation Therapy and Durvalumab for Patients With Recurrent Glioblastoma (STERIMGLI) Phase 2 Study of MEDI4736 in Patients With Glioblastoma
I
Recruiting
III
Completed
II I/II
Recruiting Recruiting
II II I I I/II
Active, no recruiting Completed Recruiting Recruiting Recruiting
I I/II
Recruiting Recruiting
I/II
Recruiting
II
Recruiting
III
Recruiting
II I
Not yet recruiting Recruiting
I
Recruiting
Not provided I/II Not provided II
Recruiting
NCT02017717 NCT02794883 NCT02866747 NCT02336165 PD-1
NCT02550249 NCT02829931 NCT02529072 NCT02423343 NCT02526017 NCT02327078 NCT02335918 NCT02667587 NCT02617589 NCT03014804 NCT02658981 NCT02313272 NCT02658279 NCT02311582 NCT02359565 NCT03018288 NCT02798406 NCT02337686 NCT02337491 NCT02852655 NCT02530502 NCT02430363 NCT01952769
NCT03058289 AntiNCT02937844 PDL-1 NCT02866747 NCT02336165 NCT01375842
Neoadjuvant Nivolumab in Glioblastoma (Neo-nivo) Hypofractionated Stereotactic Irradiation With Nivolumab in Patients With Recurrent High Grade Gliomas Nivolumab With DC Vaccines for Recurrent Brain Tumors (AVERT) A Study of Galunisertib (LY2157299) in Combination With Nivolumab in Advanced Refractory Solid Tumors and in Recurrent or Refractory NSCLC, or Hepatocellular Carcinoma Study of FPA008 in Combination With Nivolumab in Patients With Selected Advanced Cancers (FPA008-003) A Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204) A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors An Investigational Immuno-therapy Study of Temozolomide Plus Radiation Therapy With Nivolumab or Placebo, for Newly Diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate548) An Investigational Immuno-therapy Study of Nivolumab Compared to Temozolomide, Each Given With Radiation Therapy, for Newly-diagnosed Patients With Glioblastoma (GBM, a Malignant Brain Cancer) (CheckMate 498) Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma Anti-LAG-3 or Urelumab Alone and in Combination With Nivolumab in Treating Patients With Recurrent Glioblastoma Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype MK-3475 in Combination With MRI-guided Laser Ablation in Recurrent Malignant Gliomas Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, or Hypermutated Brain Tumors Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM) Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) Pharmacodynamic Study of Pembrolizumab in Patients With Recurrent Glioblastoma Pembrolizumab +/ Bevacizumab for Recurrent GBM
II II II
Recruiting Recruiting Recruiting Recruiting Recruiting Active, no recruiting Recruiting
A Pilot Surgical Trial To Evaluate Early Immunologic Pharmacodynamic Parameters For The PD-1 Checkpoint Inhibitor, Pembrolizumab (MK-3475), In Patients With Surgically Accessible Recurrent/Progressive Glioblastoma Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed Glioblastoma Evaluation Of The Treatment Effectiveness Of Glioblastoma/Gliosarcoma Through The Suppression Of The PI3K/Akt Pathway In Compared With MK-3475 Anti PD1 Antibody in Diffuse Intrinsic Pontine Glioma
Not provided I/II Active, no recruiting Recruiting I/II
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6 (IT-01) Pilot Study of Autologous Chimeric Switch Receptor Modified T Cells in Recurrent Glioblastoma Multiforme
I/II I
I/II
A Study Evaluating the Association of Hypofractionated Stereotactic Radiation Therapy and Durvalumab for Patients I/II With Recurrent Glioblastoma (STERIMGLI) Phase 2 Study of MEDI4736 in Patients With Glioblastoma II A Phase 1 Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL1] Antibody) to Evaluate I Safety, Tolerability and Pharmacokinetics in Participants With Locally Advanced or Metastatic Solid Tumors
Active, no recruiting Recruiting Recruiting Recruiting Active, no recruiting Active, no recruiting
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
5
Table 2 Summary of current CTLA-4, PD1/PD-L1 blockade agents in clinical trials in brain metastases. This information of clinical trials came from the website of clinicaltrials.gov (The last search conducted on July 7, 2017). Clinical trial identifier
Trial Name
NCT02460068 NCT02621515 NCT02097732
A Study of Fotemustine(FTM) vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis (NIBIT-M2) III Nivo/Ipi Combination Therapy in Symptomatic Brain Metastases (CA209-322) II Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery II
NCT02374242
Anti-PD 1 Brain Collaboration for Patients With Melanoma Brain Metastases (ABC)
II
NCT02886585 NCT02085070 NCT02681549 NCT03175432 NCT02834013 NCT02716948 NCT02696993
II II II II II I I/II
NCT02681549 NCT02669914 NCT02107755
Pembrolizumab In Central Nervous System Metastases MK-3475 in Melanoma and NSCLC Patients With Brain Metastases Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer Study of BEvacizumab in Combination With ATezolizumab in Patients With Untreated Melanoma Brain Metastases Nivolumab and Ipilimumab in Treating Patients With Rare Tumors SRS and Nivolumab in Treating Patients With Newly Diagnosed Melanoma Metastases in the Brain or Spine Trial of Nivolumab With Radiation or Nivolumab and Ipilimumab With Radiation for the Treatment of Intracranial Metastases From Non-Small Cell Lung Cancer Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer MEDI4736 (Durvalumab) in Patients With Brain Metastasis From Epithelial-derived Tumors Stereotactic Radiation Therapy and Ipilimumab in Treating Patients With Metastatic Melanoma
NCT01703507
Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma
I
NCT02115139
GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases
II
NCT02320058
An Investigational Immuno-therapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread II to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself
The ongoing randomized phase II (CheckMate 548) and III (CheckMate 498) studies are investigating the efficacy of nivolumab combined with brain radiotherapy, with or without concurrent temozolomide, in untreated, O(6)-methylguanine-DNA methyltransferase promoter methylated or un-methylated GBM patients. Studies investigating immune check-point(s) therapy in GBM are undoubtedly in their infancy, the results from several ongoing trials will likely help shedding light on the efficacy of this novel immune-therapeutic approach also in this invariably deadly disease (Table 1). 6. Conclusions The forthcoming activity of immune check-point(s) therapy and the results from novel therapeutic combinations being explored (Table 2) may lead to a swift change in the comprehensive management of brain metastases, thus not remaining confined to standard chemo- and radio- therapy and/or surgery. Along this line, the durability of clinical responses, the increase in patient survival, the superior efficacy in asymptomatic and previously untreated subjects so far observed across tumor histologies may help to further refine the population of patients with intra-cranial disease that suits most to systemic treatment with immune checkpoint(s) mAb. At variance with brain metastases, much remains to be gained on the therapeutic potential of immune-modulating mAb in primary brain tumors, including GBM; ongoing studies will hopefully be instrumental in this specific clinical setting. Expanding on the available comprehensive clinical and preclinical observations that weaken the role of the blood-brain barrier in limiting the efficacy of systemic therapy in the control of intra-cranial disease, future combination therapy studies will undoubtedly improve the emerging efficacy of immunotherapy in primary and metastatic brain tumors. In this direction foreseeable clinical approaches should take into consideration therapeutic
Phase Status
II II II
Recruiting Recruiting Active, no recruiting Active, no recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Active, no recruiting Active, no recruiting Active, no recruiting Recruiting
strategies designed to overcome the highly immunosuppressive tumor environment that characterizes brain tumors. Conflict of interests Anna Maria Di Giacomo served as on Advisory Boards of Incyte, Pierre-Fabre. Monica Valente has no conflict of interest to declare. Alessia Covre has no conflict of interest to declare. Riccardo Danielli has no conflict of interest to declare. Michele Maio served as on Scientific or Advisory Boards of Bristol Myers Squibb, Roche-Genentech, AstraZeneca-MedImmune and Merck Sharp & Dohme. Acknowledgment This work was supported in part by grants awarded to Michele Maio from the Associazione Italiana per la Ricerca sul Cancro (2014-IG 15373) References [1] M.C. Chamberlain, C.S. Baik, V.K. Gadi, Systemic therapy of brain metastases: non-smal cell lung cancre, breast cancer, and melanoma, Neuro Oncol. 19 (2017) i1–i24. [2] M.S. Carlino, G.B. Fogarty, G.V. Long, Treatment of melanoma brain metastases: a new paradigm, Cancer J. 18 (2012) 208–212. [3] D. Bafaloukos, H. Gogas, The treatment of brain metastases in melanoma subjects, Cancer Treat. R 30 (2004) 515–520. [4] GLOBOCAN v1.0, Cancer Incidence and Mortality Worldwide, International Agency for Research on Cancer, IARC CancerBase No. 11, 2012 http://globocan. iarc.fr./, 2013 (Accessed 19 February 2014). [5] H. Ohgaki, Epidemiology of brain tumors, Methods Mol. Biol. 472 (2009) 323– 342. [6] R. Stupp, W.O. Mason, M.J. van den Bent, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, N. Engl. J. Med. 352 (2005) 987–996. [7] K.S. Peggs, S.A. Quezada, J.P. Allison, Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists, Clin. Exp. Immunol. 157 (2009) 9–19. [8] F.S. Hodi, S.J. O’Day, D.F. McDermott, Improved survival with ipilimumab in patients with mwtastatic melanoma, N. Engl. J. Med. 363 (2010) 711–723.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002
G Model CGFR 1004 No. of Pages 6
6
A.M. Di Giacomo et al. / Cytokine & Growth Factor Reviews xxx (2017) xxx–xxx
[9] S.L. Topalian, F.S. Hodi, J.R. Brahmer, Safety activity, and immune correlates of anti-PD-1 antibody in cancer, N. Engl. J. Med. 366 (2012) 2443–2454. [10] A. Weber, D. Amin, Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial, Melanoma Res. 21 (2011) 530–534. [11] J. Weber, J.A. Thompson, O. Hamid, A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma, Clin. Cancer Res. 15 (2009) 5591– 5598. [12] K. Margolin, M.S. Ernstoff, O. Hamid, Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial, Lancet Oncol. 13 (2012) 459–465. [13] P. Queirolo, F. Spagnolo, P.A. Ascierto, Efficacy and safety of Ipilimumab in patients withadvanced melanoma and brain metastases, J. Neurooncol. 118 (2014) 109–116. [14] S.B. Goldberg, S.N. Gettinger, A. Mahajan, Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial, Lancet Oncol. 17 (2016) 976–983. [15] S. Parakh, J.J. Park, S. Mendis, Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases, Br. J. Cancer 116 (2017) 1558–1563. [16] J. Brahmer, K.L. Reckamp, P. Baas, Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 123–135. [17] N.A. Rizvi, J. Mazières, D. Planchard, Activity and safety of nivolumab, an antiPD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial, Lancet Oncol. 16 (2015) 257–265. [18] H. Borghaei, L. Paz-Ares, L. Horn, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N. Engl. J. Med. 373 (2015) 1627– 1639. [19] J.W. Goldman, L. Crinò, E.E. Vokes, Nivolumab in patients with advanced NSCLC and central nervous system metastases, J. Clin. Oncol. (2016) (abstr 9038). [20] P. Bidoli, R. Chiari, A. Catino, Efficacy and safety data from patients with advanced squamous NSCLC and brain metastases participing in the nivolumab Expanded Access Programme (EAP) in Italy, Ann. Oncol. 27 (2016) 416–454. [21] A.M. Di Giacomo, P.A. Ascierto, L. Pilla, A phase 2, open-label, single-arm study to investigate the combination of ipilimumab and fotemustine in patients with advanced melanoma: the NIBIT-M1 trial, Lancet Oncol. 13 (2012) 879–886. [22] A.M. Di Giacomo, P.A. Ascierto, P. Queirolo, Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study, Ann. Oncol. 26 (2015) 798–803. [23] A.M. Di Giacomo, A randomized, phase III study of fotemustine versus the combination of fotemustine and ipilimumab or the combination of ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis: the NIBIT–M2 trial, J. Clin. Oncol. 33 (2015) (abstr TPS9090.). [24] H.A. Tawabi, P.A.J. Forsyth, A.P. Algazi, Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the
[25]
[26]
[27]
[28]
[29]
[30]
brain: results of the phase II study CheckMate 204, J. Clin. Oncol. (2017) (abstr 9507). G.V. Long, V. Atkinson, A.M. Menzies, A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC), J. Clin. Oncol. (2017) (abstr 9508). J. vom Berg, M. Vrohlings, S. Haller, Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection, J. Exp. Med. 210 (2013) 2803– 2811. P. Agarwalla, Z. Barnard, P. Fecci, Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blackade effectively treats established murine intracranial tumors, J. Immunother. 35 (2012) 385–389. Z. Belcaid, J.A. Phallen, J. Zeng, Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model, PLoS One 9 (2014) e101764. D.A. Wainwright, A.L. Chang, M. Dey, Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors, Clin. Cancer Res. 20 (2014) 5290–5301. D.A. Reardon, A. Omuro, A.A. Brandes, Randomized phase 3 study evaluation the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma, CheckMate 143, Presented at 5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies May 4–7, 2017, Zurich, Switzerland, 2017.
Anna Maria Di Giacomo obtained her MD from the Tor Vergata 2nd School of Medicine, Rome, Italy, in 1997. During 1997–2001, Dr Di Giacomo held a Research position at the, Department of Pharmacology/Clinical Oncology, University of Rome Tor Vergata, Rome. In 2001, she subsequently obtained her Board Certification in Oncology. During 2001–2003, Dr Di Giacomo held a Postdoctoral Fellow position at the Department of Oncology, Fatebenefratelli Hospital, Rome. During 2003–2004, she held an Assistant position at the Division of Medical Oncology, General Hospital, Cuneo, Italy. Since 2004, Dr Di Giacomo is an Associate Director at the Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena. She is a member of three prestigious societies: the Associazione Italiana di Oncologia Medica (AIOM), the Italian Network for Tumour Biotherapy (NIBIT), and ESMO (European Society of Clinical Oncology). Dr Di Giacomo treats over 400 metastatic melanoma patients/ year and 150 primary brain tumors. She is currently Principal Investigator and CoInvestigator for more than 50 clinical trials in solid malignancies, investigating biochemotherapy, immunotherapeutic agents and molecularly targeted agents. She is the author of more than 50 scientific publications, and has been an invited speaker at more than 100 congresses. Dr Di Giacomo’s translational research interests include: epigenetics and the immunological and clinical activity of immunotherapeutic agents in the treatment of melanoma, and other solid tumors.
Please cite this article in press as: A.M. Di Giacomo, et al., Immunotherapy targeting immune check-point(s) in brain metastases, Cytokine Growth Factor Rev (2017), http://dx.doi.org/10.1016/j.cytogfr.2017.07.002