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Moving Immune Checkpoint Blockade in Thoracic Tumors beyond NSCLC

Journal of Thoracic Oncology, Volume 11, Issue 11, November 2016, Pages 1819 - 1836

Commentary by Stefan Zimmermann

Progress in immunotherapy of SCLC, pleural mesothelioma and thymic epithelial tumors lags behind the rapid strides observed in the treatment of NSCLC. This for various reasons, including the intrinsic biological aggressiveness of SCLC, the relative rarity of MPM hampering trial enrollment, and the concern of paraneoplastic disease flare-up in TET. Yet early clinical results hint at significant benefits in all these tumor types Facchinetti and colleagues provide an overview of the rationale for immune checkpoint blockade, present preliminary clinical results, and discuss ongoing trials. Although many trial results have been presented or updated in the meantime, especially during WCLC 2016 in Vienne, they make an interesting read, clearly heralding long-awaited changes in the treatment algorithms in these tumor types. 

Abstract

SCLC and malignant pleural mesothelioma (MPM) are historically characterized by a disappointing lack of significant therapeutic breakthroughs for novel agents, and both malignancies represent true unmet medical needs. Given the promising results of anti–cytotoxic T-lymphocyte associated protein-4 and anti–programmed cell death-1/programmed death ligand-1 antibodies in the treatment of advanced NSCLCs, these immune checkpoint inhibitors are now also under investigation in SCLC and MPM, as well as in thymic epithelial tumors (TETs). Here, we review the biological and clinical rationale for immune checkpoint inhibition in SCLC, MPM, and TETs and present preliminary clinical results with available antibodies. Immunotherapeutic perspectives for these malignancies in terms of novel agents currently under evaluation or anticipated in the near future are also discussed. Current immune checkpoint blockers targeting cytotoxic T-lymphocyte associated protein-4 and the programmed cell death-1/programmed death ligand-1 axis, administered alone or in combination and as multimodality treatment, are likely to be a valuable addition to the therapeutic array for managing SCLC and MPM; studies in TETs, which are currently in their infancy, are merited. Close attention to potential toxicities will be important to the success of such strategies in these settings.

Keywords: SCLC, Malignant pleural mesothelioma, Thymic epithelial tumors, Immune checkpoint inhibitors.

Introduction

Cancer cells harbor several mechanisms to induce a permissive and tolerant immune system. Boosting the antitumor immune response against malignant phenotypes is thus an intuitive approach in therapeutic management but remains nonetheless challenging.1 and 2 Immune checkpoint molecules are expressed by tumor, immune, and stromal cells, which together generate immune suppression in the tumor bed. Immune checkpoint inhibitors are therapeutic antibodies designed to interrupt the immunosuppressive pathways used by cancer cells to survive and proliferate in an otherwise hostile environment.3 Among them, antibodies against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4 [also known as CD152]), programmed cell death protein 1 (PD-1 [also known as CD279]), and its ligand programmed death-ligand 1 (PD-L1 [also known as CD274]) are the best studied. Many other immune checkpoint inhibitors are currently being evaluated as potential therapeutic targets.4

In the neoplastic microenvironment, antigen-presenting cells (APCs), mainly represented by macrophages and dendritic cells, present internalized tumor peptides to mature T cells. This antigen cross-presentation takes place in tumor-draining lymph nodes or in the tumor itself through intratumoral tertiary lymphoid structures.5 and 6 Tumor peptides are presented by major histocompatibility complex molecules expressed by APCs and are recognized by tumor-specific T cells (Fig. 1). This T-cell priming process classically requires the interaction of CD80 (B7.1) and CD86 (B7.2) expressed by APCs with costimulatory molecules (e.g., CD28, ICOS, OX40, and CD137) found on the T cell surface in order for them to expand and become activated.7 However, after prolonged antigen exposure, as occurs in cancers, T lymphocytes can express CTLA-4, a coinhibitory molecule with a significantly higher affinity for CD80 and CD86 than for CD28. Once coupled with its ligand, CTLA-4 causes T-cell anergy (immune unresponsiveness) through negative intracellular signaling.8

gr1

Figure 1

Graphical representation of principal mechanisms involved in adaptive T-cell–mediated immunity against tumors and in its modulation exerted by cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and the programmed cell death-1(PD-1)/programmed death ligand-1 (PD-L1) (programmed death ligand-2 [PD-L2]) axis. The following events are depicted here and approached in detail in the text: (1) antigen detection, internalization, and processing by antigen presenting cells (APCs), mainly represented by dendritic cells (DCs); (2) their presentation to naive T cells; and (3) the activity of the latter at the tumor site. As seen concerning SCLC, quantitative and qualitative variability of tumor peptides leads to a wide cross-presentation of antigens to T cells, so far able to move to tumor beds. CD8+ T cells can therefore exert their specific cytotoxic function on malignant phenotypes assisted by cytokines such as interleukin-2 (IL-2) and interferon-γ (IFN-γ) secreted by CD4+ helper T cells. Processed antigens are presented by the major histocompatibility complexes (MHCs), with type I and II MHCs interacting with the antigen-specific T-cell receptors (TCRs) of CD8+ and CD4+ T cells, respectively. CD8 and CD4 act as coreceptors of the TCR, whereas CD3 mediates its intracellular positive signaling, contrasted by coinhibitory inputs driven by PD-1 once activated by its ligands PD-L1 and PD-L2.

 

When primed T lymphocytes ultimately reach the tumor, their immune activity may again be hampered by several mechanisms.9 and 10 PD-L1 and programmed death ligand 2 are present in the tumor microenvironment and interact with the PD-1 receptor expressed by immune cells and notably by T lymphocytes (see Fig. 1). PD-1 stimulation leads to an intracellular signaling cascade that also results in T cell anergy, preventing their activity against cancer cells. However, interactions at the interface between the tumor and immune counterparts are considerably more complex than this, taking into account notably the pivotal role of other subsets of immune cells, immune secreted factors, and various microenvironment features.11 Not only is the assumption concerning the theoretical cellular distribution of PD-1, PD-L1, and programmed death ligand 2 partial and imprecise,12 but in addition their expression is prone to dynamic induction, notably upon exposure to cytokines such as interferon-γ.13 Moreover, spatial,14, 15, and 16 temporal, and therapeutic17 and 18 factors can affect PD-L1 expression in the tumor microenvironment. All these elements highlight the dynamic nature of PD-L1 and cloud a clear understanding of PD-1/PD-L1 blockade mechanisms.

Current Immune Checkpoint Inhibitors

The CTLA-4–blocking antibodies ipilimumab (immunoglobulin G1 [Bristol-Myers Squibb, Lawrenceville, NJ]) and tremelimumab (immunoglobulin G2 [AstraZeneca/Medimmune, Mountain View, CA]) were designed to release T lymphocytes by preventing CTLA-4 interactions, favoring their activation through CD28 signaling. As CTLA-4 is also expressed by regulatory T cells (which have immunosuppressive properties), anti–CTLA-4 antibodies can also act through the depletion of these protumoral lymphocytes in tumor tissues.19

The anti–CTLA-4 agent ipilimumab has established proof of concept of long-term tumor control with an immune checkpoint inhibitor in metastatic melanoma, in which its introduction has permitted a 20% overall survival (OS) rate with up to 10 years' follow-up.20

Recently approved in for use NSCLC and melanoma, nivolumab (Bristol-Myers Squibb)21 and pembrolizumab (Merck Sharp and Dohme, Hoddesdon, UK)22 and 23 are anti–PD-1 antibodies currently in different phases of clinical development for several malignancies. PD-L1–targeted inhibitors such as atezolizumab (MPDL3280A [Roche/Genentech, South San Francisco, CA]),12 durvalumab (MEDI4736, AZ/Medimmune),24 and avelumab (MSB0010718C [Pfizer/Merck Serono, Darmstadt, Germany)25 have also demonstrated activity in the same histologic types as those sensitive to an anti–PD-1.

Particularly interesting are recent reports that the combination of CTLA-4 and PD-1 blockade has synergistic potential in melanoma.26 The combination of immune checkpoint inhibitors with immunotherapy,27 surgery,28 radiotherapy,29 and cytotoxic or targeted therapies is another pertinent area of interest under development.

In light of the encouraging efficacy outcomes with both anti–CTLA-4 and anti–PD-1/PD-L1 antibodies in a range of tumor types, and notably in advanced NSCLCs, we present data supporting the biological rationale behind implementing immune checkpoint inhibition along with the current clinical status of their use in three other thoracic carcinomas: SCLC, malignant pleural mesothelioma (MPM), and the rarer thymic epithelial tumors (TETs), for which there is an acute need for novel therapeutic advances.

SCLC and Immune Checkpoint Inhibitors

Rationale for Immune Checkpoint Inhibition in SCLC

SCLC accounts for approximately 13% to 15% of lung malignancies currently diagnosed in industrialized countries.30 With a 5-year OS less than 7%, SCLC is considered an orphan disease.31 Despite experimental and clinical efforts, significant breakthroughs in improving outcomes have been sorely lacking for the past four decades.32 and 33 The intrinsic biological aggressiveness, typical premature disease progression albeit initial chemosensitivity, absence of significantly active second-line drugs, and paucity of known molecular targets (with the recent promising exception of DLL3)34 all contribute to the dismal prognosis.

SCLC's pathogenesis is influenced by inhibition of antitumor immune effectors occurring through tumor cells and the neoplastic microenvironment, mainly represented by innate immunity phenotypes (natural killer cells, antitumor macrophages, and neutrophils) and particularly CD8+ cytotoxic T cells.35 Most importantly, the tumor itself exerts protumoral features of myeloid and lymphoid elements to maintain a permissive environment for growth and spread.36 Tumor-associated macrophages and tumor-associated neutrophils,37 dendritic cells,38 myeloid-derived suppressor cells,39 and lymphocytic (regulatory B- and T-cell)40 and 41 populations harboring inhibitory activity contribute to immune impairment. The malignant microenvironment acts in parallel, both favoring cancer cell growth and inhibiting immune effectors, mainly by abnormal tumor vascularization and high proangiogenic factor (e.g., vascular endothelial growth factor) levels,42, 43, and 44 normalization of which can lead to immune impairment reversion.45 and 46 Balancing effectors and regulatory T phenotypes in tumor tissues47, 48, and 49 and the systemic circulation50 and 51 correlates with SCLC stage and affects clinical outcomes. Immunophenotypic characterization suggests that circulating natural killer and cytotoxic T cells can be hampered in their functioning,52 with concomitant absolute and relative increases in regulatory T cells.53 Although, the dichotomy between protumoral and antitumoral immune phenotypes is schematic and partial, understanding it should help uncover a role for boosting immune functioning in managing SCLC.35

Moreover, preliminary but significant evidence of tumoral genomic aberrations in melanoma,54 and 55 colorectal cancer,56 and NSCLC57 support the assumption that their number (overall mutational load) and type (neoantigen load)58 can predict response to immune checkpoint inhibitors. The tight epidemiological correlation with exposure to tobacco, a strong carcinogenic agent, supports this concept in SCLC,59 and strong evidence revealing SCLC as one of the most highly mutated tumors further sustains this hypothesis.60

Finally, autoantibodies directed against neuroendocrine peptides produced by SCLCs can cross-react with peripheral or central nervous system proteins,61 leading to paraneoplastic neurologic syndromes, which affect up to 5% of patients with SCLC.62 Serologic positivity for immunoglobulins directed against tumor and nervous system components are associated with favorable oncologic outcomes,63 although paraneoplastic syndromes themselves can dramatically affect clinical evolutions.64 These elements prove more specifically the interplay between SCLC and humoral immunity, whose specific role in immune checkpoint inhibitors is not clear, although potentially exploitable.

PD-L1 Expression in SCLC

To date, evidence is lacking for potentially useful markers to predict immune checkpoint inhibitor activity for anti-CTLA-4 antibodies in all tumor histologic types. With regard to inhibition of the PD-1/PD-L1 axis, the role of tumoral PD-L1 expression in NSCLC is controversial.23, 65, and 66 The initial data evaluating PD-L1 immunohistochemical expression in SCLC are discordant. Ishii et al. observed PD-L1 positivity (staining in more than 5% of tumor cells) with the rabbit monoclonal antibody EPR1161(2) (Abcam, Cambridge, MA) in 71.6% of 102 evaluated histologic specimens.67 Furthermore, positivity was common in cases diagnosed as limited-stage disease (LD) compared with extensive-stage disease and independently correlated with longer OS than in negative cases. Similar results were reported by Komiya and Madan, who used the same definition of PD-L1 positivity and the same antibody. Staining of commercial SCLC tissue microarrays showed that PD-L1 was expressed at the tumor cell membrane in 82 of 99 samples (82.8%).68 Conversely, however, Schultheis et al.,69 using 5H1 (provided by the laboratory of Dr. Lieping Chen, Yale University, CT) and E1L3N (Cell Signaling Technology, Danvers, MA) clones, documented the absence of PD-L1 staining in the strictly tumoral compartment in 94 neuroendocrine tumors, including 61 SCLCs. Remarkably, PD-L1 positivity was specifically observed on stromal CD68+ tumor-infiltrating macrophages in 18.5% of analyzed specimens but not on the lymphocytic counterpart, which expressed PD-1 in approximately 50% of cases. PD-L1 positivity was defined with a semiquantitative score and was observed in metastases more frequently than in primary tumors.

Using a similar semiquantitative score, Yu et al. recently documented that PD-L1 expression (SP142 antibody [Spring Bioscience, Pleasanton, CA]) in SCLC is more pronounced in the tumor immune microenvironment than in neoplastic cells and that a direct quantitative relation exists between the two entities driven by PD-L1.70 In another recent study,71 fluorescence-activated cell sorting (FACS) analyses showed weak PD-L1 expression in all four SCLC cell lines tested with the MIH2 clone (LifeSpan BioSciences, Seattle, WA), with only the SBC-3 line coexpressing PD-1.

As seen in NSCLC and other malignancies,12 the simplistic perspective dichotomizing PD-L1 expression by neoplastic cells and PD-1 by the immune counterpart does not reflect the true structural and biological complexity of the tumor environment. Other predictive markers are currently under investigation to select patients with NSCLC who may benefit from PD-1/PD-L1 blockade,72 and their applicability will be envisaged in SCLC.

Clinical Trials with Immune Checkpoint Inhibitors in SCLC

Anti–CTLA-4 Blockade

A randomized, double-blind phase II trial73 was performed to evaluate ipilimumab activity in combination with first-line chemotherapy in 130 patients with ED SCLC (Table 173, 74, 75, 76, and 77). Better clinical outcomes were seen with the addition of ipilimumab 10 mg/kg to chemotherapy, administered together with the last four of the six courses of the carboplatin-paclitaxel regimen (phased ipilimumab). CTLA-4 blockade did not produce any benefit when administered concomitantly with the first four chemotherapy cycles (concurrent ipilimumab). Progression-free survival (PFS) measured according to immune-related radiologic criteria (irPFS)78 was significantly longer than with chemotherapy alone (5.3 months) for phased ipilimumab (6.4 months [p = 0.03]), but not for the concurrent schedule (5.7 months [p = 0.11]). Adverse events were more frequent in ipilimumab-containing regimens, with 50%, 43%, and 30% grade 3 or 4 toxicity in the phased, concurrent, and chemotherapy arms, respectively, including grade 3 or 4 immune-related toxicities in 17%, 21%, and 9% of patients, respectively. Similar results in terms of activity and toxicity were observed in a parallel trial enrolling patients with NSCLC.79 The small patient population and the unusual first-line regimen used were study limitations. In a subsequent phase II study, ipilimumab was combined with first-line carboplatin-etoposide chemotherapy in the last four of six courses; as a result, immune-related toxicity was substantially elevated (41.7% of patients, including a fatal event due to neuronal autoimmunity).74 Efficacy outcomes have not been yet reported.

Table 1

Published and Preliminary data on Ipilimumab, Nivolumab, and Pembrolizumab Activity and Tolerance in SCLC

 

Study Phase No. Evaluable Patients Stage/Line Design irPFS (mo) mOS (mo) mPFS (mo) ≥G3 Toxicity (%)
Reck et al. (2012)73 II 1:1:1
randomized
130 ED/I (1) carbo + pacl vs. (1) 5.3a (1) 10.5 (1) 5.2 17–21
(2) CHT + concurrent ipib vs. (2) 5.7 (2) 9.1 (2) 3.9
(3) CHT + phased ipic (3) 5.4a (3) 12.5 (3) 5.2
Ottensmeier et al. (2014)74 II single arm 39 of 40 planned ED/I carbo + etop + epi NA NA NA 61.1 (1 TRD)
Radiologic response PD-L1 + required?
(PD-L1 in ≥1% cells)
≥G3 tox (%)
(in planned patients)
ORR (%) DCR (%)
Ott et al. (2015)75 Ib 18 of 24 enrolled ED/≥II pembro, 10 mg/kg 29.2 33.3 Yes 8.3
Calvo et al. (2015)76
Antonia et al. (2015)77
I/II 103 of 183 planned ED/≥II nivo, 3 mg/kg (30 of 80 patients)
nivo, 1 mg/kg, + ipi, 1 mg/kg, (3 of 3 patients)
nivo, 1 mg/kg, + ipi, 3 mg/kg (43 of 47 patients)
nivo, 3 mg/kg, + ipi, 1 mg/kg (0 of 53 patients)
12.7
33
31.1
NA
29.1
100
53.3
NA
No 11.3
0
31.9 (1 TRD)
NA

a Statistically significant difference.

b Concurrent ipi refers to four doses of carboplatin + paclitaxel + ipilimumab followed by two doses of carboplatin + paclitaxel + placebo.

c Phased ipi refers to two doses of carboplatin + paclitaxel + placebo followed by four doses of carboplatin + paclitaxel + ipilimumab.

irPFS, immune-related progression-free survival; mo, month; mOS, median overall survival; mPFS, median progression-free survival; G3, grade 3; ED, extensive-stage disease; carbo, carboplatin; pacl, paclitaxel; CHT, chemotherapy; ipi, ipilimumab; NA, not available; TRD, treatment-related death; ORR, objective response rate; DCR, disease control rate; PD-L1, programmed death ligand 1; pembro, pembrolizumab; nivo, nivolumab.

These data prompted a randomized phase III trial (Table 280) in the first-line setting, with a direct comparison of standard platinum-etoposide chemotherapy with or without ipilimumab starting from the third chemotherapy cycle for four courses (g1q21), with subsequent maintenance therapy every 12 weeks. The study (ClinicalTrials.gov identifier: NCT01450761) has completed enrollment and the first results are awaited.

Table 2

Studies Evaluating CTLA-4 and/or PD-1/PD-L1 Blockade in SCLC, MPM, and TETs without Available Data (as of March 31, 2016) That Are Completed, Ongoing, or Starting Recruitment

source: Data from ClinicalTrials.gov.80

 

Study Phase Planned Enrollment (No. Patients) Stage/Line Design Tissue Required for Immune Analyses? Primary End Point Principal Radiologic Criteria Preliminary Data
SCLC
NCT01450761 III
1:1 randomized
1100 ED/I (cis/carbo + etop) × 4
± ipi (phased) × 4
Not required OS irRC Awaited
STIMULI
NCT0246733
II
randomized
260 LD/I CHT + RT ± (ipi + nivo) Not required OS RECIST 1.1 October 2019
Checkmate 331
NCT02481830
III 480 ED-relapsed/II nivo vs. topotecan vs. amrubicin Not required OS NA July 2018
Checkmate 451
NCT02538666
III 810 ED/I maintenance After CHT: nivo vs. nivo + ipi vs. placebo Not required OS
PFS
NA December 2018
KEYNOTE-158
NCT02628067
II 1100 (all comers) ED-relapsed ≥II pembro Eventually, not mandatory ORR NA April 2018
NCT02359019 II 54 ED/I maintenance pembro maintenance after CHT Eventually, not mandatory PFS RECIST 1.1 July 2016
NCT02402920 I 80 LD + ED/I CHT/RT + pembro Not required MTD irRC July 2023
PembroPlus
NCT02331251
Ib/II 90 ED-relapsed/≥II Irinotecan + pembro Not required RP2D irRC
RECIST 1.1
December 2016
MISP-MK3475
NCT02551432
II 27 ED-relapsed/≥II Paclitaxel + pembro Yes, after the last previous treatment RR, toxicity RECIST 1.1 December 2017
REACTON
NCT02580994
II
1:1 random
118 ED/I cis/carbo + etop ± pembro Yes, baseline for PD-L1 status PFS RECIST 1.1 January 2019
NCT02661100 I/II 26 all comers
NY-ESO-1+ cancers
ED-relapsed/≥II CDX-1401a + Poly-ICLCb + pembro Yes, preferably from a recent biopsy or resection DLT irRC July 2018
NCT02537418 Ib 150 (all comers) ED/I CHT + durvalumab (Medi4736) ± trem Eventually, not mandatory RP2D NA August 2017
NCT02701400 II
Random
20 Relapsed/II-III Durvalumab + trem vs. durvalumab + term + RT Yes, biopsy performed at
1) baseline
2) end of cycle 2
3) progression for PD-L1, PD-1, TILs
PFS
ORR
RECIST 1.1 August 2018
NCT02658214 Ib 80 (all comers) ED/I carbo + etop + durvalumab + trem Not required Safety
Tolerability
NA April 2018
MPM
DETERMINE
NCT01843374
IIb
2:1 random
564 Advanced/≥II trem vs. placebo Not required OS mRECIST ASCO 2016
abstract 8502 (negative)
NCT02399371 II 65 Advanced/II-III pembro Not for phase a, yes for phase b PD-L1
predictivec
mRECIST March 2018
KEYNOTE-158
NCT02628067
UU 1100 (all comers) Advanced/≥II pembro Eventually, not mandatory ORR NA April 2018
NCT02661100 I/II 26
All comers
NY-ESO-1a cancers
Advanced-relapsed/≥II pembro +CDX-1401a + Poly-ICLCb Yes, preferably from a recent biopsy or resection DLT irRC July 2018
NCT02475213 I 75
All comers
B7H3+ cancers
Advanced/II-IV MGA271 (enoblituzumab)d + pembro Not required Safety
Tolerability
RECIST
irRC
August 2018
NCT02381314 I 84
All comers
B7H3+ cancers
Advanced/II-IV MGA271 + ipi Not required Safety
Tolerability
RECIST
irRC
March 2018
NivoMes
NCT02497508
II 33 Advanced/≥II nivod Ability to re-perform biopsy DCR mRECIST July 2017
MAPS2
NCT02716272
II
1:1 random
114 Advanced/II-III nivo vs. nivo + ipi Not required DCR mRECIST December 2017
NIBIT-MESO-1
NCT02588131
II 40 Advanced/I(Sect mk)-IIe trem + durvalumab Yes, archival or new biopsy irORR irRC June 2016
NCT02141347 I 62 (all comers) Advanced/II-III trem ± durvalumab Not required Safety
Tolerability
NA October 2016
NCT02592551 II 20 (16 treated, 4 controls) Resectable/preoperative Durvalumab (MEDI4736) ± trem Yes Immune phenotype modification NA February 2018
NCT02707666 I 15 Resectable/preoperative pembro → surgery → CHT with optional adjuvant pembro Yes IFN-γ gene expression profile
Safety
Feasibility
mRECIST March 2018
TETs
NCT02607631 II 30 TETs Advanced/≥II pembro Yes, archival/baseline (for PD-L1 status) RR RECIST 1.1 February 2018
NCT02721732 II 250 all comers
Rare tumors
Advanced/NA pembro Yes, archival or new biopsy 27 wk NPR RECIST 1.1 June 2019

a CDX-1401 is a vaccine of a human monoclonal antibody specific for DEC-205 (Deca-lectin, a dendritic cell surface receptor) fused to full-length tumor antigen NY-ESO-1.

b Poly-ICLC is a Toll-like receptor-3 agonist.

c PD-L1 predictive refers to the ability of PD-L1 to predict response.

d MGA271 (enoblituzumab) is a B7-H3 antagonist.

e First-line treatment with tremelimumab + durvalumab is specifically addressed to patients refusing platin-based regimens.

CTLA-4, cytotoxic T-lymphocyte–associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; MPM, malignant pleural mesothelioma; TET, thymic epithelial tumor; ED, extensive-stage disease; cis, cisplatin; carbo, carboplatin; etop, etoposide; ipi, ipilimumab; OS, overall survival; irRC, immune-related response criteria; LD, limited-stage disease; CHT, chemotherapy; RT, radiotherapy; nivo, nivolumab; DCR, disease control rate; NA, not available; PFS, progression-free survival; pembro, pembrolizumab; ORR, objective response rate; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose; RR, response rate; DLT, dose-limiting toxicity; trem: tremelimumab; TIL, tumor-infiltrating lymphocyte; mRECIST, modified Response Evaluation Criteria for Solid Tumors (modified for MPM); ORR, overall response rate; irORR, overall response rate according to irRC; ASCO, American Society of Clinical Oncology; IFN-γ, interferon-γ; NPR, nonprogression rate.

Blocking the PD-1/PD-L1 Axis

Data on the clinical application of anti–PD-1/PD-L1 antibodies in SCLC are preliminary but encouraging, although they are currently limited to pretreated patients (see Table 1). Among the 147 samples from patients with SCLC who underwent immunochemical testing for PD-L1 (Merck’s 22C3 clone) in an ongoing phase I trial (KEYNOTE-028), 42 (28.6%) satisfied criteria for PD-L1 positivity defined as staining in at least 1% of tumor or stromal cells, and pembrolizumab (anti–PD-1 immunoglobulin G4) was thus administered in these patients.75 Among the 17 evaluable treated patients, seven had a partial response (PR), at least four of which were confirmed at more than 16 weeks, and one had stable disease. The toxicity profile was optimal considering that grade 3 or 4 immune-related toxicities occurred in only two patients.

Nivolumab (anti–PD-1 immunoglobulin G4) administered as monotherapy or combined with ipilimumab was tested in the CheckMate 032 study in patients progressing after platinum-based therapy.76 and 77 Among the first 73 evaluable patients treated with nivolumab, 3 mg/kg, or nivolumab, 1 mg/kg, plus ipilimumab, 3 mg/kg, concomitant blockade of PD-1 and CTLA-4 gave a better response rate (31.1%) than did PD-1 inhibition alone (12.7%).77 Disease responses were reported early (a median time to response of approximately 2 months in both arms) and were maintained (the median response duration was not reached for nivolumab and was 7 months for the combination). A specific benefit was observed with nivolumab in platinum-resistant tumors, in particular when combined with ipilimumab, achieving a 37.5% disease control rate.77 Although preliminary, PFS and OS are encouraging, with a 1-year OS of 27.1% and 47.5% for monotherapy and combination treatment, respectively. As seen in melanoma,26 association of the two compounds led to increased toxicity, with grade 3 or 4 adverse events in 11.3% and 31.9% of patients treated with nivolumab and nivolumab plus ipilimumab, respectively. Beyond anticipated gastrointestinal and cutaneous toxicities, the emergence of serious neurologic events related to pareneoplastic syndromes affecting the central and peripheral nervous systems deserves attention. A fatal event of myasthenia gravis with combination therapy and three cases of limbic encephalitis (two with monotherapy and one in the dual regimens) were reported, one of which, occurring in the monotherapy arm, was grade 4 and resistant to steroid administration.

Cytotoxic treatment and radiotherapy can promote antigenic exposure and microenvironment remodeling, favoring immune checkpoint inhibitor activity.18, 81, and 82 A randomized phase II study (STIMULI, NCT02046733) is evaluating the impact of combined ipilimumab-nivolumab on OS after completion of standard chemoradiation in LD SCLC (see Table 2). Memory lymphoid cells generated during chemoradiation may be useful immune phenotypes in the event of subsequent microscopic subclinical tumor cells proliferation.83

Of particular note, in both studies PD-L1 expression levels were variable and did not correlate with response.75 and 77 Circumventing the current limited global evidence in terms of PD-L1 staining, the morphologic features of SCLC, deficient in lymphocyte at the tissue level,84 support this lack of concordance. In the absence of in situ immunologic effectors, CTLA-4 and PD-1/PD-L1 blockers can operate at a systemic level by facilitating effector recruitment and action. This, together with the high immunologic propensity of SCLC, may explain the concerning rate of serious neurologic adverse events, especially for dual blockade, which was not observed in patients with melanoma.26 Immune checkpoint inhibitors require a scrupulous clinical approach in SCLC; patients experiencing paraneoplastic syndromes may be at high risk, and close monitoring is globally needed as manifestation of symptoms may be latent.

Importantly, in trials examining both pembrolizumab and nivolumab with and without ipilimumab in SCLC, a nonnegligible number of patients seems to benefit of the treatments for a significant period of time.75 and 77 Identifying the patients more suitable for prolonged disease control by means of clinical, histologic, or humoral biomarkers therefore represents a translational research objective of primary relevance to provide them with exposure to immune checkpoint blockers.

Although preliminary, the studies to date, which are summarized in Table 1, reveal new relevant therapeutic perspectives. Achieving stable disease under nivolumab with or without ipilimumab in a substantial percentage of patients after first-line chemotherapy failure, when disease is often uncontrolled, is noteworthy. Given that radiologic disease stability with pembrolizumab was rare (occurring in one of 18 treated patients), upcoming data will hopefully clarify these differences, which are currently biased by small sample sizes. If confirmed, further pharmacological understanding will be essential.

Table 2 summarizes current and planned (soon to enroll) studies evaluating immune checkpoint inhibitors in SCLC. In addition to chemoimmunotherapy combinations (with eventual radiotherapy in LD SCLC) evaluated in seven studies, two trials propose PD-1/PD-L1 blockade as switch maintenance after standard first-line chemotherapy. At the end of chemotherapy, leukocytes usually return to paraphysiologic quotas and disease burden is considerably lower, reflecting lower interference with immunity counterparts and thus constituting a favorable time point for potentiating the antitumoral immune system with checkpoint inhibitors.

MPM and Immune Checkpoint Inhibitors

Rationale for Immune Checkpoints Inhibition in MPM

MPM represents an epidemiologic and clinical entity of relevant interest. The latency period between exposure to asbestos, the main carcinogenic agent, and mesothelioma diagnosis is estimated to be at least 20 years, with a median of 32 years from the initial exposure.85 Given the only recent prohibition of asbestos use, the peak of worldwide incidence is expected in the next two decades.86 and 87

Combined chemotherapy, radiotherapy, and (for initial stages) surgery is the current standard of care, albeit with a lack of well-defined strategies. Outcomes are disappointing, with a median survival of 17 to 20 months for surgically removed epithelioid tumors, which are biologically and clinically less aggressive than sarcomatoid tumors. Median OS from diagnosis ranges from 10 to 11 months, with 1- and 5-year survival in Europe of 43% and 7%, respectively.88

Development and combination of new chemotherapeutic agents, along with novel radiotherapy and surgical techniques, have not met expectations. Unlike in the case of NSCLC, no inhibitors of effective tyrosine kinase or other signaling proteins have been identified, although hampering tumor vascularization by adding the anti–vascular endothelial growth factor drug bevacizumab to standard first-line chemotherapy recently demonstrated a significant survival benefit versus chemotherapy alone.89 Expectations driven by emerging results from the first clinical trials of the immune checkpoint inhibitors anti–CTLA-4 and anti–PD-1/PD-L1 in MPM are therefore justified, although the data are preliminary.

Relationships between neoplastic and inflammatory/immunity counterparts play a pivotal role in MPM pathogenesis, as suggested by the strong association with asbestos exposure (Fig. 2). Through the mesothelial cells, this induces chronic phlogosis with macrophage and stromal cell recruitment,90 activated inflammasome of which acts on the epithelial phenotype, potentially resulting in neoplastic transformation (see Fig. 2).91 Mesenchymal phenotypes acquire characteristic features of cancer-associated fibroblasts, exerting dynamic interactions between cancer cells and stromal compartments.92 The tumor environment hosts a wide spectrum of innate and adaptive immune cytotypes acting as proneoplastic or antineoplastic elements and whose complex network and equilibrium are of crucial importance in mesothelioma initiation, promotion, and progression (see Fig. 2). Recent preliminary data93 confirm mesothelioma's “inflammatory” features, defined by abundant macrophage infiltration and CD8+ tumor-infiltrating lymphocytes and, in a variable proportion of samples,94 by the so-called T-cell–inflamed phenotype. Complex interplays between neoplastic cellular elements, lymphocytes, and innate immunity phenotypes95 can result in global inhibition of tumor-directed immunity, with a primary role of PD-L1 expression induced by interferon gamma.13 PD-L1 expression, which is more frequently observed in sarcomatoid histologic subtypes, has been reported as an independent negative prognostic factor in patients affected by pleural mesothelioma.96, 97, and 98 Utilizing the E1L3N clone with a cutoff of at least 1% of cells with membranous or cytoplasmic staining, Cedrés et al. reported PD-L1 positivity in 16 of 77 MPM samples (20.8%), with most specimens (nine [56.2%]) weakly expressing the molecule.96 The 5H1-A3 clone, coupled with a positivity threshold of at least 5% cells, revealed PD-L1 expression in 42 of 106 analyzed samples (40%).97 Whereas only one of five or seven epithelioid MPMs expressed PD-L1, approximately half of the nonepitheliod specimens (pooling together the sarcomatoid and biphasic histologic subtypes) tested positive in the two studies96 and 97 and only one case (with desmoplastic features) of 17 sarcomatoid MPMs was not stained for PD-L1 in one series.97

gr2

Figure 2

Schematic representation of synergistic contributions to cancer support generated by chronic inflammation factors (e.g., exposure to asbestos powders exposure and tobacco) but applicable to several other tumor models. Interacting mechanisms involved and concurring to carcinogenesis, tumor promotion, and progression are detailed in the text. VEGF, vascular endothelial growth factor; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; Breg, regulatory B cell.

 

Although in line with the aforementioned data, staining with two reliable anti–PD-L1 clones, E1L3N and SP142, gave nonharmonious results in terms of PD-L1 positivity (defined as the expression in ≥1% of cells) in neoplastic phenotypes and tumor-infiltrating lymphocytes,98 emphasizing the difficult comparability of studies adopting different technical tools and definitions of positivity threshold.

Taken together with data from the initial clinical trial results, these data generate a strong rationale for evaluation of immune checkpoint inhibitors in MPM (Table 3).

Table 3

Definitive and Preliminary Data for Toxicity and Efficacy of Therapeutic Antibodies Directed Against CTLA-4 or PD-1/PD-L1 Axis in MPM

 

Study Phase No. Evaluable patients Drug Radiological Criteria ORR
(%)
DCR
(%)
mOS
(mo)
mPFS
(mo)
≥G3 Toxicity
(%)
Calabrò et al. (2013)99 II single arm 29 trem, 15 mg/kg mRECIST 6.9 37.9 10.7 6.2 14
Calabrò et al. (2015)100 II single arm 29 trem, 10 mg/kg irRC/
mRECIST
13.8/
3
65.5/
41.4
11.3
(irRC)
6.2
(irRC)
7
Alley et al. (2015)103; Alley et al. (2015)104 Ib 25 of 38 planned pembro,
10 mg/kg
RECIST 1.1 28 76 NA 5.8 16
Hassan et al. (2015)105 Ib 20 of 50 planned Avelumab,
10 mg/kg
RECIST 1.1 15 60 NA 3.8 15

CTLA-4, cytotoxic T-lymphocyte–associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; MPM, malignant pleural mesothelioma; ORR, objective response rate; DCR, disease control rate; mOS, median overall survival; mo, month; mPFS, median progression-free survival; G3 toxicity: grade 3 or higher toxicity; trem, tremelimumab; mRECIST, modified Response Evaluation Criteria for Solid Tumors for MPM; irRC, immune-related response criteria; pembro, pembrolizumab; NA, not available.

Clinical Studies with Immune Checkpoints Inhibitors in MPM

Anti–CTLA-4 Blockade

Tremelimumab is the first and only anti–CTLA-4 immunoglobulin tested to date in MPM. In the Italian MESO-TREM-2008 phase II trial,99 activity was evaluated in 29 patients with advanced mesothelioma (one peritoneal mesothelioma and 28 MPMs, including 25 epithelioid, three sarcomatoid, and one biphasic histologic subtype) progressing after first-line chemotherapy. Although the primary end point (objective response rate of 17%) was not reached, two patients had PRs lasting more than 6 months, with an encouraging disease control reported in nine patients. Median PFS and OS were 6.2 and 10.7 months, respectively, and the 1- and 2-year survival rates (48% and 37%, respectively), were consistent with the rates for a long-term acting compound. Adverse events, mainly autoimmune, were manageable, with grade 3 or 4 in 14% of patients.

On the basis of these data, a second phase II study (MESO-TREM-2012) with a different administration schedule was launched100; in the first trial, the antibody was infused at a dose of 15 mg/kg every 90 days until disease progression or toxicity; in MESO-TREM-2012, tremelimumab was administered at 10 mg/kg every 4 weeks for six cycles during induction, followed by a maintenance period with administration at 12-week intervals. Among the 29 enrolled cases, 21, six, and one corresponded to the epitheliod, biphasic, and sarcomatoid histologic subtypes, with one additional undefined subtype. According to immune-related response criteria (irRC), PR was observed in four of 29 patients. In one patient the response was observed at the first computed tomography scan, whereas the remaining three patients achieved responses at the second radiologic evaluation (at 24 weeks)—two after initial disease progression and the third after initially stable disease. Disease control was obtained in 15 patients (52%), with a median duration of response or stability of 10.9 months. Survival outcomes were similar to those in MESO-TREM-2008. The median OS of 15.8 months in the seven patients with the biphasic or sarcomatoid histologic subtype is remarkable given their poor prognosis. A 75% disease control rate was achieved in nonepithelioid histologic subtypes; in MESO-TREM-2008, all four patients with these forms had disease progression, highlighting the need for further studies to address this subpopulation. Toxicities were consistent with the previous report, with 26 patients (90%) and two patients (7%) respectively experiencing grade 1 or 2 and grade 3 or 4 adverse events, mainly represented by gastrointestinal disorders, cutaneous reactions, and febrile syndromes.

Although generating the proof of concept for CTLA-4 inhibition in MPM, immune checkpoint inhibition is nonetheless not without associated complications, mainly concerning radiologic evaluation. In the MESO-TREM-2008 trial, responses were evaluated according to mesothelioma-modified Response Evaluation Criteria in Solid Tumors (mRECIST),101 whereas in the second study irRC were also used, showing that response rates vary according to different criteria (see Table 3). This discrepancy, which makes definition of response challenging in the experimental setting, would also translate into clinical daily practice and needs to be resolved.

The results for tremelimumab led to the design of a phase IIb/III randomized (2:1), double-blind multicenter study (DETERMINE) enrolling patients with MPM or peritoneal mesothelioma whose disease progressed after one or two lines of systemic treatment (see Table 2). The tremelimumab dose and administration schedule were identical to those in the MESO-TREM-2012 study. Disappointingly, however, in a recent press release, it was announced that the primary end point of improved OS was not met.102 Nevertheless, the large cohort receiving tremelimumab (including more than 350 patients) will include responders. The type of responses observed could be helpful, together with the data concerning the anti–PD-1/PD-L1 compounds, in stating which of the two sets of criteria, between mRECIST and irRC, could be the most adequate for the evaluation of immune checkpoint blockers efficacy in MPM.

Anti–PD-1/PD-L1 in MPM

Pembrolizumab is currently the best-studied compound in MPM among anti–PD-1/PD-L1 inhibitors (see Table 3). Interesting data, albeit preliminary,103 and 104 come from the expansion cohort phase Ib trial evaluating this molecule in a range of cancer types (KEYNOTE-028, NCT02054806). Among the 80 screened patients with MPM progressing while they were receiving or not suitable for standard chemtherapy treatment, 38 (45.2%) were PD-L1 positive and received the experimental therapy. PD-L1 immunohistochemical positivity, an inclusion criterion, was defined as membrane staining in at least 1% of tumor cells accompanied by concomitant PD-L1 expression in the stroma or by the presence of an inflammatory infiltrate. According to RECIST 1.1 (i.e., neither mesothelioma related nor immune related), PR and stable disease were observed in seven and 12 of 25 evaluable patients, respectively, achieving a 76% disease control rate with a median PFS of approximately 6 months. This first cohort included 18 epithelioid, two sarcomatoid, two biphasic, and three not specified MPMs. Levels of PD-L1 expression were not predictive of response. Four patients had grade 3 or 4 adverse events (an increase in aminotransferase level, thrombocytopenia, uveitis, and hyperpyrexia). A phase II trial has been designed with a primary end point of PD-L1 staining reliability for predicting MPM response to pembrolizumab (see Table 2).

The first anti–PD-L1 antibody tested in advanced pleural and peritoneal mesothelioma was avelumab (see Table 3). Preliminary safety and efficacy data from a phase Ib expansion cohort were recently presented.105 Among the 20 patients (13 epithelioid, three biphasic, one sarcomatoid, and one undetermined case) previously treated with platinum-pemetrexed, three (15%) achieved a PR, whereas nine (45%) experienced stable disease. Bearing in mind the preliminary nature of the data, median PFS was estimated to be 16 weeks. Of the nine reported reactions to the avelumab infusion, none had serious outcomes, and grade 3 or 4 toxicities, mainly intestinal, were observed in three patients. The expansion cohort is expected to include 50 patients with pleural or peritoneal mesothelioma; PD-L1 positivity and expression levels will be correlated with response. Updates will be presented at the 2016 American Society of Clinical Oncology annual meeting (abstract 8503).

In addition to being examined in two phase II single-arm studies in relapsed disease (see Table 2), pembrolizumab treatment will be evaluated as a maintenance strategy after first-line cytotoxic therapy in a phase II trial and as second-line therapy in a comparative phase III study.106 A randomized phase II study evaluating nivolumab alone or combined with ipilimumab (neither molecule has been tested in MPM) in relapsed MPM will be initiated soon (MAPS2 [see Table 2]).

Tremelimumab will be coupled with durvalumab in a phase II study in patients with pleural or peritoneal mesothelioma previously exposed to or unsuitable for a first-line platinum-containing regimen (see Table 2). Moreover, durvalumab would be associated with first-line standard systemic treatment in a planned phase Ib/II Australian trial.106

As seen for SCLC and consistent with the envisaged inclusion of immune checkpoint inhibitors in multimodal therapies for other curable cancers,107 and 108 assessment of this approach in resectable MPM is planned. A single administration of durvalumab alone or combined with tremelimumab before radical surgery will be performed in a phase II study targeted to uncover modifications of the tumor immunologic environment induced by inhibition of PD-L1 alone or concomitant with CTLA-4 inhibition (see Table 2). Another feasibility study will assess pembrolizumab administration followed by surgery and adjuvant chemotherapy, with an option of adjuvant pembrolizumab for 1 year after surgery.

Pembrolizumab would also be evaluated in association with the focal adhesion kinase (FAK) inhibitor VS-6063 in advanced MPM106 given that FAK signaling is associated with global immunosuppressive features, as was recently robustly demonstrated in squamous cell carcinoma.109 Combined FAK and PD-1 inhibition in association with gemcitabine, is currently being evaluated in an “all comers” phase I trial (ClinicalTrials.gov identifier: NCT02546531).

Beyond CTLA-4 and PD-1/PD-L1, a wide spectrum of less “mainstream” immune checkpoint inhibitors are currently under investigation (see Table 2).110 Among the evaluated strategies, stimulation of CD40 signaling, which is mainly involved in immune-related events,111 may have a role in MPM. Preclinical models sustain this concept112 and a recent phase Ib trial reported positive safety data with the addition of an antibody stimulating CD40 in first-line chemotherapy treatment, with grade 2 or 3 cytokine release syndrome in 10 and two of 15 patients, respectively.113

Immune Checkpoint Inhibitors Therapy in TETs

Immune Context of TETs

TETs are rare neoplastic proliferations of thymic epithelial cells harboring increasing clinical aggressiveness from type A, AB, B1, B2, and B3 TETs to thymic carcinomas (type C TET), according to the WHO histologic grade classification. TETs may be accompanied by paraneoplastic syndromes, most commonly myasthenia gravis, arising in approximately 30% of patients.114 The neuromuscular system may be affected, whereas central nervous system, hematologic (mainly pure red cell aplasia and Good’s syndrome),115 endocrine, cutaneous, gastrointestinal, renal, and rheumatologic affections are present in a smaller proportion of patients. B2 tumors, which are the most frequently diagnosed,116 are commonly associated with other autoimmune disorders.117 Importantly, thymic carcinomas are not associated with paraneoplastic diseases; in a recent series, only three of 304 patients (1%) suffering from thymic carcinoma was affected by myasthenia gravis too.118

The physiopathology of this indication involves alterations in T-cell maturation, leading to autoimmune disorders. Physiologic thymic function is required for the normal T lymphocyte maturation119; thymic epithelial cells are central to positive and negative T cell selection, filtering T-cell receptor–expressing lymphocytes and eliminating clones recognizing self-antigens, respectively.120

Abnormal thymic epithelial cell proliferation drives inefficient positive and negative selection of immature T lymphocytes as a consequence of dysregulated expression of major histocompatibility complex II and the autoimmune regulator gene, respectively.121, 122, and 123 Altered interactions between thymic epithelial cells and T cells can generate, in thymomas, autoimmune paraneoplastic manifestations.124 Their extreme rarity in thymic carcinomas can be explained by loss of the ability to promote lymphocyte maturation.125 Thus, although involvement of the immune counterpart in TET biology suggests an eventual role for therapies modulating the immune system, their potential exploitation is still exploratory.

In terms of tumoral architecture, lymphocyte agglomerates are mainly observed in type AB, B1, and B2 thymomas, being less frequent in B3 thymomas and thymic carcinomas, thus orienting pathologic diagnosis.126 and 127 Within a series of 32 resected thymic carcinomas, Shim et al. observed that tumor-infiltrating lymphocytes were more abundant in the stromal compartment than in the tumor nest.128 Although stromal cytotoxic CD8+ T lymphocytes did not show prognostic significance when considered independently, high rates of stromal CD4+ T-helper and CD20+ B lymphocytes, separately or in combination with the other phenotypes, generally correlated with better OS.

PD-L1 Expression in Thymic Epithelial Tumors

Immunohistochemical and fluorescence-activated cell sorting analyses over the past decade have reported PD-L1 expression in thymic epithelial tumors.129 More recently, PD-L1 positivity has been detected in normal thymus tissue, thymomas, and thymic carcinomas, with an apparent differential distribution between histologic grades.130 and 131 PD-L1 positivity/high expression was reported in 70% (26 of 38)131 and 75% (three of four)130 of thymic carcinomas when a semiquantitative score coupling intensity rate of stained cells and an intensity evaluation was used. Among thymomas, PD-L1 staining was observed in 23% (23 of 101)131 and 67% (44 of 65)130 of specimens, globally correlating with higher-grade WHO histologic types. Nonpathologic thymic epithelial tissues showed less high–PD-L1 staining (three of 17 [17.6%]) than did thymic malignant tissue (47 of 69 [68.1%]) (p = 0.0036).130 In terms of prognostic value, PD-L1 positivity did not show any relationship to OS in either thymomas or thymic carcinomas in one study,131 whereas in the other study high expression of PD-L1 was associated with worse OS.130 Remarkably, in this same study lymphocytes with PD-L1 expression were detected in 14.8% of TETs (eight of 54) and 29.4% of control samples (five of 17), but no lymphocyte staining was observed in the other study.131 This latter discrepancy reflects technical and methodologic issues, mainly owing to different assays and antibodies (the clones 15 and E1L3N, respectively), inconsistent definitions of positive expression, innate heterogeneity of PD-L1 expression, and interoperator variability.

A third study globally confirmed the reported PD-L1 expression in thymomas.132 Yokoyama et al. detected high PD-L1 expression in 54% (44 of 82) of cases. PD-L1 staining correlated with Masaoka–Koga stage, B2/B3 WHO grades, and a negative impact on disease-free survival (but not OS) after complete resection, as confirmed by multivariate analysis.132 Combined intensity and extent of PD-L1 staining (rabbit antibody [Cell Signaling Technology]) correlated with more advanced stages and higher grades in an additional cohort of 52 thymomas.133 Naidoo et al. reported PD-L1 expression (E1L3N) in all 12 B3 thymomas and in 34% (four of 12) thymic carcinomas. Within the limits of the small sample size, PD-L1 positivity (defined as ≥25% of stained tumor cells) correlated with shorter OS. All samples contained CD8+ tumor-infiltrating lymphocytes.134

Taken together, TET lymphocytic infiltration, the initial evidence of PD-L1 expression, and the reported correlation between stromal lymphoid cell abundance and better outcomes in thymic carcinomas127 support immune checkpoint inhibition strategies in TETs.

Clinical Scenario of TETs and Perspectives on Immune Checkpoint Inhibition

Although thymic malignancies, especially thymomas, can benefit from repeated local treatment, only poor evidence is available regarding systemic therapies beyond first-line cisplatin and/or anthracycline containing regimens.135 Several biological agents are currently being tested in this setting,135 with sunitinib recently showing activity in advanced thymic carcinoma, whose chemosensitivity is often scarce.136 Clinical evaluation of immune checkpoint inhibition in thymic malignancies is justified by the unmet need and the apparently permissive biology of these tumors. Three phase II studies to evaluate pembrolizumab in TETs are ongoing or will soon enroll patients (see Table 2).137

Given the aforementioned autoimmunity mechanisms leading to paraneoplastic syndromes in thymomas and the documented toxicity profiles of CTLA-4 and PD-1/PD-L1 blockers, mainly represented by autoimmune disorders,138 extremely close attention will be required during treatment. As seen with severe paraneoplastic syndromes in patients with SCLC who are undergoing treatment with immune checkpoint inhibitors,76 releasing the immune system can generate related dysfunctions in an already susceptible disease state. In this scenario, the induced immune stimulation could concomitantly lead to a pathologic boost of self-directed T cells previously clinically silent but now able to drive autoimmune reactions. This situation cannot be excluded in thymic carcinomas, albeit their weak or absent intrinsic paraneoplastic-inducing potential, with a recent report of this occurrence.137 Among 22 thymic carcinoma patients treated with pembrolizumab, serious adverse events developed in two, one having severe myositis/myocarditis requiring pacemaker placement and the other having emergence of type I diabetes after discontinuation of treatment. Pembrolizumab has nevertheless shown remarkable activity in thymic carcinomas, with one complete response and four PRs (all ongoing) and nine cases of stable disease among the 21 evaluable patients.137

Conclusions

Although interplay between the tumor and the body’s immune system is extremely complex and gathering a clear understanding of these processes remains challenging, using immune checkpoint inhibitors in SCLCs, MPMs, and TETs to exploit the biological conditions of the tumor and thus gain potential benefit is relevant with these indications, for which few novel therapeutics have proved clinically relevant.

Various immune checkpoint blockers targeting CTLA-4 and the PD-1/PD-L1 axis have shown valuable activity as single agents or in combination in patients suffering from SCLC and MPM, meriting evaluation in comparative phase III trials. Initially they are likely to offer novel treatment options for advanced disease beyond first-line cytotoxic regimens and subsequently may address other settings (upfront, maintenance, adjuvant, or multimodality treatment for local diseases), including eventual combinations with different systemic therapies (see Table 2). With respect to the current scenario of administration of compounds in advanced pretreated diseases, considering the long-term biological effect of immunotherapy agents and the benefit observed in melanoma and NSCLC, we would recommend OS as the preferred final end point for trials comparing these new strategies with the standards of care in the three diseases approached in this review.

The reported toxicity profile, notably for dual blockade, draws clinical attention to both ongoing and upcoming clinical trials, notably those enrolling patients with SCLC and TETs. Preexisting paraneoplastic disorders likely represent a strong limitation to checkpoint inhibitor use, potentially precluding their administration in these patients. Preclinical studies to further our knowledge of the complex and fine-tuned balance between neoplastic activity and the counteracting immune components—and the subtle differences between different pathologies—will assist in the development of novel agents and optimization of combination treatments. Finally, technical issues (uniform positivity definitions and varying results with different antibody clones) affecting biomarkers evaluation need to be resolved. As is the case for the vast majority of histologic diagnoses of cancer, investigating predictive markers for identifying probable responders remains a central issue, representing an important aspect to address in future studies so as to optimize the use of these drugs.

Acknowledgments

We thank Dr. Sarah MacKenzie for medical writing assistance (funded by Gustave Roussy Cancer Campus).

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Footnotes

a INSERM, U981, Gustave Roussy Cancer Campus, Villejuif, France

b Medical Oncology Unit, University Hospital of Parma, Parma, Italy

c Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France

d INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, France

e Division of Pathology, University Hospital of Modena, Modena, Italy

f University Paris-Sud Kremlin Bicetre/Chatenay-Malabry, Le Kremlin-Bicêtre, France

g Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France

Corresponding author. Address for correspondence: Francesco Facchinetti, MD, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94805 Villejuif, France.

Disclosure: Dr. Soria has received consultancy fees from Roche, Astra-Zeneca, Pfizer, and Merck Sharp Dohme and is a scientific cofounder of Gritstone Oncology. Dr. Marabelle has received consultancy fees and honoraria from Roche/Genentech, Pfizer, Novartis, Lytix Pharma, Bristol-Myers Squibb, and Merck Sharp Dohme. Dr. Besse has received research grants from Roche/Genentech, Merck Sharp Dohme, Bristol-Myers Squibb, Pfizer, and AstraZeneca. The remaining authors declare no conflict of interest.