The Future of Immunotherapy in the Treatment of Small Cell Lung Cancer

This review discusses the rationale for using immunotherapy in small cell lung cancer and the immunotherapeutic agents being investigated for patients with this tumor type, focusing on antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) pathways.

Abstract

Small cell lung cancer (SCLC), which accounts for 10%–15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Although up to 80% of patients respond to first-line chemotherapy, most eventually relapse, and there are no approved agents beyond the second line. Despite the high incidence of mutations in SCLC, to date no targeted therapy has shown a benefit for this patient population, and systemic treatment has not changed significantly during the past 3 decades. Given that extensive-stage SCLC has a 5-year survival rate of only 1%–2%, novel therapies are desperately needed. Recent evidence shows that the immune system is capable of generating antitumor responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable therapeutic approach to the treatment of patients with SCLC. Of the immunotherapies being investigated for patients with SCLC, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are perhaps the most promising. Because these immune checkpoint pathways, which under normal circumstances function to protect healthy tissues from damage during inflammatory responses and maintain self-tolerance, can help tumor cells evade elimination by the immune system, they represent potential therapeutic targets. This review discusses the rationale for immunotherapy and the early clinical results of immunotherapeutic agents being investigated in SCLC.

Implications for Practice:

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype. Despite sensitivity to first-line chemotherapy, SCLC has high recurrence rates, and responses to second-line treatments are poor. Recent evidence shows that the immune system is capable of generating responses against various tumors, including lung cancer, suggesting that immunotherapy may be a viable approach for patients with SCLC. Of several immunotherapies being investigated, antibodies that target the programmed cell death protein-1 (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (ipilimumab) immune checkpoint pathways are among the most promising for patients with SCLC and are the focus of this review.

Introduction

Small cell lung cancer (SCLC), which accounts for 10%–15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis [1–3]. The aggressive nature of SCLC is underscored by its high mutational burden, which includes biallelic inactivation of tumor suppressor genes p53 and retinoblastoma 1 in nearly all tumors [4]. Almost always attributable to cigarette smoking, SCLC is a poorly differentiated, high-grade carcinoma originating from neuroendocrine-cell precursors within the bronchi [5]. At the time of diagnosis, approximately 70% of patients have extensive-stage disease (ED-SCLC), defined as the presence of overt metastatic disease by imaging or physical examination; the remainder have limited-stage disease (LD-SCLC), defined as tumors confined to the hemithorax that can be encompassed in a tolerable radiation port [6, 7].

Systemic treatment options for patients with SCLC have not changed significantly during the past 3 decades, and few therapies are in late-stage development. Standard-of-care first-line therapy for ED-SCLC is a combination of etoposide with cisplatin or carboplatin in the U.S. and Europe [2, 3, 8–10] and combinations of etoposide or irinotecan with cisplatin or carboplatin in Asia [11, 12]. Although up to 80% of patients respond to first-line chemotherapy, most (approximately 80% of LD-SCLC and almost all ED-SCLC patients) relapse within the first year of treatment [13]. Subsequent-line treatment options are limited; only one agent, topotecan, is approved as second-line therapy in the U.S. and Europe [14], whereas in Japan, amrubicin is approved for second-line treatment [15]. Beyond second-line therapy, there is no standard of care [16]. Furthermore, the great strides recently made with tumor genomics and molecular targeted therapy in non-small cell lung cancer (NSCLC) adenocarcinoma have not been matched in SCLC, for which no actionable mutation has been identified to date. Consequently, the prognosis for patients with SCLC remains poor, with a median overall survival (OS) of 15–20 months for LD-SCLC and 8–13 months for ED-SCLC [7]. The 5-year survival rate is 10%–13% with LD-SCLC and 1%–2% with ED-SCLC [7, 17].

Limitations in the current standard-of-care options for patients with SCLC serve as the impetus for investigating novel therapeutic approaches, including immunotherapy. The goal of immunotherapy is to enhance the immune system’s ability to detect and eradicate tumor cells. Recent evidence suggests that the tumor microenvironment is an important determinant in the capacity of tumor cells to induce an antitumor response and that tumor cells can create immunosuppressive conditions favoring tumor growth and limiting response to therapy [18–20]. Therefore, approaches aimed at counteracting immune evasion mechanisms by tumor cells are especially attractive. This review discusses the rationale for using immunotherapy in SCLC and the immunotherapeutic agents being investigated for patients with this tumor type, focusing on antibodies that target the programmed cell death protein-1 (PD-1; nivolumab and pembrolizumab) and cytotoxic T-lymphocyte antigen-4 (CTLA-4; ipilimumab) pathways.

Rationale for Immunotherapy

Preclinical and clinical evidence suggests that the immune system is capable of detecting and eradicating tumor cells, providing a rationale for immunotherapy in oncology [21]. The antitumor immune response is initiated by the uptake and processing of tumor protein antigens by antigen-presenting cells (APCs), which subsequently activate T cells. T-cell activation requires two steps: (a) the presentation of antigenic peptides on the surface of APCs in conjunction with major histocompatibility complex (MHC) molecules to naïve T cells expressing the appropriate T-cell receptor (TCR) and (b) costimulatory interaction between the CD80/CD86 ligands on APCs and the CD28 receptor on T cells [22]. The antitumor immune response is composed of activated CD4⁺ helper T cells that recruit other immune cell populations to the tumor by secreting cytokines and of activated CD8⁺ cytotoxic T cells that recognize and directly kill tumor cells through interactions between their TCR and the tumor cell’s MHC–antigen complex. However, the immune system can also promote tumor growth and progression via immunosuppressive cell types within the tumor microenvironment (e.g., regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) [18, 19], and tumor cells can evade the immune system by exploiting immune checkpoint pathways (e.g., PD-1 pathway) that normally protect healthy tissues from damage during inflammatory responses and maintain self-tolerance (as will be further discussed) [20].

Increasing evidence shows that the immune system is involved in the pathophysiology of SCLC [23–27]. In fact, SCLC has long been considered immunogenic because of the occurrence of paraneoplastic disorders, such as Lambert-Eaton myasthenic syndrome (LEMS), that result from an immune response directed against specific antigens expressed on both SCLC tumor cells and normal nerve cells (HuD, HuC, and Hel-N1) [23]. Interestingly, SCLC patients with LEMS tend to have a better prognosis, perhaps because the immune response generated against the nervous system is also targeting tumor cells [24].

Additional evidence that SCLC is immunogenic comes from the relationship between immune activity and prognosis. For instance, more CD45⁺ T cells infiltrating SCLC tumors were found to be predictive of better OS, independent of stage and performance status [25]. In addition, more effector T cells were found in LD-SCLC as compared with ED-SCLC [26], and higher effector-to-regulatory T-cell ratios were associated with longer survival [26, 27].

Further supporting the rationale for immunotherapy, recent data suggest that lung cancers with a high mutation burden may be particularly sensitive to immunotherapeutic agents that inhibit the PD-1 pathway [28]. In a study that sequenced exomes (protein-coding genomic regions) from the tumors of patients (n = 34) with NSCLC treated with the anti-PD-1 antibody pembrolizumab, a high mutation burden and a molecular smoking signature were associated with improvements in objective response rate (ORR), response duration, and progression-free survival (PFS) [28]. It is believed that the benefits of anti-PD-1 therapy in the setting of high mutation burden are due to the formation of neoantigens, which are available for presentation to T cells and can ultimately trigger an immune response. Because SCLC is characterized by a high mutation burden [4, 29, 30] and is almost always associated with cigarette smoking [5], PD-1 pathway inhibition might be an effective approach for this disease as well.

It is believed that the benefits of anti-PD-1 therapy in the setting of high mutation burden are due to the formation of neoantigens, which are available for presentation to T cells and can ultimately trigger an immune response. Because SCLC is characterized by a high mutation burden and is almost always associated with cigarette smoking, PD-1 pathway inhibition might be an effective approach for this disease as well.

Immunotherapy

Despite the compelling rationale for using immunotherapeutic agents in SCLC, relatively few studies of these agents have been completed. To date, trials have assessed immune checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab), interferon (IFN), and vaccines (Table 1). Among these, immune checkpoint inhibitors are the furthest along in clinical development, with some promising results.

Table 1.

Completed trials of immunotherapy agents in small cell lung cancer

Immune Checkpoint Inhibitors

CTLA-4 is the best-characterized immune checkpoint receptor to date. A transmembrane protein receptor expressed on the surface of T cells, CTLA-4 is believed to regulate responses in the early stages of T-cell activation [20, 31]. By virtue of a higher binding affinity, CTLA-4 outcompetes the CD28 receptor for binding to its ligands, CD80/CD86, expressed by APCs, providing an inhibitory rather than stimulatory signal to the T cell. Under normal circumstances, CTLA-4 helps limit inflammatory responses and maintain tolerance to self-antigens (i.e., preventing autoimmunity). However, CTLA-4 may also play a detrimental role by inhibiting antitumor immunity. CTLA-4 blockade, therefore, may remove the inhibitory signal and stimulate antitumor immunity (Fig. 1).

Figure 1.

CTLA-4 pathway inhibition. The antitumor immune response is initiated by the uptake and processing of tumor protein antigens by APCs, which subsequently activate T cells. T-cell activation requires two steps: first, the presentation of antigenic peptides on the surface of APCs in conjunction with MHC molecules to naïve T cells expressing the appropriate TCR, and second, costimulatory interaction between the CD80/CD86 ligands on APCs and the CD28 receptor on T cells (A). Expressed on the surface of T cells after activation, CTLA-4 delivers an inhibitory signal to the T cell by outcompeting the CD28 receptor for binding to CD80/CD86 (B). CTLA-4 blockade may remove this inhibitory signal and stimulate antitumor immunity (C).

Abbreviations: APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.

Insights into the immunologic functions of CTLA-4 have led to the development of ipilimumab, an antibody that binds to CTLA-4 and blocks its interaction with CD80/CD86. Approved for treating patients with unresectable or metastatic melanoma based on significant improvements in OS in two phase III studies [32, 33], ipilimumab has been investigated in combination with chemotherapy in patients with SCLC [34].

A randomized, double-blind, phase II trial (NCT00527735) examined the efficacy of ipilimumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in treatment-naïve patients with advanced NSCLC or SCLC [34] (Table 1). The rationale for combining ipilimumab with chemotherapy was based on preclinical and clinical findings suggesting that certain chemotherapeutic agents augment the activity of ipilimumab [35, 36]. Although paclitaxel plus carboplatin is not a traditional regimen for SCLC, it was chosen as the comparator because it is a standard regimen for NSCLC patients and because data show benefits with this combination in SCLC [37, 38]. Treatment administration was concurrent (ipilimumab plus paclitaxel and carboplatin for four cycles followed by placebo plus paclitaxel and carboplatin for two cycles; n = 43) or phased (placebo plus paclitaxel and carboplatin for two cycles followed by ipilimumab plus paclitaxel and carboplatin for four cycles; n = 42), with a control group receiving only placebo plus paclitaxel and carboplatin for the same total number of doses (n = 45) [34]. Treatment was given every 3 weeks for up to 18 weeks (induction) followed by maintenance ipilimumab or placebo every 12 weeks.

To better account for the unique tumor response patterns exhibited by immunotherapy, including regression of index lesions in the face of new lesions and initial progression followed by tumor stabilization or regression, immune-related response criteria were used. Immune-related PFS (irPFS), defined as the time from randomization to immune-related progression or death, was the primary endpoint of this study. Median irPFS significantly improved with paclitaxel and carboplatin with phased ipilimumab compared with paclitaxel and carboplatin alone (6.4 months vs. 5.3 months; hazard ratio [HR], 0.64; p = .03), but not with paclitaxel and carboplatin with concurrent ipilimumab (5.7 months). There was also a nonstatistical trend toward improved median OS with phased (12.9 months) but not concurrent (9.1 months) ipilimumab administration with chemotherapy versus chemotherapy alone (9.9 months). Furthermore, immune-related best overall response tended to be better with phased (71%), but not concurrent (49%), administration compared with control (53%). In general, ipilimumab did not exacerbate the adverse event profile of platinum-based chemotherapy. Although treatment-related grade 3–4 adverse events were more frequent in the ipilimumab-containing arms (concurrent, 43%; phased, 50%) than in the control arm (30%), rates of discontinuation due to adverse events were similar across treatment arms (concurrent, 7%; phased, 5%; control, 9%). Patients treated with ipilimumab experienced toxicities consistent with its immune-based mechanism of action, including rash, pruritus, and diarrhea.

Despite the promising efficacy data in this phase II trial, the use of phased ipilimumab with platinum therapy and etoposide in patients newly diagnosed with ED-SCLC has been called into question by results from a phase III trial (NCT01450761) in which this combination did not meet its primary endpoint (improved OS) versus platinum therapy and etoposide alone [39].

Ongoing trials are investigating the use of ipilimumab in combination with other therapies, including carboplatin and etoposide, radiotherapy, and nivolumab (Table 2). An open-label phase II study (NCT01331525) of ipilimumab in conjunction with carboplatin and etoposide in ED-SCLC is ongoing, with a primary endpoint of 1-year PFS [40]. To date, 39 of 40 patients have been enrolled. In a preliminary analysis, 61% of patients experienced adverse events of grade 3 or above, among which 42% were possibly ipilimumab-related. Two patients (6%) had ipilimumab-related neurological events; one was fatal, presenting like an anti-Hu syndrome. Both events occurred in patients with positive baseline antineuronal antibodies. Ipilimumab is also being investigated in combination with stereotactic body radiation therapy in an ongoing phase I/II study (NCT02239900) with solid tumors including SCLC.

Table 2.

Ongoing immunotherapy trials involving patients with small cell lung cancer

The PD-1 receptor is another important immune checkpoint receptor being studied in oncology [20]. A transmembrane protein receptor highly expressed by activated T cells, PD-1 is thought to inhibit T-cell activation within peripheral tissues at the time of an inflammatory response, in contrast to CTLA-4, which acts at the initial T-cell activation stage in the lymph nodes. PD-1 has two ligands, PD-ligand 1 (PD-L1, B7-H1) and PD-ligand 2 (PD-L2, B7-DC), both of which are expressed on APCs, in addition to several other hematopoietic and nonhematopoietic cell types. Binding of PD-1 to PD-L1, its main ligand, results in inhibition of T-cell immune functions, and, like CTLA-4, PD-1 normally limits inflammatory responses and prevents autoimmunity. However, binding of PD-1 on activated tumor-infiltrating T cells to PD-L1 on tumor cells and immune cells in the tumor microenvironment can inhibit antitumor immune responses. Therefore, anti-PD-1/PD-L1 therapy may remove the inhibitory signal and stimulate antitumor immunity (Fig. 2). Because of the importance of PD-L1 in inducing local immune suppression in the tumor microenvironment, its expression is being investigated as a surrogate biomarker for predicting response to anti-PD-1/PD-L1 therapy (as will be further discussed).

Figure 2.

PD-1 pathway inhibition. Tumor cells may activate an antitumor immune response by presenting tumor antigens in conjunction with MHC molecules to naïve T cells in the tumor microenvironment expressing the appropriate TCR (A). However, activated tumor-infiltrating T cells can express PD-1, and binding of PD-1 to its ligands, PD-L1 and PD-L2, on tumor cells can inhibit antitumor immune responses (B). PD-1/PD-L1 blockade may remove this inhibitory signal and stimulate antitumor immunity (C).

Abbreviations: MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TCR, T-cell receptor.

Because of the importance of PD-L1 in inducing local immune suppression in the tumor microenvironment, its expression is being investigated as a surrogate biomarker for predicting response to anti-PD-1/PD-L1 therapy.

The anti-PD-1 antibodies nivolumab [41–45] and pembrolizumab [46–48] are approved in the U.S. and Europe for treating patients with advanced NSCLC. Specifically, nivolumab is approved in the U.S. for treating patients with metastatic NSCLC with progression on or after platinum-based chemotherapy or those with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genomic tumor aberrations with disease progression on approved therapy for these genetic aberrations [41, 43–45]. Furthermore, nivolumab is approved in Europe for treating patients with locally advanced or metastatic squamous NSCLC after chemotherapy [42, 44, 45]. Pembrolizumab is also approved in the U.S. for treating patients with metastatic NSCLC who progressed on or after platinum-containing chemotherapy or approved molecular therapies for EGFR and ALK aberrations, but only in patients whose tumors express PD-L1 (PD-L1 positivity is defined as a tumor proportion score of ≥50% using the U.S. Food and Drug Administration [FDA]-approved companion diagnostic test) [46, 48]. In addition, nivolumab [41, 42] and pembrolizumab [46, 47] are approved in the U.S. and Europe for advanced melanoma, and nivolumab [41] is also approved in the U.S. for advanced renal cell carcinoma.

Trials are investigating the safety and efficacy of anti-PD-1/PD-L1 therapy in patients with SCLC, with promising data beginning to emerge. For example, CheckMate 032 (NCT01928394) is an ongoing randomized, open-label, phase I/II study evaluating nivolumab plus ipilimumab versus nivolumab monotherapy in five tumor types, including SCLC (Table 2) [49]. The rationale for combining nivolumab with ipilimumab is based on restoration of the antitumor immune response through blockade of complementary (nonredundant) immune checkpoint pathways (i.e., PD-1 and CTLA-4 pathways) [20], a strategy that has already been shown to be effective in patients with advanced melanoma [50, 51]. The primary endpoint of the CheckMate 032 study is ORR per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, the secondary endpoint is safety, and exploratory endpoints include PD-L1 biomarker analysis. Patients with SCLC (n = 183) whose disease progressed after one or more lines of therapy, including a first-line platinum-based regimen, were assigned to nivolumab 3 mg/kg monotherapy every 2 weeks (n = 80) or assessed in a dose-escalating safety phase for the combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles. Depending on tolerability, patients treated with initial combination therapy were then assigned to one of two dose cohorts: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (n = 47) or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 53) every 3 weeks for 4 cycles. Although all patients met the prespecified safety and efficacy criteria, 3 remained at the initial combination dose (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles). Regardless of initial therapy, patients could continue therapy with nivolumab 3 mg/kg every 2 weeks, until progression, unacceptable toxicity, or protocol-defined reasons.

At the time of the interim analysis (July 2015), efficacy data were available for 55 patients in the group receiving nivolumab 3 mg/kg and 45 patients in the group receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. ORR was 13% with nivolumab 3 mg/kg and 31% with the combination of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, with corresponding disease control rates (complete response, partial response, and stable disease rates combined) of 29% and 53%. In these respective arms, mean time to response was 1.6 and 2.2 months, and median (range) response duration was not reached (4.4–14.1+) and 6.9 (1.3–9.5+) months. For nivolumab 3 mg/kg monotherapy and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, median OS was 3.6 months (95% confidence interval [CI], 2.7–7.5 months) and 7.8 months (95% CI, 3.7–not reached), and 1-year OS rates were 27% and 48%, , respectively (Table 3). Median PFS in the nivolumab 3 mg/kg arm and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg arm was 1.4 months (95% CI, 1.3–1.5 months) and 3.4 months (95% CI, 1.4–6.9 months), respectively. Antitumor activity with nivolumab 3 mg/kg monotherapy and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg combination therapy was observed not only in platinum-sensitive but also in platinum-resistant/refractory disease and regardless of PD-L1 expression (<1% vs. ≥1% expression by tumor cells).

Table 3.

Preliminary results with nivolumab and pembrolizumab in pretreated small cell lung cancer and comparison with second-line topotecan and amrubicin therapy

Although it is difficult to examine findings across studies, preliminary results from CheckMate 032 appear to compare favorably with results reported with second-line topotecan and amrubicin therapy [52], particularly with respect to response duration and 1-year OS rate (Table 3). As noted in previous studies with immune checkpoint inhibitors in other tumor types [32, 43, 44], and not typically seen in topotecan or amrubicin trials with patients with SCLC [14, 52], plateaus in the OS curves occurred in CheckMate 032 with nivolumab 3 mg/kg monotherapy and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg combination therapy, suggesting prolonged survival in a proportion of patients [49].

In addition to promising efficacy results, the safety profiles with nivolumab 3 mg/kg monotherapy and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg combination therapy in CheckMate 032 were acceptable and managed with established safety guidelines [49]. Grade 3–4 treatment-related adverse events were more frequent with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (32%) than with nivolumab 3 mg/kg (11%). Grade 2 limbic encephalitis, a paraneoplastic syndrome associated with SCLC, was reported in 2 patients (1 receiving nivolumab 3 mg/kg monotherapy and 1 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg) and resolved with immunosuppressive treatment. Grade 4 limbic encephalitis was reported in 1 patient receiving nivolumab 3 mg/kg monotherapy and did not resolve with immunosuppressive treatment. Pneumonitis was noted in 2 patients treated with nivolumab 3 mg/kg monotherapy (grade 1–2) and 1 patient treated with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (grade 3). One treatment-related death was attributed to myasthenia gravis, an autoimmune disease. Mature efficacy and safety results from all three arms of CheckMate 032 (nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles, and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles) are eagerly awaited to help define the role of nivolumab alone or in combination with ipilimumab in SCLC.

The use of the nivolumab (alone or combined with ipilimumab) in SCLC is also being evaluated in other trials (Table 2). A randomized, open-label, phase III study (CheckMate 331; NCT02481830) comparing nivolumab with chemotherapy is recruiting patients with LD-SCLC or ED-SCLC who relapsed after platinum-based first-line chemotherapy. A randomized, open-label, parallel-assignment, phase II study (Small cell lung cancer Trial with IpiliMUmab in LImited Disease [STIMULI]; NCT02046733) comparing nivolumab plus ipilimumab after chemoradiotherapy with chemoradiotherapy alone in treatment-naïve LD-SCLC is recruiting patients. Because recent data suggest that certain combinations of PD-1 and CTLA-4 pathway inhibitors may be associated with increased toxicity versus monotherapy, research is now comparing alternative dosing schedules in NSCLC [53] and assessing these combinations as maintenance therapy after first-line treatment in SCLC. For instance, patients with ED-SCLC who completed platinum-based first-line chemotherapy with an ongoing response of stable disease or better are being recruited for a randomized, multicenter, double-blind, phase III study (CheckMate 451; NCT02538666) comparing nivolumab, nivolumab plus ipilimumab, and placebo as maintenance therapy.

Pembrolizumab is also being investigated in SCLC. In KEYNOTE-028 (NCT02054806), an ongoing, phase Ib, multicohort study in patients with PD-L1-positive (membranous PD-L1 expression in ≥1% of cells in tumor nests or positive bands in stroma), advanced solid tumors, including SCLC, pembrolizumab is being administered for up to 24 months (Table 2) [54]. At the time of the interim analysis (June 2015), 24 patients with pretreated SCLC received pembrolizumab 10 mg/kg every 2 weeks. Among these patients, ORR based on RECIST version 1.1 was 29%, with a disease control rate of 33% and median PFS of 1.8 months (95% CI, 1.6–8.5 months) (Table 3). Responses appear to be durable, with 6 of 7 responses ongoing at the time of the data cutoff and the median duration of response of 29.1 weeks (range, ≥0.1–29.1 weeks). There was no relationship between response and PD-L1 expression on tumor and immune cells. Grade ≥3 adverse events occurred in 2 patients (8%), including 1 case of colitis resulting in death. The safety profile was consistent with previous experience with pembrolizumab in other tumor types. Other trials of pembrolizumab for ED-SCLC are ongoing, including a phase II study (NCT02359019) of pembrolizumab maintenance therapy after combination chemotherapy and a phase I study (NCT02402920) of pembrolizumab with concurrent radiation therapy and chemotherapy.

PD-L1 represents another potential therapeutic target in SCLC. In addition to being a ligand for PD-1, PD-L1 can also serve as a receptor for CD80 expressed on T cells, delivering an additional inhibitory signal [55]. Blocking PD-L1 may remove the inhibitory signals and stimulate antitumor immunity. Encouraging results are emerging in NSCLC with anti-PD-L1 antibodies (e.g., durvalumab [MEDI4736] [56] and atezolizumab [MPDL3280A] [57]), and it remains to be seen whether such agents can be successfully applied to SCLC.

IFN

IFNs, a family of immunostimulatory cytokines used as immunotherapy with various tumor types, were first investigated in combined-modality regimens for SCLC in the early 1980s but have shown inadequate antitumor activity in recent trials (Table 1) [58, 59]. IFN-α, which is known to act synergistically with various cytotoxic agents, has been evaluated in a phase II study (NCT00062010) in patients with recurrent SCLC in combination with paclitaxel and 13-cis retinoic acid (13-CRA), an agent that inhibits growth of chemoresistant tumor cells overexpressing the antiapoptosis protein Bcl-2 [58]. Among 34 patients, 3 had a partial response (9%) and another 5 (15%) had stable disease. The median PFS was 2 months (95% CI, 1.8–3.9 months), and median OS was 6.2 months (95% CI, 4.7–9.8 months). However, the study was discontinued at the first futility assessment because the regimen failed to improve outcomes. A phase II trial assessed the combination of IFN-α or IFN-γ with chemotherapy in patients with LD-SCLC or ED-SCLC (n = 164) (Table 1) [59]. Chemotherapy-naïve patients were randomly assigned to chemotherapy (carboplatin, ifosfamide, and etoposide) alone, chemotherapy plus IFN-α, chemotherapy plus IFN-γ, or chemotherapy plus IFN-α and IFN-γ; in the last arm, the dosage of each IFN was half of that when each was given alone with chemotherapy. There was no significant difference in OS between treatment arms for the overall study population, but in the subgroup of patients with LD-SCLC, those receiving IFN-α had a significantly longer median OS than those in any other treatment group (34 months vs. 13.6–19.0 months; p ≤ .039). Although more patients experienced toxicity in the IFN plus chemotherapy groups than the chemotherapy alone group, toxicity was generally mild and manageable.

Vaccines

Representing another immunotherapeutic approach, vaccines designed to elicit immune responses targeting SCLC have been investigated in clinical trials, but with limited benefit to date (Table 1). For example, one vaccine approach involved polysialic acid (polySA), a polymer side chain bound to the neural cell adhesion molecule that is highly expressed on the surface of SCLC cells [60]. In two phase I trials in patients with LD-SCLC or ED-SCLC, vaccination with keyhole limpet hemocyanin (KLH)-conjugated N-propionylated polySA produced a robust antibody response [60, 61]. The most common toxicity in both studies was injection-site reaction, although one patient experienced dose-limiting peripheral neuropathy and ataxia that resolved spontaneously once off treatment [60]. Another investigational vaccination strategy used the p53 gene, which is mutated in most SCLC patients [62]. Transduction of dendritic cells (DCs) with an adenovirus expressing p53 yielded a T-cell response in 57% of ED-SCLC patients and a high rate of objective clinical responses to subsequent chemotherapy (61.9%) [62]. An additional vaccine therapy has been studied incorporating Bec2, an anti-idiotypic antibody that mimics GD3, a ganglioside of neuroectodermal origin highly expressed on the surface of SCLC cells [63]. In a phase III study, vaccination with Bec2 conjugated to bacillus Calmette-Guérin did not improve OS in patients with LD-SCLC who previously had a major response to chemotherapy and chest radiation [63]. Vaccine trials in lung cancer are in early phases of development and are not specifically directed at the SCLC population (Table 2).

Alternative Immunologic Approaches

Several alternative immunologic approaches are being investigated in SCLC. As examples, the toll-like receptor 9 agonist MGN1703 and autologous cytokine-induced killer cells are being evaluated separately in two randomized phase II studies (NCT02200081 and NCT01592422) as maintenance therapy in patients with SCLC and disease control (complete response, partial response, or stable disease) after first-line platinum-based chemotherapy (Table 2). In addition, TF2, a bispecific antibody that targets the carcinoembryonic antigen (CEA), is being investigated in combination with a 177Lu-labeled peptide (IMP-288) as a radio-immunotherapy approach in an ongoing phase I/II trial (NCT01221675) in patients with CEA-expressing SCLC or NSCLC.

Immune-Based Biomarkers

Efforts are underway to identify predictive immune-based biomarkers that may help select patients most likely to respond to immunotherapy [64, 65]. Unlike molecular biomarkers, which offer actionable therapeutic targets (e.g., EGFR and ALK genomic tumor aberrations in NSCLC) [66], immune-based biomarkers mirror the interaction between the tumor and the host immune response [64, 65]. Several immune-based biomarkers are being evaluated, including those involving immune cell tumor infiltration, secretion of immune factors (e.g., cytokines), expression of cell surface molecules (e.g., MHC molecules), and gene signatures/patterns; however, their clinical significance has yet to be validated and their use is limited [64, 65].

Unlike molecular biomarkers, which offer actionable therapeutic targets, immune-based biomarkers mirror the interaction between the tumor and the host immune response. Several immune-based biomarkers are being evaluated, including those involving immune cell tumor infiltration, secretion of immune factors (e.g., cytokines), expression of cell surface molecules (e.g., MHC molecules), and gene signatures/patterns; however, their clinical significance has yet to be validated and their use is limited.

Because PD-L1 expression in the tumor microenvironment may induce local immune suppression, it is being investigated using immunohistochemistry (IHC) as a potential biomarker for predicting response to anti-PD-1/PD-L1 therapy [67–69]. Preliminary evidence in various tumor types suggests that PD-L1 expression is associated with higher ORRs with anti-PD-1/PD-L1 therapy. However, application of PD-L1 as a biomarker is faced by several biological and technical obstacles. First, the relationship between PD-L1 expression and efficacy is not robust because responses occur in a substantial proportion of patients with PD-L1-negative tumors, whereas not all patients with PD-L1–positive tumors respond [67–69]. Furthermore, the association of PD-L1 expression and clinical outcome may depend on histology in NSCLC patients, with PD-L1 testing possibly being predictive of response in nonsquamous [43] but not in squamous [44, 45] disease. Interpretation of PD-L1 expression results is also limited by current inconsistencies in assessment method, including the lack of consensus on PD-L1-positive expression level (definition ranging from staining of ≥1% to ≥50% of cells assessed) as well as the use of different tissue fixation techniques, IHC assays, PD-L1 staining antibodies, cell types (tumor cells vs. tumor-associated immune cells vs. both), PD-L1 staining locations (membrane vs. cytoplasm), and biopsy types (archival vs. fresh) [67–69]. Additionally, use of PD-L1 as a predictive biomarker is hampered by the dynamic and heterogeneous nature of its expression, which can vary within the same biopsy, between anatomic sites (primary vs. metastatic), with disease progression, and from the treatment-naïve to treatment-refractory settings within the same patient. FDA-approved PD-L1 diagnostic kits are available for use with pembrolizumab [48] and nivolumab [70] in NSCLC. Although pembrolizumab is indicated only in NSCLC patients with PD-L1-positive tumors, nivolumab can be used in NSCLC patients regardless of PD-L1 expression, with PD-L1 expression helping to predict the magnitude of therapeutic effect with nivolumab in nonsquamous NSCLC rather than serving as an exclusionary criterion.

PD-L1 expression has been demonstrated in SCLC, although there have been inconsistencies in its reporting [71, 72]. In one retrospective study of 102 SCLC specimens, PD-L1 expression was observed in tumor cells in 72% of SCLCs and was associated with significantly longer OS [71]. In contrast, another study involving 94 clinical cases of small cell carcinoma (pulmonary or extrapulmonary) found PD-L1 expression in stromal cells (but not in tumor cells) and in only a minority (19%) of cases [72]. The discrepancy in these findings is not well understood and may be related to differences in PD-L1 detection methods. As previously discussed, responses to nivolumab in patients with SCLC in CheckMate 032 occurred independently of tumor PD-L1 expression [49]. Therefore, the role of PD-L1 in treatment decision-making with anti-PD-1/PD-L1 therapy needs to be clarified, not only in SCLC but also in other tumor types.

Conclusion

Preliminary data suggest that immunotherapy, with its durable responses and favorable toxicity profile, holds promise for the treatment of patients with SCLC. Ongoing trials will help define the role of immunotherapy in the treatment paradigm for SCLC, including delineation of the use of monotherapy, combination immunotherapy, or combination of immunotherapy with cytotoxic therapy, as well as the relative timing of these therapies and use in early-stage versus late-stage disease. Combining immune checkpoint inhibitors with other immunotherapeutic approaches (e.g., recombinant vaccines, DC therapy, and adoptive T-cell transfer) might maximize immunologic priming and minimize blockade of effector T cells. In addition, combining different immune checkpoint inhibitors may act synergistically by affecting complementary (nonredundant) pathways (e.g., PD-1 and CTLA-4 pathways), although potentially with a higher rate of toxicities than seen with monotherapy. Adding immune checkpoint inhibitors to chemotherapy may also augment responses because chemotherapy can induce rapid tumor lysis, releasing tumor antigens that may trigger an antitumor immune response with immune checkpoint inhibitors. Identification of molecular targets in SCLC may also lead to combinations of immune checkpoint inhibitors and new targeted therapies, such as rovalpituzumab tesirine, which is regarded as the first targeted therapy to show promise in SCLC [73]. There may also be a specific interaction of chemoradiotherapy with immunotherapy, which was a rationale for the STIMULI trial.

Early clinical trial outcomes of various immunological agents, and particularly those that target immune checkpoint pathways, have shown potential for improving outcomes in patients with SCLC. Phase III trials of some of these agents are underway, and the results are eagerly anticipated. Immunotherapy may ultimately change the treatment paradigm for SCLC, providing hope for patients with limited treatment options.

Author Contributions

Conception/Design: Leora Horn, Martin Reck, David R. Spigel

Provision of study material or patients: Leora Horn, Martin Reck, David R. Spigel

Collection and/or assembly of data: Leora Horn, Martin Reck, David R. Spigel

Data analysis and interpretation: Leora Horn, Martin Reck, David R. Spigel

Manuscript writing: Leora Horn, Martin Reck, David R. Spigel

Final approval of manuscript: Leora Horn, Martin Reck, David R. Spigel

Disclosures

Leora Horn: Merck, Genentech (C/A), AstraZeneca (RF), Biodesix (H), Bristol-Myers Squibb, Xcovery, Bayer (other); Martin Reck: Hoffmann-La Roche, Eli Lilly, Bristol-Myers Squibb, Merck Sharp Dohme, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis (C/A), Hoffmann-La Roche, Lilly, Bristol-Myers Squibb, Merck Sharp Dohme, AstraZeneca, Boehringer Ingelheim, Pfizer (H); David R. Spigel: Bristol-Myers Squibb, Novartis, Genentech, Pfizer, AstraZeneca (C/A).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board