Rationale for Chemotherapy, Immunotherapy, and Checkpoint Blockade in SCLC Beyond Traditional Treatment Approaches

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David R. Spigel, MD* and Mark A. Socinski, MD†

Key Words: Cytotoxic T-lymphocyte-associated antigen-4 blockade, Introduction: Small cell lung cancer (SCLC) is an aggressive Immunomodulators, Ipilimumab, Small cell lung cancer. malignancy that although initially sensitive to chemo- and radiation therapy, inevitably relapses resulting in poor survival. Increasing evidence suggests that immune responses against SCLC cells make (J Thorac Oncol. 2013;8: 587–598) immunotherapy a viable therapeutic approach. Furthermore, preclinical data have shown that certain chemotherapeutic regimens may augment the immunotherapeutic response in SCLC. This review dis- cusses current evidence supporting immunotherapy for SCLC, prog- mall cell lung cancer (SCLC) is a rapidly growing malig- ress made, and ongoing clinical trials. Snancy with a poor prognosis. Extensive research over the Methods: We searched PubMed and abstracts presented at recent past three decades has greatly expanded the anticancer arma- oncology congresses for publications on the clinical benefit of immu- mentarium for certain types of non–small cell lung cancer notherapy/checkpoint blockade for treatment of SCLC. (NSCLC), but research in SCLC has failed to identify treat- Results: Preliminary data from ongoing clinical trials in SCLC have ments that extend clinical benefit beyond standard-of-care shown that some antiangiogenic agents, vaccines, and immunomodu- treatment. Thoracic radiotherapy in combination with che- lators, including interferon-α and immune checkpoint blockers (i.e., motherapy is recommended for the treatment of patients with anticytotoxic T-lymphocyte-associated antigen-4 [CTLA-4] antibod- limited-disease SCLC (LD-SCLC). Similarly, prophylactic ies) may be efficacious as single agents and in combination with cranial irradiation (PCI) is recommended for patients with standard-of-care regimens. Notably, in a phase II trial, ipilimumab— either LD-SCLC or extensive-disease SCLC (ED-SCLC), who a fully human anti-CTLA-4 monoclonal antibody recently approved attain a complete or partial response after initial treatment.1 for treatment of unresectable or metastatic melanoma—demonstrated Notably, both thoracic radiotherapy and PCI have resulted in encouraging results when used as part of a chemoimmunotherapeu- increased survival in LD-SCLC and ED-SCLC when com- tic regimen in patients with SCLC. Ipilimumab is undergoing further pared with chemotherapy alone. Recent studies demonstrate investigation in this population. that immune responses may occur against tumor cells of the Conclusions: Treatment options for SCLC are limited and progno- lung, including SCLC, suggesting that immunotherapy may be sis poor, emphasizing the need for novel treatments. Although cur- a novel approach for the treatment of SCLC. Immunotherapy rent strategies successfully induce a response, the response is not aims to enhance the immune system’s ability to recognize and durable. Evidence of an immune response in SCLC and a better specifically eliminate cancer cells while minimally impacting understanding of the immunosuppressive tumor environment sup- healthy lung tissue. This article provides a detailed overview port the combinatorial use of immunomodulators, such as ipilim- of immunotherapeutic agents under investigation in SCLC and umab, with traditional chemotherapy regimens to improve patient the challenges of immunotherapy in this tumor type. outcomes and potentially sustain the effect from chemotherapeutic induction. BACKGROUND Lung cancer is the most common cancer worldwide. *Lung Cancer Program Director, Sarah Cannon Research Institute and In 2008, there were an estimated 1.61 million new cases of Tennessee Oncology, PLLC, Nashville, Tennessee; and †Department lung cancer, representing 13% of all new cancers in the world.2 of Medicine, University of Pittsburgh Medical Center, Cancer Pavilion, Pittsburgh, Pennsyvania. Lung cancer was also the most common cause of death from Disclosure: Dr. Spigel is an uncompensated consultant for Bristol-Myers cancer in 2008, accounting for 1.38 million deaths (18% of the Squibb. Dr. Socinski reports no conflict of interest. total).2 SCLC comprises 15% to 20% of lung cancer cases,3 Address for correspondence: David R. Spigel, MD, Sarah Cannon Research with approximately 30,000 new cases of SCLC expected to be Institute and Tennessee Oncology, PLLC, 250 25th Avenue North, Suite diagnosed in the United States in 2012.4 Untreated SCLC has 110, Nashville, TN 37203. E-mail: [email protected] Copyright © 2013 by the International Association for the Study of Lung an aggressive clinical course characterized by rapid growth and 5 Cancer a tendency to metastasize early. SCLC is often initially highly ISSN: 1556-0864/13/0805-0587 sensitive to chemotherapy and radiation therapy; however, the

Journal of Thoracic Oncology • Volume 8, Number 5, May 2013 587 Spigel and Socinski Journal of Thoracic Oncology • Volume 8, Number 5, May 2013

majority of patients will experience relapses, and long-term Reviews of trial data and other meta-analyses, such as that by survival is rare.5 Socinski and Bogart,16 support the finding that early and concurrent thoracic radiotherapy with chemotherapy is optimal for SCLC: Limited Versus Extensive Disease the treatment of patients with LD-SCLC. Additionally, PCI is On the basis of a staging system developed and revised recommended for patients with either LD-SCLC or ED-SCLC by the Veteran’s Administration Lung Cancer Study Group and good performance status (PS), who attain at least a par- 17,18 in the United States, SCLC has traditionally been classified tial response to initial therapy. PCI has demonstrated an into two stages according to the extent of disease—LD-SCLC increase in 1-year survival in patients with ED-SCLC when 17 and ED-SCLC.6 By definition, LD-SCLC, which represents compared with controls (27.1% versus 13.3%, respectively). approximately 30% of new SCLC cases is confined to one Furthermore, a meta-analysis of all randomized PCI tri- hemithorax with regional lymph node metastasis and can als using individual patient data reported a 5.4% increase in be encompassed within a single radiation port,7 whereas 3-year survival in patients treated with PCI compared with 19 ED-SCLC (describes the remaining 70% of new cases) the control group (20.7% versus 15.3%, respectively). This extends beyond the boundaries of a single radiation port, observation was consistent between patients with LD-SCLC where cancer has spread beyond the ipsilateral hemithorax, and ED-SCLC, despite the small number of patients in the or metastasized to distant locations of the body.7 A new lung ED-SCLC group. More recently, a retrospective analysis of cancer tumor, node, metastasis staging system was developed patients with LD-SCLC confirmed this observation with the by the International Association of the Study of Lung Cancer finding that PCI increased survival at 2, 5, and 10 years com- 20 and adopted by the American Joint Commission for Cancer. It pared with those who did not receive PCI. is suggested that clinical research studies use the tumor, node, In an attempt to expound on the combination of plati- metastasis system to permit more accurate assessments of num and etoposide for the first-line treatment of ED-SCLC, a prognosis and specific therapy for patients.1 phase II trial (Cancer and Leukemia Group B 30103) assessed the efficacy and tolerability of carboplatin and etoposide with or without the Bcl-2 antisense oligonucleotide oblimersen in CURRENT TREATMENT OPTIONS FOR SCLC 56 patients. Carboplatin and etoposide with oblimersen was associated with slightly more grade 3/4 hematologic toxic- First-Line Treatment with Chemotherapy ity than carboplatin and etoposide alone (88% versus 60%, When left untreated, the life expectancy for patients respectively; p = 0.05), and response rates were similar with SCLC is approximately 4 to 6 months.8,9 Treatment for between both arms (61% versus 60%, respectively). Hazard LD-SCLC is used with curative intent through a combined ratios (HRs) for failure-free survival (1.79; p = 0.07) and OS therapeutic approach typically involving thoracic radiother- (2.13; p = 0.02) suggested worse outcome for patients receiv- apy, chemotherapy, and rarely, surgery.5 Unfortunately, the ing carboplatin and etoposide with oblimersen. Results from majority of patients diagnosed with SCLC already have exten- this study show that addition of oblimersen to standard first- sive-stage disease at presentation. Therapy for these patients is line treatment for SCLC did not improve clinical outcomes.21 limited to platinum-doublet chemotherapy.5 Meta-analyses of As stated above, many SCLC tumors are initially respon- several trials have shown that platinum-containing regimens sive to treatment, with an expected 70% to 90% response rate provide a modest, but statistically significant increase in sur- among patients with LD-SCLC treated with PE plus thoracic vival over non–platinum-containing therapies.10,11 First devel- radiotherapy, and an approximate 50% to 70% response rate oped in the early 1980s, four to six cycles of platinum and in patients with ED-SCLC treated with PE alone.1 These ini- etoposide (PE) have remained standard-of-care first-line che- tial responses, however, do not correspond to high survival motherapy for both LD- and ED-SCLC.9 In consideration of rates. Median survival for patients with LD-SCLC receiv- at-risk populations, such as the elderly, etoposide plus cispla- ing standard therapy is 18 to 30 months,22 whereas patients tin is a recommended standard of care, which is in alignment with ED-SCLC experience median survival in the range of 10 with treatment recommendations for the general treatment of to 12 months.10 These data translate to poor 5-year survival SCLC based on data from phase III trials.1 Notably, however, rates for SCLC, reported to be as low as 10% to 15%22 and a regimen of carboplatin plus etoposide can be an alternative as high as 20% to 25%7 for LD-SCLC and only 1% to 2% for for patients with SCLC when considering the risk–benefit ED-SCLC.10 balance.12 Currently, etoposide and platinum plus concurrent thoracic radiotherapy is a recommended standard treatment for patients with LD-SCLC.1 Importantly, meta-analyses of First-Line Treatment with more than 2000 patients with LD-SCLC demonstrated that Antiangiogenic Agents thoracic radiotherapy resulted in a 5% to 7% improvement in Cancer cell growth is highly dependent on angiogene- 2-year survival when compared with chemotherapy alone.13,14 sis, a process mediated predominantly by vascular endothelial Likewise, a systematic review evaluating early versus late growth factor (VEGF) and its receptors. Because approxi- time of thoracic radiation therapy in LD-SCLC demonstrated mately 80% of SCLC tumors overexpress VEGF, antiangio- that there was a significantly increased 2-year survival for genic therapy has been pursued as a novel approach to treat early radiation therapy compared with late radiation therapy— this malignancy. overall survival (OS) risk ratios for all studies were 1.17 at 2 Several phase II studies have investigated the effects of years (95% confidence interval [CI], 1.02–1.35; p = 0.03).15 adding bevacizumab to chemotherapy regimens for the first-line

treatment of ED-SCLC.23–26 In a phase II study, it was found Similarly, matrix metalloproteinases (MMPs)—a family that bevacizumab given in combination with chemoradiation of enzymes that proteolytically degrade various components increased the risk of tracheoesophageal fistulas in patients of the extracellular matrix—support the process of angiogen- with LD-SCLC,27 and therefore, future clinical development esis.33 The expression of MMPs has been found to be elevated of bevacizumab in SCLC was restricted to patients with in SCLC and this expression has also been identified as an extensive disease. In the Eastern Cooperative Oncology Group independent negative predictor of survival.34 Preclinical stud- (ECOG) phase II, single-arm study E3501,23 bevacizumab ies in animal models of malignancy showed that MMP inhibi- given in combination with cisplatin and etoposide, followed tors (MMPIs) could prevent the growth and regional spread by maintenance bevacizumab monotherapy until death or of solid tumors.35,36 The utility of MMPIs in the first-line set- disease progression, achieved improved progression-free ting have been investigated clinically. In a phase III trial of survival (PFS) and OS in patients with previously untreated 532 eligible patients previously treated with induction che- ED-SCLC, compared with historical controls in whom a motherapy (the majority of whom presented with LD-SCLC), chemotherapy regimen was given without bevacizumab.28–30 266 patients received the MMPI—marimastat—whereas the The overall response rate in study E3501 was 63.5%, median remaining 266 received placebo. Results from the trial showed PFS was 4.7 months (95% CI, 4.3–5.5 months), and median that the difference in median survival between patients treated OS was 10.9 months (95% CI, 7.9–12.2 months).23 with marimastat and placebo was not statistically significant Another single-arm phase II study in which patients (9.3 versus 9.7 months, respectively; p = 0.90).37 Likewise, with previously untreated ED-SCLC were administered beva- there was no apparent difference in the median time to pro- cizumab, carboplatin, and irinotecan produced a promising gression between patients treated with marimastat and placebo objective response rate of 84% (95% CI, 71%–93%), median (4.3 versus 4.4 months, respectively; p = 0.81). Importantly, time to progression of 9.13 months (95% CI, 7.36–9.46 treatment with marimastat also had a negative impact on qual- months), and median OS of 12.1 months (95% CI, 9.6–13.5 ity of life. months).24 These encouraging findings were recently reca- pitulated in a single-arm phase II study, in which patients Second-Line Treatment with previously untreated ED-SCLC who received bevaci- An estimated 80% of patients with LD-SCLC, and all zumab, cisplatin, and irinotecan showed an overall response patients with ED-SCLC experience disease progression or rate of 75%, median PFS of 7.0 months (95% CI, 6.4–8.4 relapse in response to first-line platinum-based therapy.38 A months), and a median OS of 11.6 months (95% CI, 10.5–15.1 patient’s response to first-line treatment and the duration of months).26 The randomized, double-blind, placebo-controlled the subsequent progression-free period influences the likeli- phase II SALUTE study, which directly compared the efficacy hood that a patient will respond to second-line chemother- of adding bevacizumab to a regimen of PE in 102 patients with apy. 39 Tumors that are refractory to first-line chemotherapy or ED-SCLC showed that addition of bevacizumab to a PE regi- relapse within 60 to 90 days are considered chemoresistant, men prolonged median PFS (5.5 months in the bevacizumab whereas tumors whose response to first-line therapy exceeds arm versus 4.4 months in the placebo arm; HR = 0.53; 95% 60 to 90 days are considered to be chemosensitive.9 CI, 0.32–0.86)—the primary endpoint of this trial.25 However, Patients in whom response to first-line therapy is there was no significant benefit of bevacizumab on median OS maintained for longer than 180 days are likely to benefit (9.4 months in the bevacizumab arm versus 10.9 months in from retreatment with platinum-based chemotherapy (i.e., the placebo arm; HR = 1.16; 95% CI, 0.66–2.04).25 The safety reinduction therapy).9 Platinum reinduction therapy is not profile for bevacizumab in this study was consistent with that recommended in patients whose disease relapses between 90 seen with its use in the treatment of other solid tumors. and 180 days after completing first-line treatment. Single- The efficacy of thalidomide, a drug with reported anti- agent topotecan is the only second-line therapy approved angiogenic activity, was investigated in a single-arm, phase by the U.S. Food and Drug Administration for the treatment II trial of 25 chemotherapy-naive patients with SCLC.31 A of relapsed SCLC for which reinduction with the first-line regimen of carboplatin and etoposide given concurrently with regimen is not considered appropriate.9 Approval was based on thalidomide in these patients, followed by thalidomide main- a randomized trial in which single-agent intravenous topotecan tenance for up to 2 years, resulted in a median PFS of 8.3 was shown to be at least as effective in terms of response months and a median OS of 10.1 months.31 These data led to a rates and survival as the cyclophosphamide, doxorubicin, and larger phase III trial, involving 724 patients with SCLC (51% vincristine (CAV) regimen in relapsed SCLC patients (n = LD-SCLC; 49% ED-SCLC), who were randomized to receive 211).40 Response rates were 24.3% and 18.3% for topotecan either placebo or thalidomide, in addition to a regimen of car- and CAV, respectively (p = 0.285), and median survival was boplatin plus etoposide.32 The median OS was 10.5 months similar between arms, with 25 weeks for topotecan and 24.7 in the placebo group and 10.1 months in the thalidomide weeks for CAV (p = 0.795). Significant improvements with group (HR = 1.09; 95% CI, 0.93–1.27; p = 0.28). The addi- regard to side effects (notably dyspnea, anorexia, hoarseness, tion of thalidomide to a chemotherapy regimen of etoposide fatigue, and interference with daily activity) were observed plus carboplatin did not significantly improve survival among in the topotecan group compared with those receiving CAV.40 patients with LD-SCLC (HR = 0.91; 95% CI, 0.73–1.15) and Oral topotecan in combination with best supportive care was associated with reduced survival among patients with has demonstrated a survival advantage over best supportive ED-SCLC (HR = 1.36; 95% CI, 1.10–1.68).32 care alone in patients with relapsed SCLC,41 and shown

comparable efficacy to the intravenous formulation.42 In a growth factors49,50 or without growth factors,51 triplet chemo- randomized phase II trial (Southwest Oncology Group 0802) therapy,52,53 quadruple chemotherapy,54 and chemotherapy in of intravenous topotecan with and without the VEGF Trap which etoposide is replaced with another agent as part of the AVE0005 (aflibercept) in patients with platinum-treated platinum doublet55–58 have not clearly demonstrated improve- ED-SCLC, the primary endpoint (3-month PFS) was met for ments in patient survival in clinical trials. Attempts at non- the combination of aflibercept and topotecan versus topotecan chemotherapeutic and targeted approaches within a clinical alone (26% versus 9%, respectively; p = 0.01); OS, however, trial setting have largely been unsuccessful. Moreover, no was similar in each arm (4.6 versus 3.9 months, respectively; trials of maintenance therapy have reported patient survival p = 0.25).43 Side effects were mainly hematologic with 19% improvements or substantially lengthened responses to first- and 14% of patients experiencing a grade 4 event with the line chemotherapy.7 combination of aflibercept and topotecan versus topotecan Low response rates associated with topotecan in the sec- alone, respectively.43 ond-line treatment setting and the heterogeneity of SCLC— Irinotecan, paclitaxel, gemcitabine, vinorelbine, and characterized by mutations or aberrant expression of a key docetaxel are all used as second-line alternatives to topote- apoptotic inhibitor (Bcl-2)—have fostered the clinical devel- can.44 Additionally, agents such as amrubicin,45 picoplatin,46 opment of other small molecules for the treatment of relapsed 47 48 belotecan, and bendamustine are currently being evaluated SCLC. In a phase II study of navitoclax (ABT-263)—a potent as potential treatment options in phase II/III clinical studies in and selective inhibitor of Bcl-2 and Bcl-xL—39 patients with relapsed SCLC patients, though to date no substantial progress relapsed SCLC received navitoclax 325 mg daily after an ini- has been made over topotecan in improving OS in this setting. tial lead-in of 150 mg daily for 7 days.59 The most common Results from a randomized, phase III study compar- side effect was thrombocytopenia. Median PFS and OS were ing amrubicin with topotecan in 637 patients with relapsed 1.5 and 3.2 months, respectively. In this trial, single-agent (chemosensitive or chemoresistant) SCLC showed a signifi- navitoclax demonstrated limited single-agent activity in recur- cantly higher response rate with amrubicin than topotecan rent SCLC. In another phase II trial of patients with relapsed (31% versus 17%, respectively; odds ratio [OR] = 2.22; 95% SCLC, the Bcl-2 antagonist obatoclax mesylate was combined CI, 1.47–3.36; p = 0.0002); however, the primary endpoint of with topotecan.60 Intravenous obatoclax mesylate 14 mg/m2 median OS was similar in the two treatment groups (7.5 ver- was administered on days 1 and 3 with intravenous topotecan sus 7.8 months, respectively; HR = 0.88; 95% CI, 0.73–1.06; 1.25 mg/m2 on days 1 to 5 every 3 weeks. This study did not p = 0.17), as was median PFS (4.1 versus 4.0 months, respec- meet its primary endpoint of overall response and there were tively; HR = 0.999; 95% CI, 0.84–1.19; p = 0.98).45 Subgroup no partial or complete responses. Common grade 3/4 adverse analyses indicated improved OS with amrubicin compared events included thrombocytopenia, anemia, neutropenia, and with topotecan among patients with chemoresistant/refrac- ataxia.60 tory disease (6.2 versus 5.7 months, respectively; HR = 0.77; 95% CI, 0.59–1.0; p = 0.047), but not in those with sensi- As in the first-line treatment of SCLC, the therapeutic tive relapse (9.2 versus 10 months, respectively; HR = 0.94; potential of targeted agents has also been explored in the 95% CI, 0.72–1.21; p = 0.62). Significantly lower incidences relapsed setting. For example, the efficacy of thalidomide of neutropenia, thrombocytopenia, anemia, and a reduced was assessed in patients with ED-SCLC who had previously requirement for transfusion favored amrubicin in this study.45 received chemotherapy in a small phase III study (n = 61 In the SPEAR study, picoplatin, a novel platinum com- 119). Patients who responded to two initial cycles of pound designed to overcome platinum resistance, was evalu- chemotherapy with etoposide, cisplatin, cyclophosphamide ated for safety and efficacy compared with best supportive care and 4′-epidoxorubicin (PCDE) were randomized to receive in 401 patients with SCLC, refractory or progressive within 6 four further PCDE cycles in combination with placebo or months, after first-line platinum-based chemotherapy.46 The thalidomide. Overall, thalidomide was not associated with a primary endpoint of this randomized phase III study was OS. significant improvement in survival, although there was some Survival analysis of 321 events showed that this trial did not evidence of slower progression and longer survival in patients achieve statistical significance (p = 0.09), with an imbalanced with a PS of 1 to 2.61Another antiangiogenic agent, cediranib, use of poststudy chemotherapy as a factor that may have was found to have no clinical activity in a phase II trial of affected this result.46 patients with relapsed/recurrent SCLC as monotherapy.62 Just Belotecan, a topoisomerase I inhibitor, demonstrated as marimastat was assessed in the first-line setting, another modest activity in the second-line treatment of sensitive relapse MMPI, BAY12-9566, was assessed in the second-line setting after irinotecan plus platinum therapy in a phase II study in as adjuvant therapy for patients with SCLC. Two independent, Korea, with an overall response rate of 22% among 25 evalu- multicenter phase III trials of patients with unresectable SCLC able patients and median survival of 13.1 months (95% CI, showed that there was no significant difference in survival 10.4–15.8 months).47 In an ongoing multicenter phase II study, between patients receiving BAY12-9566 and placebo.63 treatment with bendamustine, an alkylating agent, achieved a Collectively, results from these trials show that SCLC is a partial response in 7 of 19 evaluable patients receiving it as malignancy in which little clinical progress has been made second- or third-line treatment for relapsed disease.48 with regard to novel classes of agents. As such, there is Attempts to optimize chemotherapeutic intervention clearly a need for innovative therapies to improve the dismal have been explored. However, dose-dense chemotherapy with outcomes for this disease.

Tumor Immunology and the Antitumor actively suppressed. An analysis of T cells in peripheral blood Immune Response to SCLC samples from 35 SCLC patients revealed higher counts of The immune system has two interconnected components: Teffs in LD-SCLC patients than in ED-SCLC patients.75 In the innate system and the adaptive (acquired) system.64 The addition, long-term survivors of SCLC were found to main- innate immune system provides rapid, but nonspecific protection tain a high ratio of Teff-to-Treg cells, whereas patients with against foreign or dangerous substances with certain properties recurrent disease exhibited a low ratio of Teffs-to-Tregs. These and does not display memory to specific antigens. However, the results suggest that a Teff-to-Treg balance may be a potential adaptive immune system responds to specific antigens, with biomarker that distinguishes ED-SCLC from LD-SCLC and is repeat exposure leading to a more robust response in a phenom- predictive of recurrence. The results also support the hypothe- enon known as immunologic memory. The innate and adaptive sis that immunotherapy, by shifting the T-cell balance in favor branches of the immune system interact with each other to rec- of Teffs and/or abrogating the Treg population, may promote a ognize and defend the host against harmful substances while more effective antitumor immune response to SCLC.75 maintaining tolerance to “self.” Additionally, there is mounting evidence that the Research to date has demonstrated that some tumors may immune system may contribute to the control of cancer in con- have properties that trigger responses from both the innate and cert with conventional chemotherapy or radiotherapy. Tumor adaptive branches of the immune system.65 Moreover, some cell death that follows radiotherapy and some chemothera- evidence suggests that in certain instances the immune system peutic agents can induce immunostimulatory effects, possi- is capable of controlling or even eradicating tumor growth.65 bly by encouraging tumor antigen-specific immune responses However, in other cases, cancer growth proceeds when tumor or by altering the immunologic properties of any remaining cells are able to “escape” host immune control. Multiple tumor cells. This anticancer immune response then helps to mechanisms have been proposed for this phenomenon,66,67 eliminate residual cancer cells that survived chemotherapy or including the induction of immune tolerance.68 radiotherapy. The immune response may also maintain micro- A critical part of the adaptive immune system is the metastases in a stage of dormancy.76 It has been hypothesized network of pathways that mediate antigen-specific activation that certain chemotherapeutic regimens may enhance immu- of effector T cells (Teffs). Activated Teffs target tumor cells nologic responses against the tumor through a direct altera- directly or mediate subsequent humoral antitumor responses. tion of immune effectors or immune regulatory mechanisms. Activated T cells and antibodies specific to tumor-associated This immune enhancement phenomenon may also be a con- antigens have been isolated from patients with a variety of sequence of immune effector cell proliferation in response to tumor types.69 After T-cell activation in response to a specific chemotherapy- or radiation-induced lymphopenia.76 antigen, a subset of lymphocytes called regulatory T cells (Tregs) plays a major role in down-regulating the resulting NEW APPROACHES TO SCLC immune response and establishing immune tolerance to the The biology of SCLC is complex and has not been fully antigens, thereby allowing the body to suppress autoimmu- elucidated, which contributes to the challenge of developing nity. Ordinarily, suppression of autoimmunity is desirable; targeted therapies that demonstrate clinical benefit.77 Among however, in the setting of cancer it may contribute to poor the approaches that have been recently evaluated in phase II/III outcome. Tregs have been shown to down-regulate antigen- studies are molecular targeted therapies—notably, approaches specific immune responses to tumor cells in various cancer that seek to modulate the immune response to SCLC. types, including SCLC.70,71 Studies have shown that Treg cell numbers are higher in patients with cancer and that the num- Vaccines ber of Tregs correlates with prognosis.72–74 Treg cells that pre- Tumor vaccines are designed to present tumor antigens vent autoimmune diseases by suppression of self-reactive T to the adaptive immune system, thereby promoting a more cells may also suppress the immune response against cancer. effective response against the tumor. GD3 is a cell membrane Immunotherapy is designed to elicit an anticancer ganglioside that has been shown to be overexpressed response by modulating the patient’s immune response to the in approximately 60% of SCLC tumors,78 and has been tumor, specifically by enhancing host immune surveillance investigated as a potential vaccine target for this form of and/or decreasing tolerance to tumor cells. Several lines of cancer. Bec2, an anti-idiotypic monoclonal antibody that evidence support the existence of an ongoing, although sup- induces antiganglioside GD3 antibodies, was explored in a pressed, immune response against SCLC tumors. One example small phase I/II trial in which LD-SCLC patients achieving may be found in the occurrence of Lambert–Eaton myasthenic a partial or complete response to induction therapy were syndrome (LEMS), a paraneoplastic syndrome observed in a vaccinated with Bec2/bacille Calmette–Guerin. Improved small percentage of SCLC patients. Patients with this immune- survival was noted among those patients who developed mediated syndrome tend to have a more favorable prognosis anti-GD3 antibodies compared with historical controls.79 than patients without LEMS, and it has been hypothesized that However, results from a subsequent randomized, phase III trial the immune effects responsible for the neuromuscular damage in 515 LD-SCLC patients who had responded to induction associated with LEMS are also responsible for suppressing chemoradiotherapy were not encouraging. The study findings SCLC tumor growth.75 indicated that maintenance therapy with the vaccine provided Other data, although limited in scope, are suggestive no survival benefit and failed to improve quality of life.80 In of an ongoing antitumor immune response, which is being fact, only one third of evaluable patients in the vaccine arm

of the study developed a humoral response. The numerical survive longer after the onset of progressive disease, though improvement in survival noted for this subgroup compared these differences did not reach statistical significance.82 with nonresponders (19.2 versus 13.9 months, respectively; The lack of statistically significant outcomes reported p = 0.085) was not statistically significant, particularly after in both studies with IFN-α maintenance therapy have led adjusting for the use of PCI between the two subgroups.80 to its cessation of development as an SCLC treatment.81–83 Moreover, a systematic review by Rossi et al.84 on pooled data Immunomodulators from 3688 patients with SCLC confirmed the lack of sur- Immunomodulators, whose mechanisms of action are vival benefit received from maintenance therapy with IFN-α. independent of specific tumor antigen recognition, are attrac- Collectively, these trial results do not suggest that immuno- tive candidates for SCLC therapy based on the rationale dis- modulating agents complement chemotherapy/radiotherapy cussed above. The role of interferon (IFN)-α as a treatment induction treatment in a manner that would improve long-term option for patients with SCLC remains uncertain because of outcomes for patients with SCLC. the lack of large, well-designed, randomized phase III trials in this setting. Blockade of the immune checkpoint protein, Immune Checkpoint Proteins cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), is As part of the regulatory pathways that maintain a bal- proving to be a more promising strategy, but requires further ance between appropriate recognition and destruction of patho- validation in larger studies. gens or tumors and inappropriate overstimulation of immune responses, costimulatory and coinhibitory factors function Interferon -α to fine-tune the antigen-specific T-cell response after stimu- 85,86 IFN-α is a cytokine that not only stimulates immune lation of the T-cell receptor. T-cell receptor recognition of cells, but also promotes antigen presentation on tumor cells, antigenic peptides in the context of major histocompatibility in theory allowing cancer cells to be more easily recognized complex molecules on the surface of antigen-presenting cells by the immune system. IFN-α was evaluated as maintenance (APCs) is the first step in the generation of a specific T-cell therapy for SCLC in two important clinical trials more than a response. Full T-cell activation requires a second “costimu- decade ago, both of which suggest that it may act synergisti- latory” signal—this second signal is generated when the cally with chemotherapeutic agents.81,82 costimulatory receptor on the surface of T cells, CD28, binds The first of these studies enrolled 237 responders to to B7 ligand subtypes CD80 and CD86 on the APC (Fig. 1). induction chemoradiotherapy and found there was no difference Costimulation through CD28, and other such molecules in median survival between patients who were then random- including CD134, and CD137, supplements the excitatory ized to receive maintenance therapy with natural IFN-α, main- antigen stimulation signal that leads to T-cell activation and tenance chemotherapy (cyclophosphamide, adriamycin, and thereby helps to potentiate the immune response. Conversely, cisplatin), and a control group receiving no maintenance treat- coinhibition through molecules like CTLA-4, programmed ment.83 Median survival in this phase III trial was 11 months death-1 (PD-1), B7-H3, and B7x diminishes antigen-specific in the two maintenance therapy groups and 10 months in the immune responses by limiting their magnitude and duration. control group.83 However, there was an apparent significant dif- For this reason, these coinhibitory molecules are collectively ference in long-term survival for patients with LD-SCLC, in dubbed “immune checkpoint proteins.” favor of IFN-α maintenance therapy (p = 0.04).81 Follow-up at CTLA-4 is a well-studied immune checkpoint protein 5 years found that 10% of patients in the IFN-α group survived that is expressed on activated T cells and functions to down- 87 compared with only 2% in the cyclophosphamide, adriamycin, regulate T-cell activity. CTLA-4 expression is up-regulated and cisplatin and control groups. All long-term survivors had upon stimulation of the T cell through the T-cell receptor. It good PS, and the majority had LD-SCLC and had achieved a then competes with CD-28 for binding to CD80 and CD86 on 88 complete response to induction therapy.81 These findings fail the APC. CTLA-4’s higher affinity for B7 ligands enables to lend support to a role for IFN-α in maintaining a clinically it to competitively inhibit CD28-mediated T-cell activation, 90 disease-free status achieved with induction treatment. thereby limiting the subsequent T-cell response (Fig. 1). A second study investigated the feasibility of mainte- This dual pathway is essential in the development of nance therapy with IFN-α plus retinoic acid after a high-dose tolerance against antigens, including tumor antigens, after combination of chemotherapy and radiotherapy in patients T-cell recognition. Therefore, blockade of the CTLA-4 with SCLC.82 Patients in this multicenter, phase II study who checkpoint pathway may be a reasonable approach to combat responded to chemotherapy and radiotherapy were randomly cancer, particularly in tumor types such as SCLC where assigned to one of three maintenance therapy arms: IFN- evidence suggests that tumors may be avoiding or resisting α 91,92 and retinoic acid, trophosphamide, or no maintenance treat- natural immune responses. Use of monoclonal antibodies ment (control). Median survival time among the randomized that block CTLA-4 are currently under investigation in 93,94 patients was 17.1 months in the IFN-α plus retinoic acid arm, multiple tumor types, including SCLC. 12.4 months in the trophosphamide arm, and 13.5 months in the control arm, and did not differ significantly between groups. Preclinical Evidence of Synergy between The 1-year survival rate was higher in the IFN-α plus reti- CTLA-4 Blockade and Chemotherapy noic acid arm (82%) than in the comparator arms (55–56%), Preclinical data suggest that CTLA-4 blockade through and patients treated with IFN-α plus retinoic acid tended to anti-CTLA-4 antibodies enhances immune responses in some

A B C T-cell T-cell T-cell Activation Inactivation Activation

T cell T cell T cell CTLA-4

TCR TCR TCR CD28 CD28 CTLA-4 CD28 CTLA-4

B7 B7 B7 MHC MHC MHC Anti-CTLA-4 mAb

APC APC APC

FIGURE 1. Mechanism of action in T-cell activation: B7:CD28/CTLA-4 pathway. (Source: Shepherd et al.). Reprinted with permission from WoltersKluwer Health.89 cancer models. Cellular analysis has revealed that antibody- preclinical findings support the rationale for clinical investiga- mediated blockade of CTLA-4 on Teffs and Tregs contributes tion of CTLA-4-specific antibodies in regimens that include to antitumor activity in mouse models of cancer.95 CTLA-4 standard of care chemotherapy. blockade may prolong T-cell activation and thus intensify T-cell–mediated antitumor responses, potentially restricting Clinical Application of CTLA-4 Blockade in SCLC tumor cell evasion of the immune system.96 Blockade of the CTLA-4 receptor using ipilimumab,100 As discussed previously, some preliminary evidence a fully human anti-CTLA-4 monoclonal antibody, has suggests that immunotherapy may work in concert with che- been under clinical investigation in various tumor types.87 motherapy and radiation, resulting in enhanced or synergis- Ipilimumab was recently approved at a dose of 3 mg/kg for tic tumor control. Although the nuances of this phenomenon treatment of unresectable or metastatic melanoma by regula- remain a subject of ongoing study, murine models have pro- tory authorities in more than 40 countries across the world, vided evidence of synergistic antitumor effects when CTLA-4 including the United States, Europe, and Australia,100–103 based blockade was used in combination with other modalities, par- on a pivotal phase III trial in metastatic melanoma that dem- ticularly chemotherapy. In the M109 mouse model of lung onstrated a statistically significant OS side-effect.104 cancer, treatment of animals with an anti-CTLA-4 monoclo- Ipilimumab is presently under clinical investigation in nal antibody in combination with chemotherapeutic agents, other solid tumors, including SCLC (Table 1). A randomized, such as gemcitabine, etoposide, and ixabepilone, revealed blinded phase II study examined two dosing schedules synergistic antitumor effects with particular regimens of combining platinum-based chemotherapy (paclitaxel/ agents.97–99 Furthermore, after combination treatment with carboplatin) with ipilimumab 10 mg/kg in patients with CTLA-4 blockade and chemotherapy, animals rejected a sub- ED-SCLC or stage IV NSCLC. This multicenter, international sequent tumor rechallenge, suggesting the development of a trial stratified 334 patients by disease type (ED-SCLC, n = protective immune response in this model.97,99 130; NSCLC, n = 204 [data published elsewhere]).105,106 These preclinical data suggest that chemotherapy may Previously untreated patients with ED-SCLC in 32 centers improve the effect of CTLA-4 blockade. It is possible that this across seven countries were randomized between June 2008 potential synergy may be the result of immunogenic tumor and August 2009 to one of three treatment arms (1:1:1): antigens, released through the cytotoxic effects of chemo- ipilimumab given concurrently with paclitaxel/carboplatin therapy and then presented to T cells by APCs. In addition, (4 doses of ipilimumab + paclitaxel/carboplatin, followed certain chemotherapeutic drugs may distort tumor architec- by 2 doses of placebo + paclitaxel/carboplatin); ipilimumab ture, enhancing the penetration of immunotherapeutic agents in a phased schedule with paclitaxel/carboplatin (2 doses and the immune population.97,99 Furthermore, the described of placebo + paclitaxel/carboplatin, followed by 4 doses of

TABLE 1. Ipilimumab in SCLC—Summary of Phase II/III Clinical Trials Clinical Trial Patient Primary Outcome Identifier Phase Treatment Arm Population Measure Sponsor NCT00527735 II Ipilimumab or placebo + paclitaxel/carboplatin Previously EORTC-QLQ-30 Bristol–Myers Squibb (concurrent) vs. ipilimumab or placebo + paclitaxel/ untreated SCLC questionnaire carboplatin (sequential) vs. placebo/paclitaxel/carboplatin (and NSCLC) NCT01331525 II Ipilimumab/carboplatin/etoposide Extensive-stage 1-yr PFS Southampton University SCLC Hospitals NHS Trust NCT01450761 III Ipilimumab/etoposide/platinum vs. etoposide/platinum Extensive-stage OS Bristol–Myers Squibb SCLC

EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; NHS, National Health Service; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival; SCLC, small cell lung cancer. ipilimumab + paclitaxel/carboplatin); or a control regimen of is OS with a time frame of approximately 40.8 months after placebo plus paclitaxel/carboplatin (up to 6 doses of placebo + the first subject is randomized, assessed until 816 events have paclitaxel/carboplatin). Induction treatment, as described been observed (NCT01450761). In addition, a second phase above, was given every 3 weeks for up to six doses, and patients II trial is currently recruiting patients with ED-SCLC to deter- with no signs of disease progression were administered mine whether the addition of ipilimumab to a chemotherapy ipilimumab (phased-and concurrent-ipilimumab arms) or regimen of etoposide/carboplatin extends PFS at 1 year in this placebo (control arm) every 12 weeks as maintenance therapy patient population.108 (NCT00527735).106 The phased schedule of ipilimumab plus platinum-based chemotherapy, but not concurrent ipilimumab/ chemotherapy, resulted in improved outcomes compared with PD-1 Receptor Blockade: Potential the placebo arm. irPFS in the phased schedule arm was 6.4 Clinical Applicability for SCLC months compared with 5.3 months in the placebo arm (HR = As mentioned above, PD-1 is another key immune- 0.64; 95% CI, 0.40–1.02; p = 0.03). The best overall response checkpoint receptor expressed by activated T cells that medi- rate (71% versus 53%, respectively) using irRC and OS (12.9 ates immunosuppression. In vitro studies have shown that versus 9.9 months, respectively; HR = 0.75; 95% CI, 0.46– inhibiting the interaction between PD-1 and its ligand (PD-L1) 1.23; p = 0.13) also favored phased ipilimumab + paclitaxel/ can enhance T-cell responses, mediating preclinical antitumor carboplatin over paclitaxel/carboplatin alone, although the activity.109,110 BMS-936558 (nivolumab, formerly MDX-1106) difference in survival did not reach statistical significance.106 It is a fully human anti-PD-1 monoclonal antibody that binds to should be noted that the ED-SCLC cohort in this trial was not PD-1. Data on the cohort of patients with NSCLC from the fully powered for a formal statistical comparison. Nevertheless, phase I dose-escalating study of nivolumab (compiled up to these data suggest that this chemoimmunotherapeutic regimen February 24, 2012) were recently reported111 and subsequently results in improved clinical benefit in patients with ED-SCLC, updated to reflect longer follow-up, with approximately 6 and that choice of schedule may affect the extent of benefit. additional months of patient accrual. In general, ipilimumab did not exacerbate the adverse These data on a total of 127 patients with NSCLC were event profile of platinum-based chemotherapy in this study.106 presented at the 2012 European Society of Medical Oncology Patients treated with ipilimumab showed side effects consis- (ESMO) Annual Meeting.112 Responses were evaluable in tent with its immune-based mechanism of action, which were 122 patients (48 squamous, 73 nonsquamous, and 1 unknown usually observed in other ipilimumab trials, such as fatigue histology). Tumor responses were observed at all three doses and diarrhea.104,107 Adverse events that occurred more fre- assessed (1, 3, and 10 mg/kg twice a week) for squamous and quently in the ipilimumab arms than the placebo arm included nonsquamous histologies, with respective overall response rates pruritus (19%–24% versus 5%, respectively), rash (24%–36% of 6%, 27%, and 17%). Corresponding PFS rates at 24 weeks versus 2%, respectively), and diarrhea (26%–33% versus 16%, were 25%, 44%, and 31%. These encouraging data of nivolumab respectively).106 Overall, the incidence of treatment-related in NSCLC suggest the potential clinical applicability in SCLC. grade 3/4 adverse events appeared more often in the ipilim- There are ongoing studies exploring the clinical activity of umab-containing arms, with 43% in the concurrent ipilim- nivolumab in NSCLC, with phase III trials in both squamous umab arm, 50% in the phased ipilimumab arm, and 30% in the and nonsquamous histology NSCLC (NCT01642004 and placebo arm. Ipilimumab-related side effects were managed NCT01673867, respectively). These studies should help clarify using protocol-specific guidelines. A randomized, multicenter the activity of nivolumab in NSCLC and potentially provide a phase III trial is currently underway to determine whether a path for future development in SCLC. phased schedule of ipilimumab plus a chemotherapy regimen of etoposide/platinum (carboplatin or cisplatin) versus Challenges in Immunotherapy for SCLC etoposide/platinum alone extends OS in ED-SCLC patients. Researchers face many challenges in developing immu- The study is estimated to enroll 912 patients on approximately notherapeutic treatments for SCLC, including the high bur- 227 sites among 34 countries. The primary outcome measure den of disease and lack of a specific target for vaccine-based

treatments. In addition, the complex genetic heterogeneity T-cell activation.76 Most recently, findings from a case report observed in SCLC patients may limit the success of any treat- of a patient with melanoma suggest that the abscopal effect ment, including immunotherapy. Presently, there is not enough (a phenomenon in which local radiotherapy is associated with information to select SCLC patient subgroups that may regression of metastatic cancer at a distance from the irradiated best benefit from specific immunotherapeutic approaches. site) may be mediated by activation of the immune system— Prognostic and predictive biomarkers in SCLC have proven providing a role for combination radioimmunotherapy.117 The elusive, and identification of each may facilitate implementa- authors noted temporal associations (i.e., tumor shrinkage with tion of individualized treatment regimens that yield improved antibody responses to the cancer-testis antigen NY-ESO-1 and clinical benefit. increases in antibody responses to other antigens) that fol- Moreover, data from the phase II study of ipilimumab lowed treatment with ipilimumab and radiotherapy. Although and chemotherapy strongly imply that the timing and sched- the biological effect behind this mechanism has not yet been ule of immunotherapy in relation to other therapies may sig- characterized fully, it suggests that immunologic mechanisms nificantly affect efficacy of the regimen in SCLC. The results play an instrumental role in the biological effect. Notably, in presented by Reck et al.106 show that preceding ipilimumab a murine breast-cancer model, decreased pulmonary metasta- therapy with lead-in doses of chemotherapy is preferable to ses and improved survival were noted only for mice treated concurrent treatment with ipilimumab and chemotherapy. It with radiotherapy in combination with CTLA-4 blockade— has been suggested that the more robust antitumor effect real- supporting a role for combination radiotherapy and ipilim- ized from the phased administration of ipilimumab versus that umab for the treatment of SCLC.118 Together, these findings of concurrent ipilimumab is because of the induction of tumor support the clinical evaluation of different treatment schedules necrosis by chemotherapy. This induction results in changes of immunotherapy with chemoradiotherapy or chemotherapy in tumor architecture that releases tumor antigens into circu- alone as strategies to circumvent the challenges associated lation, enhancing expansion and infiltration of tumor-primed with immunotherapeutic intervention for SCLC. cytolytic T cells.97 Furthermore, phased administration facili- tates chemotherapeutic reduction of high tumor burden, which is believed to diminish the effects of tumor-associated CONCLUSIONS AND FUTURE DIRECTIONS immunosuppression—ultimately increasing the effect of 76 The current treatment options for SCLC are limited ipilimumab. and prognosis remains poor, underscoring the need for newer It is important to consider that development of any treatment strategies. Preclinical and early clinical studies immune response requires time. In advanced melanoma tri- have provided evidence of an immune response in SCLC, als with ipilimumab monotherapy, investigators reported and the ongoing elucidation of the immunosuppressive tumor some immediate responses of baseline lesions, but also noted environment underlying the disease continues to support the some response patterns that differed from those of cytotoxic development of not only novel agents, but also innovative therapies, including an initial increase in total tumor burden approaches, such as immunotherapy. Targeting of immune and/or the development of new lesions before a response. inhibitory pathways with ipilimumab—and more recently, These patterns may reflect the time required for an immune nivolumab—have emerged as promising anticancer strategies, response to translate into clinical antitumor activity.113,114 To partly because of their ability to target the immune system account for these response patterns that may be clinically ben- without reliance on the presence of specific tumor-associated eficial, but initially resemble disease progression, the ipilim- antigens. Current standard treatment approaches are successful umab melanoma trials stipulated that treatment should not be at inducing response, but the challenge lies in sustaining discontinued until progression is confirmed at a subsequent that initial benefit. The integration of immune modulators, screening.104,107 For ED-SCLC, this plan of action must be bal- such as ipilimumab, with traditional chemotherapeutic anced by the significant clinical deterioration that may accom- regimens—with and without radiotherapy—may lead to pany this aggressive disease. A further characterization of the improved patient outcomes as a result of targeting multiple risk-to-benefit profile of ipilimumab in ED-SCLC, and appro- pathways with a combinatorial approach. These strategies priate management of the patient’s treatment plan and adverse may best be employed in maintenance regimens that aim to events will emerge from the ongoing phase III trial. capitalize on the initial high sensitivity of SCLC to induction Despite the challenges associated with immunothera- chemoradiotherapy. peutic intervention, treatment efficacy may be optimized by concomitant treatment with chemotherapy and radiation, and with chemotherapy alone, as previously noted. Preclinical Acknowledgments studies suggest that chemotherapy and radiotherapy actively Professional medical writing and editorial assistance cause immunogenic tumor cell death and therefore may was provided by Ami Modi, PhD, Kenyon Ogburn, PhD, and “prime” the immune system—the immunogenic properties Rebecca Goldstein, PhD, (at StemScientific) who in collabo- of tumor cells may also be increased by enhancing major his- ration with the authors developed the first draft of the arti- tocompatibility complex class I expression.97,115,116 It also has cle. Moreover, medical writing and editorial assistance was been hypothesized that decreasing tumor mass through chemo- supported by Bristol-Myers Squibb. Neither Dr. Spigel nor therapy or radiation decreases the immunosuppressive proper- Dr. Socinski received remuneration for the preparation of this ties of the tumor and creates an environment better suited for publication.

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