Small cell lung cancer (SCLC) is an aggressive malignancy and carries a poor prognosis with limited effective treatments in the advanced setting. SCLC is characterized by a high tumor mutation burden and alterations in Notch signaling and DNA damage repair pathways, providing rationale for the use of immunotherapy and targeted therapies. Immunotherapies have led to the most significant advances in treating SCLC in decades, and several promising targeted approaches have emerged from the increased understanding of the biology of SCLC. However, responses to these novel approaches are far from universal, and efforts to refine these therapies are ongoing.
Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited effective treatment options in the advanced setting.
SCLC is characterized by a high tumor mutation burden, genomic instability, and alterations in Notch signaling and DNA damage repair pathways, providing rationale for the use of immunotherapy and targeted therapies in this disease.
Incorporation of immune checkpoint inhibitors has led to the most significant advances in the treatment of SCLC in decades, although response rates are limited.
Further development of novel therapies is ongoing, with promising strategies, including combination and/or novel immunotherapies, targeting of overexpression of DLL-3 in SCLC, and targeted inhibition of DNA damage repair.
Lung cancer has been and remains the leading cause of cancer-related mortality in the United States and worldwide. Surveillance, Epidemiology, and End Results data estimate that more than 228,000 people in the United States will be diagnosed with lung cancer in 2019 and that greater than 142,000 will die from lung cancer. This number is greater than the deaths expected from colorectal, breast, and prostate cancer combined. Approximately 15% of these lung cancers are small cell lung cancer (SCLC), making SCLC a significant contributor to morbidity and mortality.
The primary risk factor for SCLC is smoking, with nearly all cases being associated with a history of cigarette smoking and risk increasing with greater exposure to smoking. Although the incidence of SCLC in men has been decreasing in recent years, its incidence in women has increased, with more recent estimates reflecting an approximately 1:1 male-to-female ratio.
SCLC has been a challenging disease to treat because of its propensity for presenting at an advanced stage at diagnosis, rapid progression and metastasis, and acquisition of resistance to conventional chemotherapy and radiotherapy. Although SCLC is commonly responsive to both chemotherapy and radiotherapy initially, the response is often fleeting. Disease relapse typically occurs within several months, frequently with development of chemotherapy resistance.
The prognosis of SCLC remains quite poor, with 5-year survival rates of less than 5% for most patients who present with metastatic disease, and median overall survival of 8 to 12 months, even with recent advances in therapy, , , highlighting the need for novel therapeutic approaches in the treatment of SCLC.
Current Standard of Care
The Veterans Administration lung group 2-stage classification is most commonly used for staging SCLC. Limited-stage disease is defined as disease confined to 1 hemithorax, which can safely be encompassed within a tolerable radiation port. Disease involvement beyond this point is classified as extensive-stage disease. However, TNM staging is increasingly recommended for classification of SCLC.
The current standard of care for SCLC in the limited stage consists of concurrent chemotherapy (cisplatin and etoposide) with radiation. There is strong evidence supporting a twice-daily fractionation scheme of radiation therapy delivered over 3 weeks, although emerging evidence suggests that a longer course of once-daily fractionation may also lead to similar outcomes. Several studies support that early (ideally beginning with cycle 1 or 2 of chemotherapy) concurrent radiation is superior to sequential or late concurrent radiation. Surgical resection in the form of lobectomy, followed by adjuvant therapy, has shown promising outcomes for those with very early stage (T1-2N0M0) disease, although these patients are uncommon.
The treatment of extensive-stage SCLC had remained unchanged for many years, consisting of first-line treatment with platinum-etoposide chemotherapy. Carboplatin is frequently used in place of cisplatin because of better tolerability and several studies demonstrating similar outcomes between carboplatin and cisplatin. A recent phase 3 randomized trial has transformed this standard of care after demonstrating improved survival with the addition of the PD-L1 inhibitor atezolizumab to carboplatin and etoposide, discussed in further detail in later discussion. In addition, consolidative (sequential) chest radiotherapy has been shown to improve overall survival in extensive-stage disease, when delivered to patients with a good response after chemotherapy.
Prophylactic cranial irradiation (PCI) has shown an overall survival benefit for patients with limited-stage disease who achieve remission after initial chemoradiation and is widely recommended in this setting. , However, whether PCI affords this same benefit in extensive-stage disease is an area of controversy. Although an early randomized trial showed a survival benefit for PCI in extensive-stage disease that responded to initial chemotherapy, a more modern randomized trial, which incorporated brain MRI before randomization, failed to show such a benefit.
Treatment of relapsed/refractory SCLC has remained an area of significant challenge because of poor response rates to various therapies and rapid emergence of drug resistance. For patients who experience disease relapse at least 3 months (especially >6 months) after completion of platinum-based chemotherapy (platinum-sensitive), rechallenge with platinum plus etoposide is suggested. ,
For patients with relapse within 3 months of platinum-based chemotherapy (platinum-refractory), the use of an alternative agent is recommended. Until very recently, the only approved therapy in the United States for this setting was topotecan, , although evidence exists for the use of paclitaxel, temozolomide, irinotecan, vinorelbine, docetaxel, or combination cyclophosphamide, doxorubicin, and vincristine, with generally similar efficacy. However, efficacy for any of these agents is limited, with response rates all less than 25%, with median overall survival of 4 to 6 months.
Recent advances in currently available therapies for small cell lung cancer
First-line therapy for extensive-stage SCLC was recently transformed after the IMpower-133 trial demonstrated a significant survival benefit with the addition of the PD-L1 inhibitor atezolizumab to carboplatin and etoposide chemotherapy, leading to Food and Drug Administration (FDA) approval in March 2019. This study randomized 403 patients with newly diagnosed extensive-stage SCLC to first-line therapy with carboplatin plus etoposide, in combination with either atezolizumab or placebo. After 4 cycles of chemotherapy, patients continued on either atezolizumab or placebo as maintenance. The atezolizumab group had an improved median overall survival at 12.3 months versus 10.3 months in the placebo group (hazard ratio 0.70; 95% confidence interval 0.54–0.91; P = .007). Objective response rates were similar in the 2 groups (60.2% for atezolizumab vs 64.4% for placebo), although a higher proportion of patients had an ongoing response at the time of data cutoff (14.9% vs 5.4%). Rates of hematologic side effects were similar in the 2 groups, and immune-mediated adverse events with the combination were similar in incidence and nature to those observed with single-agent atezolizumab in other trials.
Although the 2-month difference in survival is modest, this was the first clinical trial to show any intervention to improve on the first-line use of platinum plus etoposide chemotherapy. A previous randomized phase 3 trial testing the addition of the CTLA-4 inhibitor ipilimumab failed to show any benefit for either progression-free or overall survival.
Similar findings were more recently reported for the CASPIAN trial, a phase 3 randomized study of platinum-etoposide chemotherapy with or without the PD-L1 inhibitor durvalumab. In the CASPIAN study, patients in the immunotherapy arm of the trial (n = 268) achieved a median overall survival of 13 months compared with 10.3 months for the control group (n = 269). Another similar phase 3 trial using the PD-1 inhibitor pembrolizumab (KEYNOTE-604) is ongoing.
In the IMpower-133 study, only 7.4% of the patients randomized to placebo went on to receive subsequent immunotherapy (although 57.4% of patients in this group received some second-line therapy). Although much of the benefit from adding immunotherapy up front may be because many patients who progress may never have the chance to try second-line therapy, this suggests that there may still be a role for immunotherapy beyond the first line of treatment. Notably, patients who relapse after treatment of limited-stage SCLC are typically immunotherapy naïve.
In the CheckMate-032 trial, 1 cohort enrolled patients with relapsed or refractory SCLC to receive nivolumab monotherapy or nivolumab plus ipilimumab at 2 different dose levels. An objective response was achieved in 10% (10/98) of patients receiving single-agent nivolumab 3 mg/kg, 23% (14/61) receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (10/54) receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Many responses were durable, with several patients surviving beyond 2 years. Immune-mediated toxicity was more frequent in the combination arms, with discontinuation owing to treatment-related adverse events occurring in 6%, 11%, and 7% of each of the 3 arms, respectively, as well as 3 treatment-related deaths in the combination nivolumab plus ipilimumab arms. In August 2018, the FDA approved nivolumab as a single agent for the treatment of SCLC after platinum-based chemotherapy and 1 additional line of therapy. The combination of nivolumab plus ipilimumab is included in treatment guidelines as a recommended option for relapsed/refractory SCLC.
Pembrolizumab has also been investigated in the relapsed/refractory setting for SCLC, and in June 2019, based on a pooled analysis from KEYNOTE-158 and KEYNOTE-028 trials, the FDA approved pembrolizumab for treatment of SCLC after platinum-based chemotherapy and 1 other line of therapy. In this analysis, an overall response rate of 19.3% was noted in patients who had received at least 2 prior lines of systemic therapy, and many responses were durable, with 61% of responders lasting at least 18 months.
Advances in understanding of the biology of small cell lung cancer
Recent analyses of the mutational landscape of SCLC have revealed that nearly all cases of SCLC are characterized by inactivation of both TP53 and RB1, tumor suppressor genes that play a critical role in carcinogenesis. , In addition, inactivating mutations in Notch family genes occur in about 25% of cases. DLL-3 is an inhibitory ligand of Notch signaling that is expressed or overexpressed on the cell surface in approximately 80% of SCLC and not in normal tissues, making it an attractive target for novel therapies. , Less commonly, mutations or amplifications in kinase genes, including FGFR, KIT, and PIK3CA, have been observed, although whether these can be targeted effectively in these individual patients remains unclear.
Other comprehensive proteomic and transcriptomic analysis has demonstrated upregulation of several proteins involved in DNA damage repair, including PARP1, CHK1, and WEE1. This upregulation has led to evidence of antitumor activity of DNA damage repair inhibitors in SCLC, primarily in the form of PARP inhibitors.
Several features of SCLC suggest that immunotherapy should be a rational therapeutic strategy.
First, SCLC is highly linked to chronic tobacco smoking and has been shown to carry a high rate of G-to-T DNA transversions. , This transversion results in a high frequency of somatic nonsynonymous mutations (high tumor mutational burden [TMB]), which is predictive of a larger number of tumor neoantigens expressed in these tumors, and a greater predicted likelihood for tumor-specific T-cell response across multiple cancers. Second, SCLC has long been associated with paraneoplastic syndromes, such as Lambert-Eaton myasthenic syndrome, cerebellar degeneration, and limbic encephalitis, which are mediated by well-characterized autoantibodies, which are cross-reactive with cancer cells. Furthermore, there is evidence that patients with such paraneoplastic antibodies may carry a better prognosis.
Predictors of response to immunotherapy are of significant interest given the relatively low rates of response with currently available checkpoint inhibitors. Currently, TMB and PD-L1 expression are the most commonly used biomarkers of response. A correlative analysis of TMB and outcomes in the SCLC of the CheckMate-032 study demonstrated enhanced efficacy of nivolumab with or without ipilimumab in patients with high TMB. In addition, patients within the highest tertile of TMB appeared to have the greatest benefit from the combination (46.2% response rate) versus nivolumab monotherapy (21.3% response rate). Of note, in the IMpower-133 trial, a blood-based TMB measurement did not correlate with outcomes with the addition of atezolizumab. Tumor PD-L1 expression appears to be significantly less frequent in SCLC compared with non–small cell lung cancer. , In the CheckMate-032 study, response rates did not differ significantly among patients who were evaluable for PD-L1 expression who had PD-L1–positive versus PD-L1–negative tumors. PD-L1 expression in CheckMate-032 was assessed as tumor proportion score (TPS), or the percentage of tumor cells staining positive by immunohistochemistry. In contrast to this finding, on the composite analysis of KEYNOTE-028 and KEYNOTE-158 trials, PD-L1 positivity did correlate with benefit from pembrolizumab, with 14 out of 16 responders being PD-L1 positive. In the KEYNOTE trials, PD-L1 expression was assessed as combined positive score (CPS), or the total number of tumor cells as well as associated immune cells staining positive for PD-L1 divided by the number of viable tumor cells. This difference in technique could potentially explain these divergent observations, and it remains to be confirmed whether CPS may be a better predictor than TPS for response to immunotherapy in SCLC. Further study is clearly needed to identify the optimal way to measure these and other biomarkers to predict response to various immunotherapies.
In light of the recent discovery of these targets and strategies for the treatment of SCLC, there has been renewed enthusiasm around several novel therapies for this disease. Recent developments in both immunotherapy and nonimmunotherapy treatments are discussed later, and a selection of relevant ongoing clinical trials are highlighted in Table 1 .
|Immune checkpoint inhibitors|
|PD-L1/CTLA-4||Durvalumab, tremelimumab||Phase 3, randomized||CASPIAN: Durvalumab ± tremelimumab combined with platinum-based chemotherapy in untreated extensive-stage (ES)-SCLC||NCT03043872|
|PD-1||Pembrolizumab||Phase 3, randomized||KEYNOTE-604: Pembrolizumab combined with etoposide/platinum in untreated ES-SCLC||NCT03066778|
|PD-1||Nivolumab||Phase 2, randomized||Platinum + etoposide chemotherapy with or without nivolumab in ES-SCLC||NCT03382561|
|PD-L1/CTLA-4||Durvalumab, tremelimumab||Phase 3, randomized||ADRIATIC: Durvalumab or durvalumab + tremelimumab as consolidation in limited-stage (LS)-SCLC||NCT03703297|
|PD-L1||atezolizumab||Phase 2/3||Chemoradiation with or without atezolizumab in LS-SCLC||NCT03811002|
|PD-1/CTLA-4||Nivolumab, ipilimumab and plinabulin||Phase 1/2||BTCRC-LUN17–127: Nivolumab, ipilimumab, and plinabulin in patients with recurrent SCLC||NCT03575793|
|PD-1||Pembrolizumab||Phase 1||Pembrolizumab with concurrent chemoradiation in LS-SCLC||NCT02402920|
|PD-1/CTLA-4||Nivolumab, ipilimumab, and Ad.p53-DC||Phase 1||Combination nivolumab/ipilimumab plus autologous p53-transfected dendritic cell vaccine||NCT03406715|
|PD-L1/CTLA-4||Durvalumab, tremelimumab||Phase 2||Durvalumab plus tremelimumab as 1 arm of a multiarm phase 2 study of novel combinations in platinum-refractory SCLC||NCT02937818|
|Lurbinectedin||Phase 3||ATLANTIS: (lurbinectedin vs topotecan vs CAV)||NCT02566993|
|DNA damage repair pathways|
|PARP||Olaparib||Phase 1/2||Olaparib plus temozolomide||NCT02446704|
|ATR kinase||M6620||Phase 2, randomized||Topotecan with or without M6620 in relapsed SCLC||NCT03896503|
|ATR kinase, PARP||AZD6738, olaparib||Phase 2||AZD6738 plus olaparib as 1 arm of a multiarm phase 2 study of novel combinations in platinum-refractory SCLC||NCT02937818|
|Rovalpituzumab tesirine||Phase 3 (randomized, placebo controlled)||MERU: Maintenance after first-line platinum-based chemotherapy||NCT03033511|
|Rovalpituzumab tesirine||Phase 1/2||Combination with nivolumab or nivolumab + ipilimumab||NCT03026166|
|AMG 757||Phase 1||BiTE targeting DLL-3 in relapsed/refractory SCLC||NCT03319940|
|AMG 119||Phase 1||CAR-T therapy targeting DLL-3 in relapsed/refractory SCLC||NCT03392064|
|LY3295668||Phase 1b||Single agent in platinum-sensitive ES-SCLC||NCT03898791|
|AZD1775||Phase 2||AZD1775 plus carboplatin as 1 arm of a multiarm phase 2 study of novel combinations in platinum-refractory SCLC||NCT02937818|
|Navitoclax and Vistusertib||Phase 1/2||Relapsed SCLC and other solid tumors||NCT03366103|
|Somatostatin Receptor 2 (SSR2)|
|177LU-OPS201||Phase 1/2||177LU-OPS201 with companion imaging 68 Ga OPS202 PET/computed tomography in cancers expressing SSR2||NCT03773133|
|PEN-221||Phase 1/2||PEN-221 in SSR2-expressing advanced cancers||NCT02936323|
|RRx-001||Phase 3, randomized||Third+ line SCLC (platinum + etoposide with or without RRx-001)||NCT03699956|
|EZH1/2||DS-3201b||Phase 1/2||DS-3201b plus irinotecan in recurrent SCLC||NCT03879798|
|Whole brain radiation||Phase 2/3, randomized||Whole-brain radiation therapy with or without hippocampal avoidance||NCT02635009|