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INTRODUCTION

Lung cancer is the leading cause of cancer-related death in the United States (U.S.), with a projected 236,740 new cases and more than 130,000 deaths in 2022.¹ Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers.² SCLC is challenging to treat due to rapid disease progression and metastasis, with 60% to 70% of patients presenting with extensive-stage disease at diagnosis.³ Left untreated, SCLC has a very aggressive clinical course, with a median survival from diagnosis of 2 to 4 months.² The prognosis for those with extensive-stage SCLC (ES-SCLC) is especially poor, given that most therapies result in a median overall survival (mOS) of 7 to 10 months, 1-year survival rate of 20% to 40%, and 10-year survival rate of less than 2%.⁴ SCLC is also associated with a significant economic burden, including costs of medications, surgeries, hospitalizations, emergency room visits, and additional outpatient care.⁵

Cigarette smoking is far and away the primary risk factor for SCLC, and it is rare for a patient with SCLC to be a never-smoker. Other risk factors include a family history of lung cancer, exposure to second-hand smoke or occupational carcinogens, exposure to radon or chest radiation, and air pollution.¹ The overall incidence of SCLC has been decreasing over the last 20 years, but the incidence among women has increased. This is presumably due to the steady rise in smoking among this group, resulting in nearly equal rates of diagnosis among men and women today.⁶

While many patients with advanced SCLC initially respond to standard first-line chemotherapy or radiotherapy, eventual disease progression is common.⁷ Most patients experience disease progression within the first year of treatment, and survival following second-line therapy is poor (mOS 4 to 8 months); less than 7% of patients are alive after 5 years.⁸ Increases in survival rates for patients with SCLC have been modest at best in recent years.⁹ In contrast with non-small cell lung cancer (NSCLC) for which many oncogenic mutations have been identified, SCLC has no targetable mutations nor U.S. Food and Drug Administration (FDA)-approved targeted therapies. These data highlight the need for more effective agents and regimens to improve outcomes, particularly for patients with ES-SCLC.

The number of treatments available for ES-SCLC—including chemotherapy and immunotherapy—is increasing, challenging pharmacists and nurses to remain current on therapeutic options, evolving evidence-based clinical practice guidelines, and optimal use of new agents and regimens. This monograph reviews systemic treatment options for ES-SCLC, including recently approved and late-stage novel systemic therapies, pivotal clinical trials, and selected ongoing studies. This information supports clinical decision making for health care professionals managing patients with ES-SCLC.

SCLC Staging

Accurate SCLC staging is essential for prognosis and therapy selection and to guide thoracic radiotherapy (mainly for patients with limited-stage disease). In 2009, the International Association for the Study of Lung Cancer (IASLC) proposed using the tumor, node, metastasis (TNM) staging system for more precise classification and prognostic assessment of SCLC. The 8^th and most recent TNM classification is based on clinical and pathological assessment, including presence of nodal disease or metastases.¹⁰

Using this system, limited-stage (LS) disease is defined as Stage I-III (T any, N any, M0) that can safely be treated within a definitive radiation field. ES-SCLC is defined as Stage IV (T any, N any, M1a/b/c), or T3-4 due to multiple lung nodules too extensive or tumor/nodal volume too large to be encompassed in a tolerable radiation plan. Research shows that TNM staging correlates with long-term survival (shortest for stage IV).¹ The National Comprehensive Cancer Network (NCCN) SCLC panel uses a combination of TNM and an older Veterans Administration scheme for staging.¹²

Mediastinal staging procedures are generally used unless the patient is a candidate for surgical resection. Because SCLC is a highly metabolic disease, positron emission tomography (PET) scans can increase staging accuracy, with PET/computerized tomography (CT) being more accurate than PET.¹³ Magnetic resonance imaging (MRI) is the preferred method for identifying brain/central nervous system (CNS) metastases, and CT with contrast is an option for patients with a contraindication to MRI. Contrast CT should be used if possible because non-contrast head CT scans often fail to detect brain metastases. Scans should be performed regularly since brain/CNS metastases are found in 10% to 25% of patients at SCLC diagnosis and can develop in an additional 40% to 50% of patients during their disease.¹⁴ Additionally, bone scans may be indicated for detection of bone metastases since these are found in approximately 30% of patients with SCLC. However, additional bone scans can be avoided if bone metastases are detected on PET or CT imaging.¹²

Prognostic Factors

Poor prognostic factors for SCLC include ES disease, poor performance status, weight loss, and markers associated with bulky disease such as lactate dehydrogenase (LDH).¹⁰ Favorable prognostic factors for LS-SCLC are female sex, age younger than 70 years, normal LDH, and stage I disease. For ES-SCLC, favorable prognostic factors include younger age, good performance status, normal creatinine and LDH levels, and a single metastatic site.^15,16

Initial number of metastatic sites and presence of distant metastases, as well as albumin, alkaline phosphatase, and hyponatremia, may also be prognostic for survival in SCLC. Patients with a neurologic paraneoplastic syndrome—often associated with SCLC—may have improved survival.¹⁷ PET parameters, particularly high baseline metabolic tumor volume and maximum-standard uptake value, might also be prognostic for survival.¹⁸

Histology and Molecular Biology

SCLC is a poorly differentiated, aggressive neuroendocrine malignancy, so it can be associated with various neurologic or endocrine paraneoplastic syndromes. Pathologically, it can be distinguished from other carcinoid tumors by its punctate appearance, increased mitotic rate (greater than 10 mitoses/2 mm² field), and high Ki-67 proliferative index as measured by immunostaining (generally 50% to 100%).¹⁰

Although less numerous compared with NSCLC, genetic alterations can be detected in some SCLC tumors. TP53 and RB1 loss-of-function mutations are common, and PI3K activating mutations, PTEN loss, and MYC or FGFR1 amplification can also occur.^19,20 These may contribute to aggressive disease and poor prognosis. In contrast with NSCLC, no actionable oncogenic mutations have been identified in SCLC that would allow use of similar targeted therapies. Consequently, genomic analysis is usually not applicable for patients with SCLC. In some patients with NSCLC whose tumors have EGFR mutations and develop resistance, repeat biopsy can in some instances show that the resistance mechanism is due to a transformation to SCLC.²¹

Recently, researchers identified 4 subtypes of SCLC (SCLC-A, SCLC-P, SCLC-N, SCLC-I) based on differential expression of key transcription factors (e.g., ASCL1, NEUROD1, POU2F3), neuroendocrine features, and distinct molecular profiles or increased immune infiltration.²² These subtypes may correlate with tumor phenotype and increased risk of progression or CNS metastasis. They may also exhibit differential response to certain therapies. However, at present treatment decisions are not based on SCLC subtypes.

High expression of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoints often correlates with improved outcomes with immune checkpoint inhibitor (ICI) therapy in NSCLC, but this has not been confirmed for SCLC.²³ Although most SCLC tumors lack PD-L1 expression, SCLC is considered sensitive to ICIs (see section on Immune Checkpoint Inhibitors).²⁴ Assessment of PD-1/PD-L1 tumor expression is therefore not required for use of ICIs to treat SCLC.

ESTABLISHED THERAPY FOR SCLC

SCLC is typically highly responsive to chemotherapy and radiation therapy, which can induce rapid responses in many patients. Unfortunately, most responses are short-lived, and patients ultimately experience disease progression and require additional therapy.⁴ A systematic review of real-world SCLC treatment patterns found high initial response rates with first-line platinum-based treatment, but this was followed by early relapse (mOS 12 months or less). These findings highlight the unmet need for new, more effective treatment options in both first-line and for recurrent disease.

Limited-Stage Disease

NCCN treatment guidelines indicate that cisplatin/etoposide at various doses is the preferred systemic regimen for primary treatment of LS-SCLC.¹² Alternatively, providers can substitute carboplatin for cisplatin when cisplatin is contraindicated or not tolerated (see Table 1). Because SCLC is so responsive to chemotherapy and grows so rapidly, providers often initiate chemotherapy urgently and then start concurrent radiation therapy during cycle 2 or 3 to give adequate time for radiation planning.

Extensive-Stage Disease

Preferred first-line therapy for ES-SCLC involves platinum-based regimens, with addition of atezolizumab or durvalumab for patients who are eligible for ICI therapy (see Table 1).¹⁰ While first-line chemotherapy-based regimens can result in response rates of approximately 60%, relapse commonly occurs within several months of completing chemotherapy and median survival is less than 1 year.²⁵

Similar to LS-SCLC, carboplatin instead of cisplatin is acceptable when the latter is not an option or is less desirable based on toxicity.¹² While carboplatin generally causes less emesis, neuropathy, and nephropathy than cisplatin, it may cause more myelosuppression.¹⁰ Research suggests equivalent survival using either platinum compound for SCLC therapy.^26,27,28,29 Trilaciclib—a cyclin-dependent kinase 4/6 inhibitor—is FDA approved as a myeloprotectant to lessen chemotherapy-induced myelosuppression commonly seen with platinum/etoposide- or topotecan-containing regimens for ES-SCLC and to reduce the need for supportive care.^30,31 Phase 3 trials are needed to confirm its benefit for chemotherapy-induced myelosuppression, and to determine any effects it may have on survival or other clinical endpoints.

Subsequent Therapy

Choice of subsequent systemic therapy for SCLC is based on time to relapse following first-line treatment.¹² Relapsed or recurrent SCLC within 6 months of treatment initiation is termed chemotherapy-resistant disease. Preferred therapy for these patients includes topotecan, lurbinectedin, or enrollment in a clinical trial. Patients who experience relapse more than 6 months after treatment initiation are considered to have chemotherapy-sensitive disease and can be rechallenged with a platinum/etoposide regimen. Note that cutoff definitions for resistant and sensitive SCLC can differ (e.g., 3 months based on European Society for Medical Oncology guidelines).³² Other single agents are also recommended (as opposed to preferred) by NCCN for subsequent therapy (see Table 1), but response rates to these drugs are often poor (about 10%) with resistant disease and only somewhat better with sensitive disease.³³

Oncologists have long used topotecan as chemotherapy for relapsed SCLC. This agent is FDA approved for patients with SCLC who have progressed after first-line chemotherapy. However, topotecan’s efficacy in patients with relapsed SCLC appears comparable to other chemotherapies, with low response rates (24%) and mOS of 6 months.³⁴ In patients with ES-SCLC who had no symptomatic CNS metastases, second-line topotecan was not superior to CAV (cyclophosphamide, doxorubicin, vincristine) or amrubicin.^35,36 Topotecan may cause significant adverse effects including severe myelosuppression, fatigue, alopecia, and gastrointestinal toxicity.

RECENT AND EMERGING TREATMENT OPTIONS FOR ES-SCLC

Following the development and approval of numerous nonspecific chemotherapeutics for treatment of ES-SCLC, several novel targeted agents and immunotherapies have recently been approved or are in late-stage clinical trials. These include ICIs, lurbinectedin, anlotinib, and apatinib as well as other immune therapies. Key findings from relevant clinical trials are outlined in Table 2.

Immune Checkpoint Inhibitors

ICIs are now a standard therapy option for many patients with advanced lung cancer. Monoclonal antibodies (MAbs) such as atezolizumab and durvalumab bind to PD-L1 (atezolizumab and durvalumab) or to the PD-1 receptor (e.g., nivolumab and pembrolizumab) to disrupt interactions between PD-L1 on cancer cells and PD-1 on activated B and T cells.^37,38,39,40 Other ICIs (e.g., ipilimumab) can alter cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression that can downregulate T-cell activation.⁴¹ Blocking these functions with ICIs enables the immune system to identify and target cancer cells, often producing durable antitumor responses. SCLC is known to have a high mitotic rate and tumor mutation burden (TMB), resulting in increased levels of immunogenic neoantigens that could enhance response to immunotherapy.⁴² ICIs have demonstrated efficacy in other advanced solid tumors with high TMB (e.g., melanoma, NSCLC), and TMB was shown to correlate with objective response rate to ICI therapy in certain tumor types.⁴³ However, TMB is not utilized as a biomarker to guide treatment for SCLC.

First-Line ICI Therapy

In ES-SCLC, first-line therapy using ICIs in combination with chemotherapy has provided modest OS benefit, although this increase may be clinically relevant given that survival with standard systemic therapy is often 1 year or less. In Phase 3 trials, the PD-L1 inhibitors atezolizumab and durvalumab showed prolonged survival when combined with platinum-based chemotherapy.

The IMpower133 Phase 3 trial evaluated the combination of either atezolizumab or placebo with carboplatin/etoposide in previously untreated patients with ES-SCLC.^44,45 Patients with brain metastases at baseline were allowed to enroll. Induction chemotherapy consisted of carboplatin (area under the curve [AUC] 5 mg/mL/min); etoposide 100 mg/m² on days 1-3 of each cycle; and placebo or atezolizumab 1200 mg on day 1 of each cycle for four 21-day cycles followed by maintenance placebo or atezolizumab 1200 mg every 3 weeks. Compared to placebo, addition of atezolizumab significantly increased median progression-free survival (mPFS) and mOS.^41,42 The most common Grade 3/4 treatment-related adverse events were neutropenia and anemia. The rate of all-grade immune-related adverse events (irAEs) was higher with atezolizumab (39.9% versus 24.5%), and the most common irAEs with atezolizumab were rash and hypothyroidism. This data led to approval of atezolizumab plus carboplatin/etoposide as first-line treatment of adult patients with ES-SCLC.⁴⁶ NCCN now lists this regimen as a preferred first-line treatment option for ES-SCLC.¹⁰

The Phase 3 CASPIAN trial evaluated durvalumab-based regimens in patients with ES-SCLC, including those with brain or CNS metastases.⁴⁷ Patients received platinum/etoposide alone or combined with either durvalumab or durvalumab/tremelimumab. All patients received up to 6 cycles of platinum-based therapy (carboplatin AUC 5-6 mg/mL/min or cisplatin 75-80 mg/m² administered on day 1 of each cycle) plus etoposide 80-100 mg/m² administered on days 1-3 of each 21-day cycle. Patients in the immunotherapy groups received 4 cycles of platinum/etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks, which was followed by maintenance durvalumab 1500 mg every 4 weeks. A significant increase in mOS was achieved with platinum/etoposide/durvalumab compared with platinum/etoposide alone (12.9 months versus 10.5 months; Table 2). Addition of tremelimumab did not significantly improve outcomes compared with platinum/etoposide.⁴⁴ The most common all-cause Grade 3/4 adverse events were neutropenia and anemia. Patients who received platinum/etoposide/durvalumab had a significantly higher rate of irAEs compared with the control arm (20% versus 3%), the most common of which were hypothyroid and hyperthyroid events. Results of the CASPIAN trial led to approval of durvalumab in combination with etoposide and carboplatin or cisplatin as first-line treatment of ES-SCLC in adults.⁴⁸ NCCN also lists this regimen as a preferred first-line treatment option for ES-SCLC.¹⁰ A 3-year update to the CASPIAN trial confirmed sustained clinically significant mOS benefit in favor of durvalumab.⁴⁹

Ipilimumab—an anti-CTLA-4 MAb—was not found to be effective as first-line treatment of ES-SCLC. The Phase 3 IDEATE trial compared platinum/etoposide with or without ipilimumab, followed by ipilimumab or placebo maintenance therapy.²⁴ The trial did not meet the primary endpoint of improved OS, and PFS was not significantly improved over the control arm. Treatment-related adverse events were similar between the 2 arms except for diarrhea, rash, and colitis, which were more common with the addition of ipilimumab. More treatment-related discontinuations occurred with the chemotherapy/ipilimumab regimen (18% versus 2%).²⁴

Clinical trials have evaluated pembrolizumab in previously treated patients with ES-SCLC.⁵⁰ The Phase 3 KEYNOTE-604 trial evaluated first-line treatment with platinum/etoposide combined with pembrolizumab or placebo, followed by maintenance therapy with pembrolizumab or placebo.^51,52 Patients with brain metastases were eligible if they completed whole-brain radiation or stereotactic radiosurgery 14 or more days before starting study treatment, exhibited no new or enlarging brain metastases, and were neurologically stable without steroids for at least 7 days before initiating study treatment. Median OS in the pembrolizumab arm was greater compared with the placebo arm but this finding was not statistically significant (10.8 months [95% CI, 9.2–12.9] with pembrolizumab plus platinum/etoposide and 9.7 months [95% CI, 8.6–10.7] with placebo plus platinum/etoposide; hazard ratio [HR] 0.80 [0.64–0.98], P = .0164).^48,49 An ongoing Phase 3 trial of first-line therapy for ES-SCLC is comparing pembrolizumab/vibostolimab—an anti–T-cell immunoglobulin and ITIM domain (TIGIT) therapy—plus platinum/etoposide followed by vibostolimab maintenance therapy to a regimen of atezolizumab in combination with platinum/etoposide followed by maintenance atezolizumab.⁵³ Currently, pembrolizumab is not indicated for treatment of SCLC.

Another anti-PD-1 MAb, tislelizumab, demonstrated efficacy in a Phase 2 trial in combination with chemotherapy as first-line treatment of advanced NSCLC or ES-SCLC (overall response rate [ORR] 77%); treatment-emergent adverse events were hematological.⁵⁴ An ongoing Phase 3 trial is evaluating of tislelizumab plus platinum-based chemotherapy in the first-line ES-SCLC setting, and tislelizumab is also under study as maintenance therapy.

Second-line ICI Therapy

Results using ICIs in the second-line setting for ES-SCLC generally have been disappointing, but some patients do respond. Considering these results and their increasing use as first-line therapy, ICI use is less common in previously treated patients with ES-SCLC. Researchers have yet to identify any biomarkers predictive of ICI response in SCLC. Unlike NSCLC, TMB and PD-L1 expression on tumor or immune cells are not reliable predictive biomarkers in SCLC.⁵⁵

Although effective in advanced NSCLC, nivolumab has not improved survival in pretreated patients with SCLC. The CheckMate 331 trial of second-line nivolumab versus amrubicin or topotecan, and the CheckMate 032 trial of nivolumab followed by nivolumab maintenance as second-line or greater therapy, showed no increase in OS with nivolumab.^56,57 Similarly, early data showed increased response rates with pembrolizumab, leading to initial approval of both nivolumab and pembrolizumab for relapsed/recurrent disease.⁵⁸ However, the absence of any OS benefit—including in the first-line KEYNOTE-064 trial—led to withdrawal of SCLC approvals for both agents in 2021.^59,60

The CheckMate 451 Phase 3 trial also evaluated nivolumab as maintenance therapy following platinum-based treatment.⁶¹ Researchers assessed nivolumab alone or combined with ipilimumab in patients with ES-SCLC without progression after first-line platinum-based chemotherapy. The combination regimen did not significantly increase OS, though.⁵⁷

Other Novel Monoclonal Antibodies

Newer ICIs and other novel immune targets have also been studied in SCLC. Tislelizumab, another PD-1–targeting MAb, demonstrated efficacy in a Phase 2 trial in combination with chemotherapy as first-line treatment of advanced NSCLC or ES-SCLC (ORR 77%).⁶² Treatment-emergent adverse events were hematological. An ongoing Phase 3 trial is evaluating tislelizumab plus platinum-based chemotherapy in the first-line ES-SCLC setting, and a Phase 2 trial of tislelizumab as maintenance therapy following first-line platinum-based chemotherapy is also underway.^63,64

Tiragolumab is a MAb targeting TIGIT, an inhibitory checkpoint receptor overexpressed on many solid tumors, including SCLC.⁶⁵ TIGIT expression may be prognostic for survival in patients with SCLC. Targeting TIGIT with tiragolumab might synergize with ICIs to further increase antitumor efficacy. However, despite positive results seen with the combination of atezolizumab and tiragolumab in advanced NSCLC,⁶⁶ the SKYSCRAPER-02 Phase 3 trial of first-line atezolizumab/carboplatin/etoposide with or without tiragolumab in ES-SCLC did not meet its coprimary endpoints of OS and PFS.⁶⁷ Subgroup, biomarker, and final OS analyses of this trial are pending. A Phase 2 trial of tiragolumab plus atezolizumab as consolidation therapy following chemoradiation therapy for LS-SCLC is ongoing.⁶⁸

Lurbinectedin

Lurbinectedin is a novel alkylating agent that selectively inhibits transcription and induces double-strand DNA breaks, leading to apoptosis.⁶⁹ It also inhibits and promotes degradation of RNA polymerase II activity. These effects promote immunogenic cell death and normalize the tumor microenvironment, restricting tumor growth. Lurbinectedin is a treatment option for patients with resistant or sensitive disease following first-line platinum-based chemotherapy.¹⁰

Lurbinectedin was studied in a Phase 2 basket trial in patients with SCLC without brain metastases who had received at least 1 previous chemotherapy-based regimen.^70,71 Patients received 3.2 mg/m² intravenously (IV) on day 1 every 3 weeks. For the 105 patients with SCLC (70% with ES-SCLC at diagnosis) and no brain metastases, the ORR was 35.2% and median duration of response was 5.3 months. Greater efficacy was noted in patients with chemotherapy-sensitive compared with chemotherapy-resistant disease. The most common Grade 3/4 adverse events were neutropenia (46%), leukopenia (29%), anemia (9%), and thrombocytopenia (7%). Some patients also experienced fatigue, gastrointestinal toxicity, and decreased appetite (mostly Grade 1/2).^66,67

Based on these results, the FDA approved lurbinectedin for treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.⁷² Results from the Phase 2 basket trial and a small study of patients treated with first-line platinum-based chemotherapy indicated that the efficacy of lurbinectedin compared favorably to real-world studies using rechallenge with the first-line regimen as second-line treatment for platinum-sensitive relapsed SCLC.⁷³

Lurbinectedin represents a convenient second-line treatment option for advanced SCLC since it is administered only once every 3 weeks, compared to topotecan that is typically administered IV or orally (PO) over 5 consecutive days every 3 weeks. It should be noted, however, that the Phase 2 lurbinectedin trial did not include patients with brain metastases (i.e., those most likely to have worse outcomes), so further studies are needed to confirm clinical benefit for this patient subgroup. Additionally, topotecan has a more favorable safety profile compared to lurbinectedin based on its lower rate of hematologic toxicity, lower risk of febrile neutropenia, and reduced need for primary granulocyte colony-stimulating factor (G-CSF).^67,74,71

The Phase 3 ATLANTIS trial combined lurbinectedin with doxorubicin for treatment of relapsed SCLC.⁷⁵ Researchers compared lurbinectedin/doxorubicin to either topotecan or CAV in patients who had received 1 prior platinum-based doublet and had a chemotherapy-free interval (CTFI) of at least 30 days. Patients received lurbinectedin 2 mg/m² on day 1, with doxorubicin 40 mg/m², given every 3 weeks. Patients with stable brain metastases were allowed to enroll.

The ATLANTIS trial failed to meet its primary endpoint of improved OS.⁷¹ However, the lurbinectedin/doxorubicin arm showed superior safety and tolerability compared to the control arm (treatment-related adverse events: 88.4% versus 92.0%; Grade 3/4 adverse events: 66.0% versus 86.5%). Lurbinectedin/doxorubicin showed greater improvement in mPFS and mOS in patients with a CTFI of at least 180 days. Patients in the lurbinectedin/doxorubicin arm had a mPFS of 8.2 months compared to 4.5 months for patients who received standard-of-care treatment (HR 0.469), and mOS was 12.7 months and 9.8 months, respectively (HR 0.847).⁷¹ A post hoc analysis showed that patients who completed 10 cycles of lurbinectedin/doxorubicin and then received lurbinectedin monotherapy were able to maintain or improve their tumor response (mOS 20.7 months, median duration of response 8.3 months).⁷⁶

Data from the ongoing Phase 1/2 LUPER trial indicate that the combination of lurbinectedin and pembrolizumab is tolerable in patients with SCLC who relapsed on platinum-based chemotherapy.⁷⁷ For the 13 patients enrolled in Phase 1, the ORR was 30.8% and an additional 23.1% of patients had stable disease as best response.⁷³

Preclinical studies indicate that SCLC cell lines and xenografts expressing high levels of SLFN11 (which regulates response to DNA damage and replication stress) are more sensitive to lurbinectedin.⁷⁸ They also show that combining lurbinectedin with the ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib could sensitize resistant cells expressing low levels of SLFN11. Given that its expression on tumor cells was associated with response to various DNA-damaging agents in some SCLC trials, SLFN11 might serve as a predictive biomarker to lurbinectedin as well, but further studies are needed. An ongoing clinical trial is assessing the utility of SLFN11 expression as a potential biomarker in patients with SCLC.⁷⁹

Ongoing Phase 2 and Phase 3 trials are evaluating lurbinectedin with nivolumab and ipilimumab as first-line therapy and lurbinectedin in combination with atezolizumab, pembrolizumab, or the ATR kinase inhibitor berzosertib. Phase 3 trials are also comparing lurbinectedin as maintenance therapy with or without irinotecan for relapsed SCLC following a platinum-based regimen, as well as atezolizumab with or without lurbinectedin in patients with ES-SCLC who experience disease progression on platinum/etoposide/atezolizumab.^80,81

Tyrosine Kinase Inhibitors

Anlotinib—a novel, small-molecule multikinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR)-2/3, among others—shows potential in advanced SCLC, particularly in previously treated patients.⁸²In vitro, anlotinib exhibits antiangiogenic activity in selected tumor types, including NSCLC and SCLC. Several Phase 2 trials have demonstrated the efficacy of anlotinib in SCLC as monotherapy or combined with platinum/etoposide, and some studies included patients with ES-SCLC.^83,84,85 In all studies, patients received anlotinib 12 mg once daily on days 1 through 14 of each 21-day cycle.

As monotherapy, patients on anlotinib achieved an ORR, mPFS, and mOS of 11%, 4.1 months, and 6.1 months, respectively.⁷⁸ For patients on anlotinib combined with platinum/etoposide, these values were 86­% to 90%, 6.0 to 8.0 months, and 14.0 to 15.9 months, respectively.⁷⁸ Responses were seen in patients with brain or CNS metastases, with 1 report of brain hemorrhage across all studies. A meta-analysis and real-world study confirmed its efficacy in the second-line setting and as first-line maintenance therapy.^86,87

Anlotinib plus platinum/etoposide chemotherapy has also demonstrated efficacy as first-line therapy for ES-SCLC.⁸⁸> The most common (all-grade) adverse events with anlotinib include hypertension, hypertriglyceridemia/hypercholesterolemia, stomatitis, hand-foot syndrome, elevated transaminases, and hematologic toxicity; these are consistent with adverse event profiles of other VEGF inhibitors.

One study found that combining anlotinib with a PD-1 inhibitor was safe and possibly effective in previously treated patients with SCLC.⁸⁹ Ongoing Phase 2 and Phase 3 trials are also evaluating anlotinib as first-line therapy for ES-SCLC, including in combination with platinum/etoposide (with or without durvalumab) or as part of a maintenance regimen following first-line chemotherapy. A Phase 3 trial is investigating anlotinib/carboplatin/etoposide plus a novel PD-L1 MAb, TQB2450, as first-line therapy.⁹⁰

Apatinib is another kinase inhibitor primarily targeting VEGFR-2 to normalize tumor angiogenesis, inhibit the growth of certain tumor types, and potentially enhance antitumor immune response.⁹² Phase 2 trials indicate a clinical benefit in patients with previously treated ES-SCLC.^91,92 In these trials, patients received apatinib 500 mg PO daily as monotherapy or 250 mg PO daily when administered with concurrent chemotherapy and as maintenance therapy. Apatinib monotherapy resulted in an ORR of up to 17% and disease control rate of up to 95%; for combination chemotherapy regimens, these values were 68% and 83%, respectively.^86,87 Other studies suggest that apatinib may be beneficial when combined with chemotherapy or as maintenance therapy.^93,94 In ES-SCLC clinical trials, the most common adverse events of apatinib were anemia, proteinuria, hypertension, increased aspartate aminotransferase, fatigue, and hand-foot syndrome; these are consistent with adverse event profiles of other VEGF inhibitors.

The Phase 2 PASSION trial evaluated apatinib in combination with the anti–PD-1 MAb camrelizumab as second-line therapy.⁹⁵ Daily therapy yielded a 34% ORR, but 72.9% of patients experienced Grade 3 or greater treatment-related adverse events. Ongoing trials are evaluating apatinib combined with cisplatin/etoposide/camrelizumab as first-line therapy for SCLC,⁹⁶ and in the second-line setting in combination with the anti-PD-1 MAb SHR-1210⁹⁷ or the poly (ADP-ribose) polymerase [PARP] inhibitor fluzoparib.⁹⁸ A Phase 3 trial is also evaluating apatinib/cisplatin/etoposide for ES-SCLC followed by apatinib maintenance therapy.⁹⁹

Other Novel Agents

In addition to ICIs and MAbs, many other novel agents are under investigation for treatment of advanced SCLC. Most data regarding these agents are still preliminary, and some drugs have not yet been evaluated specifically for ES-SCLC. Examples include¹⁰⁰

• agents targeting specific cytokines, such as interleukin-2 and interferon
• activators of apoptosis (e.g., navitoclax)
• inhibitors of cell cycle checkpoints (e.g., trilaciclib)
• PARP inhibitors to block DNA repair
• new tyrosine kinase inhibitors of angiogenesis
• epigenetic modulators targeting EZH2

Other immunotherapies in clinical trials for SCLC include

• adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy
• DLL3-targeted bispecific T-cell engagers (e.g., tarlatamab)
• antibody-drug conjugates (e.g., sacituzumab govitecan)
• tumor cell and dendritic vaccines

At present, results with most of these immunotherapeutics are limited to small, early-stage SCLC clinical trials.

PARP Inhibitors

PARP plays a key role in DNA repair, so PARP inhibition could be a novel therapeutic strategy for SCLC. While results with single-agent PARP inhibitors (e.g., olaparib, veliparib, talazoparib) have been mixed, trials of select PARP inhibitors combined with chemotherapy have produced clinical responses in ES-SCLC; however, none have yielded significant increases in survival.^{101,102,103,104} Additional studies are evaluating PARP inhibitors with radiotherapy or other novel therapeutic agents targeting the tumor microenvironment, angiogenesis, DNA damage response, and immune checkpoints (although combinations with durvalumab appear ineffective). Multiple Phase 1/2 trials of PARP inhibitors combined with chemotherapy, radiotherapy, or other ICIs in the first-line, second-line, and maintenance settings are ongoing.

Temozolomide

Temozolomide is a DNA alkylating agent that generates single- and double-strand DNA breaks, resulting in apoptosis.¹⁰⁵ Given its longstanding use for treatment of selected CNS cancers and its potential to act synergistically with PARP inhibitors, the combination of temozolomide and a PARP inhibitor was evaluated in advanced SCLC. A Phase 2 trial assessed temozolomide 200 mg/m²/day PO on days 1-5 plus placebo or veliparib 40 mg PO twice daily on days 1-7 of a 28-day cycle in patients with recurrent SCLC.¹⁰⁶ Results showed an increase in ORR (39% versus 14%), but 4-month median PFS (36% versus 27%) and median OS (8.2 months vs 7.0 months) were not significantly improved. Survival was significantly better in a subgroup of patients with SLFN11-positive tumors.

In another trial, the combination of temozolomide 75 mg/m² PO daily and olaparib 200 mg PO twice daily (both on days 1-7 of a 21-day cycle) resulted an ORR of 41.7%, mPFS of 4.2 months, and mOS of 8.5 months in patients with platinum-resistant SCLC.¹⁰⁷ Treatment-related adverse events were significant, however, including hematologic toxicity, fatigue, nausea, and vomiting.

In a small dose-escalation trial, the combination of temozolomide 20-30 mg PO once daily on days 1-21 and the PARP inhibitor senaparib 40-80 mg PO once daily on days 1-28 in 28-day cycles produced responses in 3 of 12 evaluable patients with ES-SCLC (ORR 25%).¹⁰⁸ This prompted initiation of a dose-expansion study.

CASE STUDY

GB is a 74-year-old male who presented in November 2020 with a persistent, worsening cough and scant hemoptysis. A chest x-ray revealed a left hilar mass, and a CT scan of the chest, abdomen, and pelvis showed a large left lung mass with several enlarged lymph nodes in the hilum and mediastinum. The abdominal CT scan also showed several likely liver metastases. He underwent a liver biopsy with fine needle aspiration under radiographic imaging, which confirmed a diagnosis of SCLC. CT scans also revealed several bone metastases, and an MRI indicated several very small, asymptomatic brain metastases.

GB had a significant past medical history of type II diabetes, hypertension, and coronary artery disease with a history of sudden cardiac arrest in 2016. He also has a history of atrial fibrillation, congestive heart failure, chronic obstructive pulmonary disease, and chronic pain from prior injuries. Socially, he had smoked cigarettes (1 pack per day) for 50 years before quitting about 5 years ago. A retired safety director, he served several years in the Army and suffered from post-traumatic stress disorder as a result.

His baseline medication list was extensive:

• Amlodipine 5 mg PO daily
• Calcium 600 mg plus vitamin D 500 units PO twice a day
• Clopidogrel 75 mg PO daily
• Dofetilide 500 mcg PO twice a day
• Ferrous sulfate 325 mg PO daily
• Lisinopril 20 mg PO daily
• Magnesium 400 mg PO daily
• Metformin 850 mg PO twice a day
• Morphine ER 30 mg PO twice a day
• Pantoprazole 40 mg PO daily
• Polyethylene glycol powder PO daily
• Rivaroxaban 20 mg PO daily
• Zolpidem 5 mg PO nightly

As needed (PRN) medications:

• Bisacodyl suppository rectally daily PRN constipation
• Guaifenesin-codeine 100-10 mg/5 mL PO every 4 hours PRN cough
• Lorazepam 0.5 mg PO daily PRN anxiety
• Ondansetron 8 mg every 8 hours PO PRN nausea
• Prochlorperazine 10 mg every 6 hours PRN nausea

Added later:

• Prednisone 80 mg PO daily then taper as directed for irAE treatment and for pneumonitis
• Atovaquone 750 mg/5mL PO 10 mL daily while on prednisone

In the medical oncology clinic, an oncologist informed GB and his wife that GB has ES-SCLC, which is unfortunately an incurable disease. They discussed treatment options and decided to initiate chemoimmunotherapy with

• carboplatin AUC 5 mg/mL/min on day 1, etoposide 100 mg/m² on days 1-3, and atezolizumab 1200 mg on day 1 IV every 3 weeks for 4 cycles
• maintenance atezolizumab 1200 mg IV every 3 weeks
• denosumab 120 mg subcutaneous injection every 4 weeks and oral calcium plus vitamin D tablets to prevent skeletal-related events due to his bone metastases

GB’s pharmacist educated him about increased bleeding risk with rivaroxaban and clopidogrel while receiving chemotherapy, as this regimen can potentially lead to thrombocytopenia. During his chemotherapy treatment, GB developed significant nausea. The pharmacist reviewed his medications and instructed him to use his PRN ondansetron as prescribed. The pharmacist also identified a significant drug interaction with dofetilide and prochlorperazine. This combination is contraindicated due to potential prochlorperazine-mediated inhibition of the renal secretion of dofetilide secretion, which can increase dofetilide concentration and effects. The pharmacist instructed GB to discontinue any use of prochlorperazine and removed it from his active medication list. Ondansetron improved GB’s nausea, and he was able to continue with chemoimmunotherapy.

After 4 cycles of chemotherapy plus ICI therapy, GB showed disease improvement at all cancer sites, but his brain metastases had progressed. GB continued with maintenance atezolizumab and was offered whole-brain radiation (WBXRT), which he received in April 2021 between atezolizumab treatments.

In June 2021, GB developed rapid disease progression, which occurred about 5 months after completing platinum-based chemotherapy. His performance status was still relatively good, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 1. He experienced some lingering fatigue from the WBXRT, but his labs were otherwise within normal limits and he generally felt well. At this time, GB’s oncologist initiated second-line treatment with lurbinectedin 3.2 mg/m² IV every 3 weeks. Although the Phase 2 trial of lurbinectedin did not include patients with brain metastases, GB’s provider chose this agent based on its ease of administration and better tolerability compared with topotecan.

GB began lurbinectedin treatment in June 2021 and tolerated it fairly well. The main adverse effects he experienced were fatigue, anemia, thrombocytopenia, and neutropenia requiring the use of G-CSF. After 3 cycles of lurbinectedin, GB experienced significant improvement in liver metastases and the disease in his chest was stable. He remained on treatment until September 2021, when he developed dyspnea. Imaging and labs revealed Grade 2 pneumonitis in the lungs and Grade 2 transaminitis, respectively.

Initially, GB’s provider held lurbinectedin therapy and treated him with prednisone 1 mg/kg/day. After a week of prednisone 80 mg PO daily, his pneumonitis symptoms improved and his liver function tests returned to Grade 1. Following discussion with the clinical pharmacist and the lurbinectedin manufacturer, however, it was determined that these symptoms were likely due to the recent ICI therapy, as these adverse effects had not been reported to date in lurbinectedin clinical trials or post-marketing data.

Given this insight, the patient received a full-course treatment of steroids that was tapered over 6 weeks for suspected ICI-induced pneumonitis and transaminitis. GB’s care team instructed him to continue taking pantoprazole to prevent steroid-induced gastritis, especially given his elevated risk caused by anticoagulation medication (rivaroxaban and clopidogrel). The team also instructed GB to continue calcium and vitamin D supplements to prevent osteoporosis. Additionally, GB’s oncologist prescribed atovaquone to prevent Pneumocystis jiroveci infection because he was receiving at least 20 mg of prednisone daily for more than 4 weeks. The pharmacist recommended atovaquone over sulfamethoxazole-trimethoprim due to a significant drug-interaction with dofetilide (trimethoprim inhibits the renal transporters responsible for eliminating dofetilide, which can increase dofetilide’s concentrations and effects).

Prednisone improved GB’s Grade 2 irAEs, allowing a restart of lurbinectedin, with no recurrence of pneumonitis or transaminitis. He remained on lurbinectedin until December 2021 until scans showed increasing disease progression. He clinically deteriorated and ultimately died in February 2022.

ROLE OF PHARMACISTS AND NURSES IN ENSURING OPTIMAL OUTCOMES

Toxicity Management

Effective monitoring and proactive management of treatment-related adverse events are essential for maintaining therapy in patients with ES-SCLC and optimizing outcomes. Poor adverse event management can result in significant and potentially serious or life-threatening toxicities, reduced adherence, decreased patient quality of life, or dose reductions/discontinuations that worsen outcomes. Because ICIs and targeted agents are often used in combination regimens with other anticancer drugs or modalities, toxicities may be further exacerbated.

ICI-associated irAEs have been well characterized in SCLC.¹⁰⁹ These can include gastrointestinal and dermatologic toxicities, pneumonitis/interstitial lung disease, hypo- or hyperthyroidism, hepatotoxicity, endocrine effects, cardiotoxicity, and nephropathy. IrAEs may be acute or chronic, with some not appearing until after therapy completion. A meta-analysis of ICI trials in lung cancer found that the incidence of any-grade irAEs was 13.8% (severe irAEs 9.2%), and these were more common with chemoimmunotherapy regimens compared to ICI monotherapy.¹¹⁰ Researchers noted differences in irAE profiles and organ specificity among agents, similar to trials evaluating ICIs in NSCLC.¹¹¹

Pharmacists and nurses should recognize ICI-related irAEs and other common treatment-related toxicities and be familiar with published guidelines regarding their prevention and management.^112,113 Health care providers should pay particular attention to those patients who may be at increased risk of irAEs and all black box warnings regarding potentially serious toxicities.

Pharmacists can also address questions regarding dosing, supportive care management (e.g., about nausea and vomiting), adherence concerns, and potential drug interactions that could affect absorption and bioavailability. Pharmacist-led medication therapy management programs can reduce drug-related problems in cancer patients, particularly in elderly individuals, and may improve patient satisfaction.^114,115,116

In contrast with ICIs and MAbs that are administered IV, some novel agents such as apatinib and PARP inhibitors are administered orally. Also, patients sometimes choose to take etoposide orally for days 2 and 3 of the 3-day etoposide regimen for convenience. In such cases, ensuring therapy adherence is vital for maintaining adequate drug levels and optimizing outcomes. Potential barriers to adherence include treatment-related adverse events, age, cognitive issues, comorbidities, financial or insurance issues, pill burden, and low health literacy.¹¹⁷ Pharmacists and nurses can educate patients on the importance of adherence, collaborate with the multidisciplinary oncology team to identify and address adherence issues, and suggest practical approaches for overcoming barriers (e.g., medication reminder smartphone apps and text messaging).

Financial Toxicity

Many approved novel targeted therapies and immunotherapies for SCLC, as well as G-CSF used for supportive care, are costly, presenting a treatment barrier to treatment known as “financial toxicity”. Pharmacists, pharmacy technicians, and nurses can work to minimize this challenge by aiding with drug access and prior authorizations, patient assistance programs, and manufacturer rebates. This reduces out-of-pocket drug costs, avoids treatment delays, and facilitates therapy. Interventions by these health care professionals can ensure access to oncology specialty medications, reduce costs, improve patient education, identify treatment issues, and help coordinate care between patients and providers.^118,119,120 Clinical pharmacists and nurses can also aid in the early identification and mitigation of treatment-related adverse events, which can reduce hospitalizations and health care costs and serve to improve outcomes. Collaboration between oncology pharmacists, pharmacy technicians, and nurses may thus lower patients’ cost of therapy and improve medication access.

Nursing Interventions

Oncology nurses are well positioned to proactively assess and manage symptoms in patients with advanced SCLC. Several studies indicate that high-quality oncology nursing interventions can positively impact care for patients with advanced lung cancer.^121,122 Evidence-based nursing for pain management was shown to improve sleep quality, enhance quality of life, and increase nursing satisfaction among such patients.¹²³ Additionally, these approaches may help reduce patient anxiety and depression.^124,125 Oncology nurses must be familiar with common treatment-related adverse events associated with SCLC therapies and current guidelines on their management, including dosing modifications specified in prescribing information.

It is important for oncology nurses to understand the aggressiveness of SCLC and to recognize the urgency for chemotherapy and its timely administration. This is especially important in the first-line setting where high response rates can significantly impact quality of life. Early detection and management of common toxicities such as nausea/vomiting, myelosuppression, and irAEs can help patients remain on treatment and receive effective doses.

Patient Education

Oncology pharmacists and nurses are pivotal in educating patients with SCLC about their disease and its treatment, especially regarding use of novel agents and immunotherapy. Discussion topics include, but are not limited to

• how these drugs work
• common and serious adverse effects
• the importance of monitoring and reporting of adverse effects
• potential psychological or emotional issues
• available patient assistance programs

Educating patients on common treatment-related adverse events, possible drug interactions, and the importance of early reporting can aid in mitigation and help reduce treatment interruptions or discontinuations. Education regarding irAEs with ICIs is especially crucial given their potential for serious sequelae such as interstitial lung disease and pneumonitis. Pharmacist-led patient education and interventions have proven effective for patients with lung cancer, helping to reduce the discontinuation rate due to treatment-related adverse events and to minimize drug-drug interactions.¹²⁶,¹²⁷ Studies suggest that better patient education can reduce some lung cancer symptoms (e.g., fatigue), decrease anxiety and depression, and improve lung function.^128,129,130 Moreover, through education and regular discussion, pharmacists and nurses can support patients who are at increased risk for drug interactions due to polypharmacy (i.e., older patients and those with comorbidities).

CONCLUSION

Progress in SCLC treatment has lagged for decades given its aggressive nature, relative lack of research compared with NSCLC, and stigmatization due to its association with smoking. Within the past few years, however, FDA has approved several drugs that provide clinical benefit for patients with advanced disease. These include ICIs and drugs with novel mechanisms of action, such as lurbinectedin. Other emerging angiogenesis inhibitors (apatinib and anlotinib) show encouraging activity in ES-SCLC when combined with platinum-based chemotherapy. Continued clinical trials will help to optimize these regimens and reduce treatment-related toxicities. The identification of reliable biomarkers for such therapies will further improve patient selection and personalized treatment for patients with advanced SCLC.

Update: February 20, 2023

Subsequent Therapy (PS 0-2)

Preferred Regimens

• Platinum-based doublet (Rechallenge with the original regimen or similar platinum-based regimen is recommended if there has been a disease-free interval of more than 6 months and may be considered if there has been a disease-free interval of at least 3 to 6 months.)
• Clinical trial

Other Recommended Regimens

• Topotecan (PO or IV)
• Lurbinectedin
• Cyclophosphamide/doxorubicin/vincristine
• Docetaxel
• Oral etoposide
• Gemcitabine
• Iriniotecan
• Nivolumab
• Paclitaxel
• Pembrolizumab
• Temozolomide
• Vinorelbine
• Bendamustine

Reference: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Small Cell Lung Cancer Version 3.20232 — December 21, 2022. Available at: https://www.nccn.org/. Accessed February 20, 2023.

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