Treating patients with platinum-sensitive extensive-stage small-cell lung cancer in a real-world setting

Extensive-stage small-cell lung cancer (ES-SCLC) is an aggressive disease with poor 5-year survival. The first-line standard-of-care for ES-SCLC is platinum plus etoposide, along with 1 of the immune checkpoint inhibitors atezolizumab or durvalumab. Although SCLC first-line therapy often leads to rapid responses, treatment becomes more challenging at progression, particularly for those with a chemotherapy-free interval (CTFI) of ≤6 months. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for SCLC no longer specify treatment recommendations in this setting, but options approved by the US Food and Drug Administration include topotecan and lurbinectedin. Participation in a clinical trial is recommended as an option regardless of CTFI. Other NCCN-recommended regimens are paclitaxel, irinotecan, temozolomide, and cyclophosphamide/doxorubicin/vincristine, among others. Nivolumab and pembrolizumab are options in those not previously treated with a checkpoint inhibitor. For patients with platinum-sensitive SCLC (CTFI >6 months), preferred treatment per the NCCN Guidelines® for SCLC is retreatment with platinum and etoposide, although the use of immune checkpoint inhibitors is discouraged if there is progression on a drug in this class. Further research on immunotherapies and combination regimens is ongoing, and continuing work on the subcharacterization of SCLC may lead to better precision of therapies that promote more durable responses in individual patients with ES-SCLC.


Introduction
Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor strongly associated with a significant smoking history and represents ~13% of all lung cancer cases (1).In the United States alone, an estimated 33,006 patients were diagnosed with SCLC in 2021, with a 5-year survival rate of only 7% (1).
Staging of SCLC is often categorized in clinical practice as limited stage (LS) or extensive stage (ES) (2); approximately 70% present with ES-SCLC (3).SCLC is aggressive regardless of the disease stage at diagnosis.While responses to initial therapy are common (2,3), aggressive and resistant disease at the time of progression results in median survival of 12-13 months for patients with ES-SCLC (3)(4)(5).
In this review, we describe our experiences in the diagnosis and treatment of SCLC, focusing on regimens within the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for SCLC we consider most useful in the second-line setting and beyond.

Diagnosis and staging of SCLC
SCLC diagnosis is generally made based on a hematoxylin and eosin stain and classic immunohistochemical stains (6,7).Dual inactivation of 2 tumor suppressors, p53 (TP53) and RB (RB1), is present in most cases (8,9).Although genomic testing is not typically part of the workup, molecular profiling is recommended for patients without a smoking history in ES-SCLC (7).The most prominent staging systems are the Veterans Administration (VA) and Tumor, Node, Metastasis (TNM) classification systems (7, 10).The National Comprehensive Cancer Network ® (NCCN ® ) describes TNM staging within a VA description, including a subcategorization within LS-SCLC (7).
The VA classification system is a 2-stage scheme that defines LS-SCLC as confined to the ipsilateral hemithorax and safely encompassed within a radiation field (7, 10).ES-SCLC is defined as disease present beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion, or hematogenous metastases (7, 10).The VA classification system is most commonly used for clinical decision making, although the TNM system may assist in further categorization of LS-SCLC, as highlighted by the NCCN Guidelines ® for SCLC (7,10,11).For example, the TNM system can be useful in selecting patients with T1-2, N0 disease who are eligible for surgery and radiation (7).
Full staging of SCLC includes a history and physical examination, computed tomography (CT) scan of the chest, abdomen, pelvis, and brain imaging with magnetic resonance imaging (MRI) or CT scan if MRI cannot be performed (7).Scanning with positron emission tomography (PET) is recommended in LS-SCLC (7).Lesions detected by PET/CT that would result in upstaging should be confirmed by pathologic examination if not considered definitive by imaging alone (7).

First-line treatment of patients with ES-SCLC Chemoimmunotherapy
According to the NCCN Guidelines for SCLC (V.3.2023), the preferred first-line regimen for patients with LS-SCLC is platinum plus etoposide with concurrent radiotherapy (7).For patients with ES-SCLC, the NCCN recommends platinum plus etoposide with either atezolizumab or durvalumab (7) for first-line therapy based on overall survival (OS) results from the IMpower133 and CASPIAN phase 3 trials, respectively (4,5).
Other immunotherapies have been tested for use as first-line treatment, including pembrolizumab and nivolumab (15,16), which were previously given accelerated approval by the US Food and Drug Administration (FDA) for the treatment of metastatic SCLC in later-line settings (17, 18).In the KEYNOTE-604 trial, first-line treatment with pembrolizumab plus platinum-etoposide was associated with significant prolongation of progression-free survival (PFS) versus placebo plus platinum-etoposide (12-month PFS estimate: 13.6% vs 3.1%; HR=0.75 [95% CI: 0.61-0.91];P=0.0023), but pembrolizumab just missed the significance boundary for OS (15).When considered along with the results of CheckMate 331, in which nivolumab in the second-line setting did not outperform chemotherapy (19), applications for full FDA approval were withdrawn (20,21).It is important to note, however, the potential benefit that still exists from single-agent nivolumab or pembrolizumab in the first-line setting, particularly in the durability of responses.

Supportive care for the management of chemotherapyinduced myelosuppression
Standard treatments for ES-SCLC often result in some degree of chemotherapy-induced myelosuppression (22).According to the NCCN Guidelines, granulocyte colony-stimulating factor (G-CSF) or trilaciclib may be used prophylactically to decrease the incidence of chemotherapy-induced myelosuppression when treating with particular regimens (7).G-CSF has demonstrated reduced neutropenia and febrile neutropenia compared with placebo when given with chemotherapy (cyclophosphamide, doxorubicin, and etoposide) for SCLC (23).Although the regimen in the study is no longer used, G-CSF is an accepted adjunct and utilized in patients considered to be at higher risk for complications of neutropenia.G-CSF has not demonstrated any impact on cancer treatment outcomes such as response rate or survival (24).
Pooled data from 3 randomized, double-blind, placebo-controlled trials (NCT02499770, NCT03041311, and NCT0251447) evaluating the effects of trilaciclib versus placebo when administered prior to chemotherapy found that trilaciclib was associated with significant decreases in most measures of myelosuppression and improvement in health-related quality of life (HRQoL) metrics (22,(25)(26)(27).These trials did not allow for primary prophylaxis with G-CSF.Many patients do not require prophylaxis, but we usually consider G-CSF for cases when concerned about neutropenia and consider trilaciclib only for patients at risk for prolonged anemia or thrombocytopenia.The HRQoL metrics noted to be improved with trilaciclib, such as anemia, highlight the potential for greater impact of chemotherapy-induced anemia than is often clinically appreciated.

Second-and later-line treatment of patients with platinum-sensitive SCLC
Platinum sensitivity or resistance is often defined differently among clinical trials, as shown in Table 1 (28,30,31,(33)(34)(35).FDAapprovals of topotecan and lurbinectedin are defined by the enrollment criteria of the respective trials (32,36).Although definitive cutoff times for chemotherapy-free interval (CTFI) exist, platinum sensitivity should be considered a continuum in clinical practice (28).
The likelihood of response to treatment in the second-line setting and beyond decreases, and prognosis worsens (8,37).However, a longer CTFI increases the likelihood of a clinically meaningful response to other cytotoxic agents (2).

NCCN-recommended subsequent systemic therapies
According to the NCCN Guidelines, rechallenge with the original regimen or similar platinum-based regimen (without immune checkpoint inhibitors [ICI] if previously given) is the preferred regimen in patients with a CTFI >6 months and may also be considered in patients with a CTFI 3-6 months (7).Retreatment with platinum-based therapy has been a longstanding standard of care, originating at a time of substantially fewer options.A more recent comparison to topotecan as secondline therapy in patients with at least a 3-month CTFI demonstrated an improvement in PFS with platinum-etoposide retreatment but no significant difference in OS (38).Inclusion of a clinical trial as recommended therapy highlights the ongoing need for improved options in this setting.Topotecan and lurbinectedin are the FDAapproved options after progression on first-line platinum-based therapy (30,31,36).Other regimens are described by NCCN (7); we consider the most relevant to be paclitaxel, irinotecan, and temozolomide.We consider nivolumab and pembrolizumab to be important options only for patients not previously treated with ICI as part of first-line treatment (7).Table 2 presents data on subsequent therapy options for ES-SCLC.

Topotecan
Topotecan was the first drug approved for second-line treatment of relapsed SCLC, in 1996 (30, 31).Intravenous topotecan was approved based on a second-line trial including patients with a CTFI ≥60 days (31).Outcomes with topotecan 1.5 mg/m 2 /day were not significantly different from CAV (cyclophosphamide 1000 mg/m 2 , doxorubicin 45 mg/m 2 , and vincristine 2 mg) for median PFS (13.3 vs 12.3 weeks) or OS (25.0 vs 24.7 weeks), but topotecan was associated with significantly better symptomatic improvement (33).
Oral topotecan was approved for second-line SCLC after a CTFI ≥45 days (30) after a trial randomized patients who were not candidates for further intravenous chemotherapy to oral topotecan 2.3 mg/m 2 /day or best supportive care.A significantly longer median OS was noted with topotecan (25.9 vs 13.9 weeks; adjusted HR=0.61 [95% CI: 0.43-0.87]);measures of symptomatic improvement and HRQoL also favored topotecan (34).

Lurbinectedin
Lurbinectedin is the first drug to be approved for SCLC in the second-line setting since topotecan (32).Lurbinectedin  (32,36).Treatment was associated with a manageable safety profile, with grade 3-4 events most commonly cytopenias (32).Although neutropenia was common, neutropenic fever was noted in 5% of patients, and primary G-CSF prophylaxis was not allowed in the trial.In clinical practice, primary G-CSF prophylaxis may be considered, particularly for patients at higher risk for prolonged neutropenia or infection.Among patients with a CTFI ≥6 months, Subbiah and colleagues reported on the 20-patient subset from the lurbinectedin monotherapy (3.2 mg/m 2 ) basket trial (39).The subset achieved an ORR of 60.0% (95% CI: 36.1-86.9)and median OS of 16.2 months (95% CI: 9.6 to upper limit not reached) (39).Combined with the acceptable safety profile, the data suggest lurbinectedin is a favorable option in this setting (39).A phase 3 confirmatory trial (NCT05153239) in patients with relapsed second-line SCLC was initiated in 2021 (57, 58).
ATLANTIS, a randomized trial comparing combination lurbinectedin (2.0 mg/m 2 ) and doxorubicin versus physician's choice of topotecan or CAV following progression on one platinum-containing line did not meet its primary endpoint of significance for OS (59,60).Nonetheless, the ATLANTIS trial showed a superior safety and tolerability profile for lurbinectedindoxorubicin compared to the control arm, with significantly lower rates of hematologic toxicities (59,60).It should be noted that the approved dose of lurbinectedin monotherapy is 3.2 mg/m 2 , as opposed to the lower dose used in combination therapy in the ATLANTIS trial.The confirmatory phase 3 study noted above includes a 3-arm design that will compare lurbinectedin as either monotherapy or in combination with irinotecan versus investigator's choice of irinotecan or topotecan.

Other NCCN-recommended options
Irinotecan and paclitaxel are common treatment options for SCLC despite lacking FDA approval.Data specific to SCLC efficacy for each are limited, but the side effect profile is well described as cornerstone treatments for other common cancer diagnoses (61)(62)(63).Irinotecan has shown responses with weekly dosing and is generally well tolerated, with diarrhea being a notable toxicity (43).We generally start with dosing 100 mg/m 2 on Days 1 and 8 of a 21-day cycle.Paclitaxel can be dosed every 3 weeks or weekly and has similarly shown responses (40).We prefer weekly dosing (6 weekly doses of an 8-week cycle) due to the toxicity profile.Temozolomide is another option included in the NCCN Guidelines that is worth noting due to excellent central nervous system (CNS) penetration, highlighted by its standard use for brain tumors such as glioblastoma (64).Brain metastases are common complications in SCLC and can be challenging to treat at recurrence after prior whole brain radiation.This setting, in particular, is one for consideration of temozolomide as a treatment.
After ≥2 prior lines of therapy, pembrolizumab as a single agent showed a median PFS of only 2.0 months but an ORR of 19%, with a durability beyond 18 months in >60% of responders (55).The durability of responses to single-agent pembrolizumab and nivolumab along with their tolerable side effect profiles (51,52,55) is why both immunotherapy agents are present in the NCCN recommendations for second-line treatment and beyond, but these are only options for patients not previously treated with an ICI (7).
Practical considerations for the secondline treatment of platinum-sensitive SCLC following chemoimmunotherapy Data on second-line and beyond treatments for patients with prior exposure to immunotherapy are limited; thus, second-line treatment options are not restricted based on prior immunotherapy.Individuals with progression on first-line chemoimmunotherapy are not candidates for subsequent immunotherapy treatment.For patients not treated with an ICI in the first-line setting, the role for single-agent ICI is debated but we feel should be considered in certain patients.This situation arises almost exclusively in patients who were treated for LS-SCLC.
If the time to recurrence is prolonged, combination platinumetoposide and an ICI can be considered, but for patients with a shorter duration to recurrence or a contraindication to platinumetoposide, we might consider treatment with an ICI alone based on the impressive durability noted when there is a response.A pooled analysis of 2 single-arm trials of pembrolizumab demonstrated an ORR of 19%, with more than half of responders experiencing ongoing disease control beyond 2 years (55).Similarly, nivolumab demonstrated a median duration of response of ~18 months (65).Ipilimumab in combination with nivolumab in the second-line setting did not demonstrate advantages over nivolumab alone and increased toxicity was noted, leading to removal of ipilimumab from the NCCN Guidelines (52).

Case report
A 73-year-old woman with a 25 pack/year history of smoking was diagnosed with metastatic SCLC from a liver biopsy with radiographic findings, including a right-lung lower-lobe nodule, extensive bilateral hilar and mediastinal adenopathy, and liver metastases.Brain MRI was negative for metastasis.She received 4 cycles of carboplatin-etoposide and atezolizumab with good treatment response and, in shared discussion with radiation oncology, elected for MRI brain monitoring every 3 months without prophylactic cranial irradiation.Maintenance atezolizumab continued for an additional 7 cycles before progression was noted with multiple brain metastases and progressive liver lesions.She received whole brain radiation therapy (WBRT) followed by second-line treatment with single-agent lurbinectedin.Although platinum-based doublet is preferred by the NCCN in the setting of CTFI >6 months (rechallenge may also be considered for patients with CTFI 3-6 months), this patient chose lurbinectedin for the easier side effect profile and once every 3 weeks schedule.We do not regularly retreat with carboplatin-etoposide due to the diminishing durability of response with future therapy lines unless it was initially very well tolerated with a particularly prolonged CTFI.The patient did well on lurbinectedin, with shrinking liver metastases before progression at 6 months,which included growing liver metastases and new bone metastases.
In this setting, we usually choose irinotecan rather than topotecan due to the side effect profile and treatment schedule.Paclitaxel is also a favorable option.If the patient had not previously received ICI, we would consider nivolumab or pembrolizumab to be important considerations and generally try to initiate ICI in the setting of low tumor burden, if possible.Due to the limited responses to nivolumab and pembrolizumab as single agents, an opportunity for other treatment options may be lost in those with large tumor burden and/or symptoms, but duration of response and drug toxicity for ICI is favorable enough that these should be considered if no prior ICI has been received.
If brain metastases were noted as the site of progression after prior WBRT, temozolomide would have been our preference due to excellent CNS penetration.Topotecan is another option with CNS penetration in patients not previously treated with a topoisomerase I inhibitor.
Additionally, we prioritize clinical trial enrollment for most patients and recommend referral to a center with trials for patients being treated in a setting without local trial options.
Unmet need and future therapies in the treatment of SCLC Although therapeutic options are still limited for patients with ES-SCLC, preclinical and clinical studies are ongoing.Studies are being conducted on various immunotherapies that attempt to stimulate a stronger immune response and on antibody-drug conjugates deliver cytotoxic drugs with greater precision (66).Tarlatamab is a bispecific T-cell engager molecule that targets delta-like ligand 3 (DLL-3), as well as CD3 on T cells (66, 67).DLL-3 is selectively expressed on SCLC tumors, with little to no expression in healthy lung cells (66, 67).In preclinical studies, tarlatamab has shown good potency and specificity, promoting SCLC lysis even in cell lines with low DLL-3 expression (68).A phase 1 study (NCT03319940) investigating tarlatamab plus pembrolizumab in patients with relapsed/refractory SCLC is ongoing (67,69), as is a monotherapy dose-ranging trial in relapsed/refractory SCLC (NCT05060016) (70).HPN328 is an anti-DLL-3 T-cell engager that directs T cells to DLL-3-expressing SCLC cells and initiates tumor cell lysis (71).A phase 1/2 study (NCT04471727) to assess the safety and pharmacokinetics of HPN328 in patients with advanced cancers that have failed standard therapy is currently open and recruiting (72).
Poly(ADP-ribose) polymerase inhibitors may have a role in the treatment of SCLC.A randomized, double-blind study of veliparib and temozolomide versus temozolomide plus placebo in relapsed/ refractory SCLC showed no improvement in the primary endpoint, 4-month PFS (36% vs 27%; P=0.19), but the ORR was higher (39% vs 14%; P=0.016) (73).SLFN11 expression correlated with a significantly longer PFS and OS for the combination of veliparib and temozolomide, highlighting the potential as a biomarker pending further study (73).SLFN11 immunohistochemistry is being used to select patients for a phase 2 trial (NCT04334941) of atezolizumab plus talazoparib versus atezolizumab alone as maintenance therapy for ES-SCLC (74,75).
Multiple other studies are ongoing for second-line and beyond SCLC (76,77).Many challenges remain, but novel discoveries and improved diagnostics (including proposed subtypes) may lead to better selection for novel therapies, which could improve responses (78-82).

Conclusions
ES-SCLC is an aggressive disease with poor 5-year survival.SCLC generally responds to first-line treatment with platinum-etoposide along with atezolizumab or durvalumab, but treatment in the secondline setting and beyond is more challenging.Topotecan was the only approved second-line treatment for 40 years, and lurbinectedin monotherapy was granted accelerated FDA approval in 2020 for the treatment of disease progression on or after platinum-based chemotherapy.The NCCN Guidelines for SCLC include various subsequent treatment options after progression on first-line treatment.We consider the most relevant to be the FDA-approved options, including topotecan and lurbinectedin, as well as paclitaxel, irinotecan, and temozolomide.Nivolumab or pembrolizumab are important considerations in patients not previously treated with ICI.Further understanding of SCLC subtypes has the potential to improve treatment selection, and enrollment in clinical trials continues to be an important treatment option for patients with SCLC.

TABLE 1
Definitions of Platinum-sensitive and Platinum-resistant Disease in Relapsed SCLC.* *Based on time until progression after last platinum dose.