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Small-cell lung cancer (SCLC) is an aggressive disease with distinct pathological, clinical, and molecular characteristics from non–small-cell lung cancer. SCLC has high metastatic potential, resulting in a clinically poor prognosis. Early concurrent chemo-radiation is the standard of care for limited-stage SCLC (LS-SCLC). Prophylactic cranial irradiation (PCI) is recommended for patients with LS-SCLC without progression of disease after initial therapy. A combination of etoposide and cisplatin or carboplatin remains the mainstay of first-line treatment for ES-SCLC, with the addition of atezolizumab, now becoming standard. Most SCLCs initially respond to therapy but almost invariably recur. Topotecan and amrubicin (in Japan) remain the primary chemotherapy options for relapsed SCLC. Immunotherapy, including nivolumab with or without ipilimumab, is now available for refractory disease. In general, the poor prognosis of SCLC has not improved significantly for more than 3 decades. Recently, next-generation molecular profiling studies have identified new therapeutic targets for SCLC. A variety of proapoptotic agents, compounds capitalizing on DNA-repair defects, immunotherapy agents, and antibody–drug conjugates are being evaluated in SCLC, with a number of them showing early promise.
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Learning Objectives: On completion of this article, you should be able to (1) recognize the clinical features, diagnostic tests, and clinical staging of small cell lung cancer (SCLC), (2) implement the current standard of care treatment in SCLC, and (3) familiarize with the novel agents under investigation for the therapy of SCLC.
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Small-cell lung cancer (SCLC) accounts for approximately 15% of all newly diagnosed lung cancers and is most commonly diagnosed in patients with histories of heavy smoking. In general, SCLC grows rapidly and is highly metastatic. These 2 properties contribute to a high mortality rate.
Despite a typically dramatic initial response to therapy, patients with extensive-stage SCLC (ES-SCLC) inevitably develop resistance, with a median survival of 10 to 12 months from diagnosis. The most important advances in the treatment of SCLC in decades have been attributed to the application of radiotherapy.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.
Chest irradiation (CRT) and prophylactic cranial irradiation (PCI) have both been shown to increase survival. In limited-stage disease (LS-SCLC), early concurrent CRT and chemotherapy remains the gold standard. In ES-SCLC, several promising treatment strategies have failed over the past 30 years.
Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.
Numerous therapeutic opportunities have emerged from our new understanding of the biology of SCLC, including targeted therapies and immunotherapies.
This review addresses the current status of diagnosis and treatment of SCLC, focusing on the scientific advances that have had impact on the management of SCLC. Furthermore, we review new targeted therapies, immunotherapy, and other pharmacologic agents that have shown initial promise and are currently being studied in clinical trials.
Methods
A systematic analysis of the English-language literature was conducted by performing a search in PubMed, using the terms small-cell lung cancer, SCLC combined with therapeutics, staging, epidemiology, and management. Articles published between January 1, 1990, and November 31, 2018, were reviewed. Abstracts published from the annual meetings of the American Society of Clinical Oncology, European Society of Medical Oncology, American Association for Cancer Research, and AACR-EORTC-NCI Conference on Molecular Targets and Cancer Therapeutics between January 1, 2000, and July 31, 2018, were also considered for this review. The reference lists of the articles identified were also searched for other relevant articles. The ClinicalTrials.gov website was interrogated in July 2018, using the terms small-cell lung cancer and SCLC, and relevant ongoing and/or recruiting trials have been included in the text and tables.
Epidemiology and Risk Factors
SCLC accounts for approximately 15% of all new lung cancers, with an annual incidence of over 200,000 cases worldwide.
More than 90% of patients with SCLC are elderly and have heavy smoking histories. The risk of SCLC rises with the duration and intensity of tobacco use.
The 5-year survival rate for patients with SCLC remains dismally low at 10%. Predictors of poor prognosis include male gender, poor performance status (PS), and age (70 years or older).
Because of the aggressive nature of disease, screening by radiologic imaging is unlikely to reduce mortality. Cessation and prevention of smoking are the primary and most important interventions to further decrease mortality.
Characteristics and outcomes of small cell lung cancer patients diagnosed during two lung cancer computed tomographic screening programs in heavy smokers.
SCLC originates from neuroendocrine-cell precursors and is characterized by rapid growth and early metastasis. The disease typically presents as bulky symptomatic masses, and mediastinal involvement is common. Extrathoracic spread is present in 75% to 80% of patients at initial diagnosis.
The onset of symptoms is rapid, with usual duration from onset of symptoms to diagnosis of 8 to 12 weeks. The most common symptoms are cough; wheezing; dyspnea; hemoptysis; symptoms arising from intrathoracic spread to the chest wall, superior vena cava, or esophagus; weight loss; debility; recurrent nerve paralysis; pain; fatigue; anorexia; and neurologic defects caused by distant spread and paraneoplastic syndromes.
Brain, liver, adrenal glands, bone, and bone marrow are the most common sites of metastasis. Approximately 20% of patients have brain metastases at diagnosis, with approximately half of them being symptomatic and the others detected incidentally.
Neurologic syndromes include Lambert-Eaton syndrome, encephalomyelitis, and sensory neuropathy. The most frequent endocrinologic paraneoplastic syndromes are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
and Cushing syndrome. These syndromes result from the production of polypeptide hormones, such as antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH),
by the malignant cells. SIADH occurs more frequently than Cushing syndrome. Treatment of SIADH includes fluid restriction, demeclocycline, or vasopressin receptor inhibitors. ADH levels and hyponatremia usually improve after successful treatment for SCLC. Rarer manifestations are hyperglycemia, dermatomyositis, hypercalcemia, hypoglycemia, and gynecomastia.
Molecular Aberrations
SCLC is almost universally induced by smoking and exhibits a high frequency of aberrations in both oncogenes and tumor suppressors.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.
The founding transformational processes for SCLC are alterations in retinoblastoma 1 (RB1) and tumor protein p53 (TP53) genes. In 2 studies that used focused gene panels to identify molecular aberrations in SCLC, the most commonly identified alterations were in PIK3CA (5% mutations and 10% amplifications) and MET (4.4% mutations).
A more comprehensive analysis of 236 cancer genes in 98 patients using next-generation sequencing demonstrated that all patients had at least 1 genomic alteration, and an average of 3.9 alterations were seen per tumor.
Although a number of these alterations are not targetable based on currently available technologies, it is hoped that further sequencing and validation efforts will yield actionable aberrations that will improve survival of SCLC. In addition to the aberrations described above, other reported gene alterations are described in Table 1.
Table 1Molecular Aberrations of Small-Cell Lung Cancer
Gene
Molecular aberration
Incidence
TP53
Inactivating mutations, translocations, homozygous deletions, hemizygous losses, copy-neutral losses of heterozygosity (LOH) and LOH at higher ploidy
78.7% to 98%
RB1
Inactivating mutations, translocations, homozygous deletions, hemizygous losses, copy-neutral losses of heterozygosity (LOH) and LOH at higher ploidy
44.7% to 91%
PIK3CA
Activating point mutation exon 9 and 20, amplification
SCLC is defined histologically as “a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.”
Typical SCLC involves only small cells and accounts for approximately 90% of cases. The remaining cases are classified as combined disease, in which the tumor also contains large cell components.
Pathological Diagnosis
Pathological diagnosis should be made according to the World Health Organization (WHO) classification using morphology (uniform round to spindled-shaped small cells, sparse cytoplasm, high mitotic index, necrotic areas). Immunohistochemistry to identify markers—such as synaptophysin, chromogranin A, CD56, thyroid transcription factor 1, and MIB-1—are often helpful in confirming diagnosis. High Ki-67 helps in differentiating small-cell carcinoma from carcinoid tumors. Based on the site of tumor in the chest, biopsies may be obtained by bronchoscopy, mediastinoscopy, endobronchial ultrasound (EBUS), transthoracic needle aspiration, or even thoracoscopy, if necessary. In extensive-stage disease, biopsy from a metastatic lesion—such as liver, lymph nodes, and subcutaneous nodules—is the preferred approach, as this will pathologically stage the patient at the same time.
An initial computed tomography (CT) scan with contrast material of the chest and abdomen is recommended. All patients should have brain imaging. Unless contraindicated, in which case a contrast-enhanced CT scan is acceptable, a magnetic resonance imaging (MRI) scan is preferred. A bone marrow biopsy may be indicated in case of abnormal blood count or signs of bone marrow invasion (eg, peripheral blood erythroblasts). A 2-fluor-2-deoxy-D-glucose positron emission tomography (FDG-PET) CT scan has become a preferred imaging modality of choice, as it can assess the bones, as well.
The Veterans' Administration (VA) lung group classification scheme is used routinely in the clinic to stage SCLC. Limited-stage small-cell lung cancer (LS-SCLC) is defined as tumor confined to 1 hemithorax, with or without regional lymph-node involvement, which can be safely encompassed in a tolerable radiation field. Extensive-stage small-cell lung cancer (ES-SCLC) is defined as disease that cannot be safely encompassed in a tolerable radiation field. Two thirds of patients have extensive disease at initial diagnosis. Although the tumor node metastasis (TNM) staging is available for SCLC, most clinical trials and treatment decisions are based on the VA staging scheme (Table 2).
The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
Primary tumor (T) (Size depends on largest dimension)
T1
Primary tumor no more than 3 cm
T2
More than 3 cm but no more than 5 cm or invading the visceral pleura or main bronchus T2a: More than 3 cm but no more than 4 cm T2b: More than 4 cm but no more than 5 cm
T3
More than 5 cm but no more than 7 cm or those directly involving the chest wall, parietal pleura, phrenic nerve, or pericardium or a separate tumor nodule(s) in the same lobe
T4
More than 7 cm or any tumors involving the diaphragm, heart, great vessels, recurrent laryngeal nerve, vertebral body, esophagus, carina or separate tumor nodules in a different ipsilateral lobe
Regional lymph nodes (N)
N0
No regional lymph-node metastasis
N1
Ipsilateral peribronchial and/or hilar and intrapulmonary nodes including involvement by direct extension lymph-node metastasis
The management of SCLC is complicated by aggressiveness, frequent substantial comorbidities caused by smoking, and impaired performance status, which make it challenging to enroll patients with SCLC to appropriate clinical trials. The standard management algorithm of SCLC is outlined in Figure 1.
LS-SCLC is typically treated with a combined modality therapy of radiation therapy and chemotherapy. The recommended systemic chemotherapy is the combination of etoposide and cisplatin, administered concomitantly with thoracic irradiation. There may also be a role for surgery in the management of patients with very early-stage SCLC, generally without nodal involvement.
Surgical Resection
Emerging data have suggested that surgical resection may play a role in multimodal therapy of early-stage SCLC. A retrospective analysis of 82 patients reported a 5-year survival rate of 68% with surgical resection followed by adjuvant platinum based chemotherapy.
A retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database also demonstrated improved survival in localized as well as regional disease following surgical resection.
Another retrospective analysis of 277 patients with LS-SCLC also showed that surgical resection was associated with significantly improved 5-year survival compared with nonsurgical treatments (62% vs 25%; P=.01) in patients with stage I disease.
A propensity score-matched pair analysis of patients with stage II or III disease showed improved 5-year survival with surgical resection (P=.04). Retrospective reports suggested that surgery led to good local control and favored the long-term survival in highly selected patients with stage I to stage III SCLC.
recommend only patients with clinical stage I disease (T1-T2 N0) to be considered for surgery. Comprehensive staging with CT or PET-CT imaging, brain MRI, and mediastinal lymph-node evaluation is recommended before surgery. Adjuvant chemotherapy followed by PCI is recommended in patients who undergo surgery.
Chemoradiation Therapy
The combination of radiotherapy and cisplatin-based chemotherapy is the standard of care for LS-SCLC. In a meta-analysis of 2140 patients by Pignon et al, chemoradiation was associated with an improved 3-year OS vs chemotherapy alone (14.3% vs 8.9%).
Another meta-analysis of 11 randomized trials reported that chemoradiation led to better 2-year intrathoracic tumor control rate compared with chemotherapy alone (34.1% vs 16.5%) and that radiation therapy improved 2-year survival by 5.4% (95% confidence interval [CI], 1.1% to 9.7%).
Ideally, radiation should begin concurrently or within 30 days of starting chemotherapy. A meta-analysis carried by Fried et al reported improved 2-year OS with early radiotherapy (within 9 weeks of chemotherapy) vs late radiotherapy.
Another study demonstrated improved 5-year survival when thoracic radiation was initiated within 30 days of starting platinum-based chemotherapy than after 30 days (hazard ratio [HR] 0.57; 95% CI, 0.38-0.85; P=.005).
Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials.
Survival advantage was more pronounced if total treatment duration of radiotherapy was shorter than 30 days. Dosage and fractionation of radiation have also been extensively studied. In a pivotal phase 3 study,
45 Gy of total radiation administered in 1.5-Gy twice-daily fractions over 3 weeks was associated with improved 5-year OS vs 1.8-Gy once-daily fractions over 5 weeks (26% vs 16%, P=.04), suggesting that a twice-a-day radiation schedule for a shorter duration may be a more effective approach. Therefore, current recommendations include early administration of 45 Gy with concurrent 4 to 6 cycles of cisplatin and etoposide. For patients unable to tolerate concurrent chemoradiation—and occasionally for patients with extensively bulky disease—induction chemotherapy can be administered before radiation. Furthermore, the radiotherapy schedule is still a matter of debate. The randomized CONVERT trial failed to establish the superiority of a once-daily regimen to a twice-daily fractionation regimen.
Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
This trial randomized patients to receive 30 twice-a-day 1.5-Gy fractions for 19 days or 33 once-daily 2.0-Gy fractions for 45 days, starting with second cycle of cisplatin–etoposide chemotherapy. At median follow-up of 45 months, OS was 30 months in the twice-daily radiation group vs 25 months in the once-daily group (HR 1.18; 95% CI, .95-1.45; P=.14). Based on these data, twice-daily radiation can still be considered as standard of care and should be used when logistically possible. PCI is currently recommended for those achieving a good response to initial therapy. The risk of developing cranial metastasis can be more than halved with use of PCI.
A meta-analysis of 7 randomized trials studying PCI showed a 25% decrease in 3-year incidence of brain metastasis, from 58.6% in the control group to 33.3% in the treatment group (P<.001). It also showed a 3-year OS advantage of 5.4%, from 15.3% in the control arm to 20.7% in PCI arm (P=.01).
Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission: Prophylactic Cranial Irradiation Overview Collaborative Group.
In conclusion, concurrent chemotherapy with cisplatin and etoposide and thoracic radiation is the standard of care for all patients as initial therapy. For patients with extensive or bulky intrathoracic disease, neoadjuvant chemotherapy may be considered to reduce radiation field before starting chemoradiation. Surgery and adjuvant chemotherapy may only benefit selected patients with early-stage node-negative disease. PCI has been shown to decrease the incidence of brain metastases and improve OS in patients who respond to initial treatment. There is, at present, no evidence to support maintenance treatment in patients with LS-SCLC after completion of chemoradiation. A single-arm phase 2 trial from Asia is currently enrolling patients to receive maintenance durvalumab following chemoimmunoradiation (NCT03585998).
Extensive-Stage Small-Cell Lung Cancer
Sixty percent to 70% of patients with SCLC have extensive-stage disease at the time of diagnosis. Combination chemotherapy with a platinum agent and etoposide is the standard of care in ES-SCLC. With chemotherapy, objective response rates range from 40% to 70%, with up to 10% having complete radiographic response, and the median OS is ranging from 7 to 12 months, with a 2-year survival <5% and a 5-year survival rate of <2%.
Unfortunately, responses are often short lived, and SCLC universally becomes resistant to subsequent chemotherapy. Although multiple studies have been conducted to evaluate alternative first-line chemotherapy regimens, most of them have failed to advance the standard of care.
Initially, a Japanese phase 3 study with a limited patient size (n=154) reported encouraging results comparing etoposide and cisplatin with cisplatin and irinotecan.
Objective response rate (ORR) and OS were significantly higher in the irinotecan group at the initial interim analysis, prompting termination of further accrual. Thereafter, a separate phase 3 trial by the Southwest Oncology Group (SWOG 0124) was conducted using a similar design to Japan Clinical Oncology Group (JCOG) 951i,
Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124.
with similar eligibility criteria and treatment parameters. This study enrolled 651 patients. Median OS for irinotecan and etoposide arms were 9.9 and 9.1 months (P=.71), respectively. There was no significant survival advantage of using irinotecan over etoposide. Irinotecan was associated with higher incidence of severe diarrhea (19% vs 3%), whereas severe thrombocytopenia and neutropenia were more common with etoposide (68% vs 33% and 15% vs 4%, respectively). Thus, based on the results of this trial, a platinum-based doublet with etoposide remains the chemotherapy regimen of choice for patients with extensive-stage disease, at least for non-Japanese (or, more accurately, North American) populations. Carboplatin is a reasonable substitute for cisplatin in ES-SCLS, based on a randomized phase 3 trial comparing the 2 drugs in combination with etoposide. No significant difference was seen in OS (12.5 months in cisplatin arm and 11.8 months in carboplatin arm) and in response rates (50% for cisplatin arm and 64% for carboplatin arm). Patients enrolled to the carboplatin–etoposide arm also had better toxicity profiles.
Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer: a Hellenic Co-operative Oncology Group study.
A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500).
Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20.
A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621.
A recently published, large randomized phase 3 trial of carboplatin and etoposide with and without the PD-L1 immune checkpoint inhibitor atezolizumab showed an OS advantage for the immunotherapy arm.
IMpower 133 was a double-blinded, placebo-controlled trial of 403 patients with ES-SCLC, randomized 1:1 to receive carboplatin and etoposide for 4 cycles with atezolizumab or placebo followed by atezolizumab or placebo maintenance. The atezolizumab group had an improved median OS at 12.3 months vs 10.3 months in the placebo group (HR 0.70; 95% CI, 0.54 to 0.91; P=.007). Based on these findings, chemoimmunotherapy with carboplatin, etoposide, and atezolizumab is likely to become the new standard of care in treatment of ES-SCLC.
Radiotherapy (Prophylactic Cranial Irradiation and Thoracic Radiotherapy)
carried out a randomized study led by the European Organization for the Research and Treatment of Cancer (EORTC), in which patients with ES-SCLC who had had response to systemic chemotherapy underwent either 5 to 12 fractions of 20 to 30 Gy PCI or no further therapy. Patients randomized to the PCI group were at lower risk of symptomatic brain metastases (HR 0.27; 95% CI, 0.16-0.44, P<.001) (primary end point). There was also an improvement in the secondary end point of OS with PCI compared with observation (6.7 months vs 5.4 months, HR 0.68; 95% CI, 0.52-0.88, P=.0003). Disease-free survival (DFS) at 6 months with PCI or observation alone was 23.4% vs 15.5%, respectively. This trial established PCI as a standard of care for patients with ES-SCLC responsive to first-line platinum-based chemotherapy. In another randomized phase 3 trial, 163 patients with ES-SCLC who responded to platinum-based chemotherapy and had no brain metastasis on MRI were randomized to receive prophylactic cranial irradiation (25 Gy in 10 fractions) or observation. The study was stopped early for futility because it failed to demonstrate a benefit in OS for the PCI arm. Median OS was even worse at 10.1 months with PCI vs 15.1 months with observation alone (HR 1.38; 95% CI, 0.95-2.02), although this difference was not statistically significant. PCI significantly reduced the risk of development of brain metastases compared with observation alone (32.4% vs 38% at 12 months, P<.001). This study challenged the standard use of PCI in the treatment of ES-SCLC after induction responsive chemotherapy. This trial mandated radiologic screening for brain metastases at baseline, whereas the EORTC required symptomatic screening only, with the result of key differences in the study populations that have to be taken into account when interpreting these results. The benefit from PCI also comes at a cost of side effects, especially neurocognitive defects. Delayed neurologic effects and quality-of-life defects caused by PCI are observed in patients, with risk higher for patients older than 60 years of age or with poor performance status.
Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).
Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups.
These risks need to be strongly considered when evaluating a patient for PCI, and a detailed discussion with the patient is warranted. Memantine, an N-methyl-D-aspartate (NMDA) receptor agonist may help in reducing neurocognitive decline due to PCI, based on a randomized clinical trial, but this was not statistically significant.
Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.
Although PCI is standard treatment post-chemotherapy in LS-SCLC, it is currently not considered standard of care for ES-SCLC. In these patients, it should be reserved for select cases, such as those who are unable to undergo regular MRI scans, and only after discussions with patients about the risk-to-benefit ratio.
Consolidation thoracic radiotherapy (TRT) has been evaluated in a randomized phase 3 European study, in which patients with ES-SCLC were randomized to receive either consolidative TRT or no TRT
; 495 patients with ES-SCLC who had any response after 4 to 6 cycles of platinum–etoposide chemotherapy were randomized to receive 30 Gy of TRT in 10 fractions or no TRT within 6 weeks of completion of chemotherapy. Although the primary end point, OS at 1 year, did not show a statistically significant difference between 2 groups, OS at 2 years reached 13% (95% CI, 9-19) in the TRT group vs 3% (95% CI, 2-8; P=.004) in the no-TRT group. Similarly, PFS was better in the TRT group compared with the no-TRT group (24% vs 7%, P=.001). Furthermore, local control was improved, with significantly lower rates of intrathoracic progression (43.7% of group with TRT vs 79.8% of group with no TRT, P<.001). Similarly, intrathoracic progression as the first site of relapse (41.7 vs 77.8%, P< .001), and as the only site of relapse (19.8% vs 46.0%, P<.001), favored the TRT group. Despite the encouraging results of this study, the clinical relevance of the findings have been called into question given that it failed to meet its primary end point, and significant findings were observed only in the fraction of patients who survived beyond 2 years.
Topotecan as a single agent is the only regimen that has been proved to prolong survival of patients with relapsed SCLC compared with best supportive care (BSC).
However, topotecan is not effective in patients with SCLC who have relapsed within 3 months after the end of the previous platinum doublet chemotherapy. The ORR of topotecan for patients with refractory-relapsed SCLC is only approximately 5%.
Although various chemotherapeutic regimens have been evaluated either alone or in combination, and some have shown promising antitumor activity, no standard chemotherapy has been established as second-line treatment of SCLC until recently.
In a randomized trial comparing topotecan with cyclophosphamide, doxorubicin, and vincristine (CAV) for patients with recurrent SCLC, topotecan led to greater control of symptoms than CAV and had a better toxicity profile.
Single-agent chemotherapy compared with combination chemotherapy as second-line treatment in extensive-stage small cell lung cancer: a retrospective analysis.
Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker.
MA09.05 nivolumab alone or with ipilimumab in recurrent small cell lung cancer (SCLC): 2-year survival and updated analyses from the Checkmate 032 trial.
copy-number alterations analysis, and transcriptomic studies have provided insight into the biology of SCLC and identified potential therapeutic targets. More than 200 ongoing and recruiting clinical trials (Table 3) are currently evaluating new drugs for the systemic therapy of SCLC, most of which can be classified, for the purpose of this review, as drugs targeting recurrent genomic alterations, immunotherapeutics, cytotoxics, or antibody–drug conjugates. Select phase 1 and 2 trials that have yielded promising results based on key efficacy end points are highlighted in Table 4.
Table 3Select Ongoing and Recruiting Trials Classified by Therapeutic Targets of Interest in SCLC
MA09.05 nivolumab alone or with ipilimumab in recurrent small cell lung cancer (SCLC): 2-year survival and updated analyses from the Checkmate 032 trial.
ORR 25% vs 11% 1-y OS 42% vs 30% 2-y OS 30% vs 17%
Randomized cohort: ORR 21% vs 12% 3-ms PFS 30% vs 18% 3-ms OS 64% vs 65% Pooled cohorts: Second-line: ORR 19% vs 12% Third-line and beyond: ORR 26% vs 11% Platinum sensitive: ORR 26% vs 13% Platinum resistant 15% vs 10%
1527OTop-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod.
In contrast to lung adenocarcinoma, the genomic landscape of SCLC is not characterized by a set of mutually exclusive targetable driver oncogenes, and transcriptional dysregulation plays a central role.
Signaling pathways recurrently affected in SCLC include cell-cycle regulation, receptor tyrosine kinase/PI3K signaling, transcriptional regulation, and Notch signaling. On an epigenetic level, SCLC is characterized by aberrant gene promoter methylation patterns and histone acetylation; on a proteomic level, a number of genes implicated in DNA damage repair are aberrantly expressed.
Inhibiting Cell-Cycle Progression
Universal bi-allelic inactivation of tumor suppressors TP53 and RB1 is a hallmark of the disease, resulting in a lack of G1/S checkpoint activity and, accordingly, increased dependency on the G2/M checkpoint for adequate DNA repair. This provides therapeutic opportunities through inhibition of other key regulators of the cell cycle such as WEE1 and Aurora kinase A and B. WEE1 inhibitor AZD1775 is being investigated in 3 studies: in a phase 1 study in combination with olaparib (NCT2511795); in monotherapy in a phase 2 study in the relapsed setting (NCT2593019); and in the phase 2 BALTIC trial, comparing AZD1775 plus carboplatin with durvalumab plus tremelimumab (NCT02937818). Aurora kinase A is critical for centrosome function and chromosome alignment and, ultimately, the G2/M transition. Aurora A kinase inhibitor alisertib was evaluated in a randomized phase 2 study comparing alisertib or placebo plus paclitaxel as second-line therapy (Table 4), and showed an improvement in mPFS from 66 to 101 days (HR 0.71, P value 0.038), with a trend for higher ORR and median (m)OS.
Aurora B kinase inhibitor (and inhibitor of VEGFR and CSF-1R) chiauranib is being investigated in a phase 1 trial of relapsed SCLC (NCT03216343). Nonetheless, limited efficacy of these agents against solid tumors was observed, and current trials largely focus on hematologic malignancies.
CDK4/6 inhibitor trilaciclib is studied in 2 phase 2 trials in the first-line setting: in combination with carboplatin plus etoposide plus atezolizumab vs carboplatin plus etoposide plus atezolizumab alone (NCT03041311) and in a trial of carboplatin plus etoposide with or without trilaciclib (NCT02499770). Taking into account the high frequency of Rb (retinoblastoma) loss, arguably a negative predictive factor for CDK4/6 inhibitors, its therapeutic application will likely warrant some population enrichment. Proteins of the bromodomain and extra-terminal (BET) family, among various biological functions, function as cell-cycle regulators, and several small-molecule inhibitors of the bromodomains 2 and 4 have been developed.
BRD2/4 inhibitor mivebresib is currently evaluated in phase 1 in solid tumors, including SCLC (NCT02391480). BET inhibitor GSK525762 is being evaluated in a phase 1 trial in monotherapy in patients with MYC amplification (NCT01587703) and in combination with trametinib in patients with HRAS, NRAS, KRAS mutations (NCT03266159).
Epigenetics
Dysregulation of epigenetic processes, such as gene-promoter methylation and histone acetylation, lead to alterations in chromatin and other associated factors that modify the ability of genes to be transcribed.
Acetyltransferases and histone deacetylases (HDAC) regulate histone acetylation, which leads to increased accessibility of promoter regions and increased gene transcription.
Two phase 1 and 2 studies of HDAC inhibitor vorinostat, in combination with carboplatin and etoposide in the first-line setting (NCT00702962) and in combination with topotecan in the chemosensitive-recurrent setting (NCT00697476), have been terminated, and no results have been presented. A phase 1 trial of belinostat identified a maximal tolerated dose (MTD)
; no further clinical trial with this compound is ongoing at present. SCLC is characterized by high expression of the histone methyltransferase gene EZH2
that also plays a crucial role in the gene-silencing machinery implicated in tumor-suppressor loss and has been associated to acquired resistance to chemotherapy.
Expression of EZH2 is under direct control of the E2F family of transcription factors that are negatively regulated by the product of RB1, which is almost universally lost in SCLC. First-in-class EZH2 inhibitor tazemetostat is expected to be investigated in recurrent SCLC. LSD1 is a histone modifier that maintains the pluripotency of embryonic stem cells through demethylation of histone H3 lysine 4 (H3K4) and subsequent repression of genes controlling cell differentiation;
several inhibitors are in development, including RO7051790 (NCT0213443). A phase 1 study of LSD1 inhibitor GSK2879552 has been completed, with results pending (NCT02034123). Finally, hypomethylating agent guadecitabine, a DNA methyltransferase (DNMT) inhibitor, is being studied in combination with durvalumab and tremelimumab (NCT03085849).
DNA Damage Repair
Aberrant expression of DNA repair proteins, such as MGMT, PARP1, CHK1, and BRCA1 and 2 in SCLC, present attractive treatment targets.
PARP activity is essential for the repair of single-stranded DNA breaks through the base excision-repair pathway. PARP inhibitors work through competitive inhibition and compete with nicotinamide for the catalytic domain of the enzyme.
Several PARP inhibitors are under investigation. In a phase 1 and 2 study of cisplatin plus etoposide plus veliparib or placebo (Table 4), the addition of the PARP inhibitor was associated with improved mPFS of 6.1 m vs 5.5 (HR 0.75, P value 0.06). A randomized phase 2 study with 104 patients with recurrent SCLC compared veliparib and temozolomide vs temozolomide and placebo and showed no difference in 4-month PFS (27%; P=.19) and mOS (8.2 months; 95% CI, 6.4 to 12.2 months vs 7.0 months; 95% CI, 5.3 to 9.5 months; P=.50) between 2 arms.
Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer.
Veliparib is also being investigated in the first-line setting in combination with carboplatin and etoposide (NCT2289690). BMN673 is being investigated in a phase 1 study and demonstrated activity in refractory SCLC.
Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.
Olaparib is being evaluated in a number of settings and combinations, including in combination with durvalumab (NCT2734004) and CRLX (nanoparticle camptothecin) (NCT02769962). A phase 2-3 single-arm trial of olaparib and temozolomide combination in relapsed or refractory SCLC showed promising results with a mPFS of 87 days, mOS of 220 days, and median diagnostic odds ratio (mDOR) of 103 days.
Checkpoint kinase 1 (CHK1) inhibitor prexasertib is being evaluated in a phase 2 trial in the recurrent setting (NCT02735980). DNA-dependent protein kinase (DNA-PK) is part of a critical double-strand repair mechanism. Inhibitor M3814 has been found to be safe and tolerable
; however, a phase 2-3 trial in combination with cisplatin and etoposide was terminated (NCT3116971). Finally, ataxia telangiectasia and rad3-related (ATR) is a regulator of cellular responses to replication stress, where it signals DNA damage repair by homologous recombination. First-in-class inhibitor VX-970
Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.
is being investigated in a phase 2-3 trial in the recurrent setting in combination with topotecan (NCT02487095).
Notch Signaling
The Notch signaling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues,
regulating neuroendocrine vs epithelial cell differentiation. Although the Notch signaling cascade is an important tumor suppressor in several tissues, including neuroendocrine tumors, Notch can, in fact, be either oncogenic or tumor suppressive, depending on the tissue and cellular context. In SCLC, damaging mutations affect the NOTCH gene in about 25% of cases and occur most frequently in the extracellular domain. Conversely, Notch signaling is also implicated in cancer stem-cell renewal and proliferation, leading to the development of monoclonal antibodies targeting its receptors. Tarextumab, a monoclonal antibody-targeting Notch 2 and 3 receptors, failed to improve mPFS or mOS in the randomized phase 2 PINNACLE trial in the first-line setting.
Receptor Tyrosine Kinase/PIK3CA Signaling
A very recent targeted exome sequencing analysis of extensive disease SCLC identified RICTOR (RPTOR independent companion of MTOR, complex 2) amplification as one of the most frequent actionable gene alterations, found in 14% of patients.
RICTOR is a subunit of mTORC2, and copy number gain has been associated with increased sensitivity to mTOR inhibitors in cell lines; mTOR inhibitor vistusertib is being investigated in patients with relapsed SCLC harboring RICTOR amplifications (NCT03106155).
Immunotherapy of SCLC
SCLC has a strong association with smoking, with only 2% of cases occurring in patients who have never smoked
and consequently has a high load of somatic mutations induced by tobacco carcinogens. Importantly, the high mutational burden of SCLC might provide opportunities for therapeutic intervention, owing to its positive correlation with response to immune checkpoint therapy.
which remains of unknown predictive value, and by low numbers of tumor-infiltrating lymphocytes. Several commercially available anti-PD-1 and anti-PD-L1 monoclonal antibodies have been tested in pretreated patients with SCLC and are under current investigation in the both in the front-line setting and as maintenance therapy.
Pembrolizumab was investigated in the phase 1b multicohort KEYNOTE-028 trial in patients with pretreated relapsed/refractory PD-L1-expressing (tumor proportion score ≥1%), in which it demonstrated a response rate of 33.3%, with a median duration of response of 19.4 months, a mPFS of 1.9 months, and mOS of 9.7 months.
KEYNOTE-158 was a phase 2 trial investigating pembrolizumab in relapsed or refractory SCLC regardless of PD-L1 expression and showed an OR rate of 18.7%, mPFS of 2.0 months, mOS of 9.1 months.
It failed to show any advantage over historical control with observation, with a mPFS of 1.4 months and mOS of 9.6 months. Pembrolizumab was also studied in combination with paclitaxel in a phase 2 trial in platinum-refractory ES-SCLC.
Of 26 evaluable patients, ORR was 23.1%, mPFS and mOS were 5.0 months and 9.2 months, respectively. Furthermore, pembrolizumab is being investigated in the front-line setting in a randomized phase 3 trial (NCT03066778), as well as in various schedules and combinations with radiation (NCT02580994, NCT02934503, NCT02402920).
Nivolumab has been studied in the phase 1-2 CheckMate 032 study in patients with pretreated SCLC, among other tumor types; initial results showed durable responses and encouraging survival,
prompting the addition of a randomized cohort to evaluate nivolumab further in either monotherapy or in combination with anti-CTLA-4 monoclonal antibody ipilimumab. In the nonrandomized cohort, ORR to nivolumab was 11%, and ORR to nivolumab plus ipilimumab was 23%. Updated results from the nonrandomized cohort showed a mOS of 4.1 months in the nivolumab arm and 7.8 months in the combination arm, with promising 2-year OS rates of 26% and 14%, respectively.
MA09.05 nivolumab alone or with ipilimumab in recurrent small cell lung cancer (SCLC): 2-year survival and updated analyses from the Checkmate 032 trial.
Similar findings were obtained in the randomized cohorts, in which patients had a maximum of 2 previous lines of therapy: ORR 21% vs 12%; it is noteworthy that responses occurred regardless of platinum sensitivity, line of therapy, or PD-L1 status. This study also identified tumor mutational burden (TMB) using whole-exome sequencing and classified patients according to nonsynchronous somatic mutations into 3 groups: high (>243 mutations), medium (100 to 243 mutations), and low (<100 mutations).
ORR, PFS, and OS were higher in both arms among patients with high TMB and higher for the combination vs nivolumab alone. Based on these data, the nivolumab–ipilimumab combination is recommended as a second-line treatment option in ES-SCLC. FDA has also granted accelerated approval to nivolumab for third-line treatment of metastatic SCLC. The randomized trial CheckMate 331 is currently comparing nivolumab with topotecan or amrubicin in the second-line setting (NCT02481830), and CheckMate 451 is comparing nivolumab, nivolumab plus ipilimumab, and placebo as maintenance after first-line chemotherapy (NCT2538666).
The combination of anti-CTLA-4 and anti-PD-1/PD-L1 was also recently presented in a phase 1 trial of durvalumab and tremelimumab, which showed an ORR of 13.3%, mPFS 1.8 months, and mOS 7.9 months.
This regimen is now being studied in the front-line setting in the randomized phase 2 CASPIAN study, comparing durvalumab plus tremelimumab plus platinum/etoposide with durvalumab and platinum/etoposide, with a comparator arm of standard platinum/etoposide (NCT3043872). These studies will inform on the optimal place of PD-1/PD-L1 and CTLA-4 blockade, better define the safety profile of the combination, and address unanswered questions on the predictive value of biomarkers.
Diverse combination trials are ongoing, investigating various compounds on a backbone of anti-DP-1/PD-L1 antibody, with the intent of increasing tumor antigenicity and eliciting immune responses: GITR-agonist INCAGN01876 in combination with pembrolizumab and IDO1-inhibitor epacadostat (NCT03277352) and in combination with nivolumab and ipilimumab (NCT03126110). Antibody–drug conjugate rovalpituzumab tesirine (see below) is evaluated in combination with anti-PD-1 monoclonal antibody ABV-181 in the second-line setting (NCT3000257). Beyond the PD-1/PD-L1 axis, several novel immune checkpoint modulators are in phase 1 development in SCLC, including anti-CD47 monoclonal antibodies TTI-621 (NCT02663518) and Hu5F9-G4 (NCT02216409). Finally, promising signals have emanated from some novel classes of immunotherapeutics, including the Toll-like receptor 9 (TLR9) agonist lefitolimod. Lefitolimod, an immune surveillance reactivator, was investigated in the randomized first-line trial IMPULSE, and showed an OS benefit over standard of care in predefined, clinically relevant subgroups including patients with low counts of activated B cells (HR 0.59).
1527OTop-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod.
Several novel cytotoxic agents engineered to concentrate in tumor tissue, either through pegylation or linkage to a monoclonal antibody, are currently in clinical development. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor under development.
A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors.
A phase 2 trial of the drug in the relapsed setting (Table 4) showed an ORR of 38.9% in the platinum-sensitive cohort and 20% in the platinum-resistant cohort, while demonstrating an acceptable toxicity profile and a convenient schedule. Grade 3 and higher adverse events included leukopenia, neutropenia, lymphopenia, and diarrhea (10% each). Dinutuximab, a chimeric antiglycolipid disialoganglioside antibody that induces tumor lysis via antibody-dependent, cell-mediated, and complement-dependent cytotoxicity, is being studied in a combination with irinotecan vs irinotecan alone in a phase 2-3 study (NCT03098030).
A two-part, open-label, randomized, phase 2/3 study of dinutuximab and irinotecan versus irinotecan for second-line treatment of subjects with relapsed or refractory small cell lung cancer.
Lurbinectedin is a transcription inhibitor that binds to the DNA minor groove and inhibits RNA polymerase II. In a multicohort phase 2 study, it showed a mPFS of 4.2 months and an acceptable tolerability in platinum refractory SCLC.
The most notable grade 3 or higher adverse events were neutropenia (96%) and febrile neutropenia (29%). The combination is currently being compared with topotecan or vincristine, doxorubicin, cyclophosphamide (VAC) in the phase 3 ATLANTIS trial (NCT02566993).
Rovalpituzumab-tesirine (Rova-T), a DLL3-targeted antibody–drug conjugate, consisting of a humanized DLL3-specific IgG1 monoclonal antibody, the DNA cross-linking agent SC-DR002 (D6.5), and a protease-cleavable linker. DLL3 is a member of the Notch receptor family that inhibits Notch activation and is expressed in most SCLC and large-cell neuroendocrine tumors. In a phase 1 trial in relapsed or refractory disease (Table 4), Rova-T yielded an ORR of 17% in assessable patients with SCLC, with response rates of 35% in DLL3-high tumors (expression in ≥50% of tumor cells by immunohistochemistry [IHC]) and 0% in DLL3-low tumors.
The most frequent grade 3 or higher treatment-related adverse events were thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%). However, a recently reported phase 2 trial (TRINITY) demonstrated only marginal benefit in DLL-3-high refractory SCLC with mPFS of 4.1 months and mOS of 6.7 months.
Efficacy and safety of rovalpituzumab tesirine in patients With DLL3-expressing, ≥ 3rd line small cell lung cancer: results from the phase 2 TRINITY study.
More than one third of patients discontinued treatment because of adverse events or progression of disease. The most significant grade 3 or higher adverse events were thrombocytopenia (11%), photosensitivity reaction (7%), and pleural effusion (5%), whereas fatigue (38%), photosensitivity rash (36%), and pleural effusion (32%) were the most common adverse events of all grades. The drug is being tested in 2 randomized double-blind placebo-controlled phase 3 trials: vs placebo as maintenance therapy following first-line platinum-based chemotherapy in the MERU trial (NCT03033511) and vs topotecan in the second-line setting in the TAHOE trial (NCT03061812 [this trial was halted by US FDA because of poor results and high toxicity from the phase 2 TRINITY trial]). Another antibody–drug conjugate, SC-002, is being tested in the relapsed setting (NCT2500914); the target of the monoclonal antibody has not been disclosed publicly.
Conclusion
Despite a high rate of response to therapy, SCLC almost always invariably recurs. Molecular aberrations in SCLC have been known for over a decade; however, targeting a number of these aberrations has been uniformly unsuccessful, and SCLC remains a disease with a dismal prognosis. It is therefore noteworthy that SCLC has been identified as a target under the Recalcitrant Cancer Research Act of 2012, signed into law by the United States Congress. This law identified a number of difficult-to-treat cancers and directed the National Cancer Institute (NCI) to allocate resources to tackle these cancers. The NCI formed working groups to identify promising scientific advances, assess whether sufficient qualified researchers are working in relevant areas, and develop recommendations and plans to coordinate and advance research in SCLC. The scientific framework formulated key objectives: identifying better research tools for the study of SCLC, comprehensive genomic profiling of SCLC, therapeutic development efforts, and elucidating the mechanisms underlying both the high rate of initial response and rapid emergence of drug and radiation resistance. Resources encompass a patient-derived xenograft model repository, development of drugs for preclinical testing, and the building of research teams supported by the NCI's center for biomedical informatics and a genomic data sharing policy for researchers and clinicians. It is hoped that, with this type of collaborative approach across institutions and rational translation of research findings into clinical trials, survival of patients with SCLC can be significantly improved in the coming years.
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Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer.
Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients.
Phase I trial of a first-in-class ATR inhibitor VX-970 as monotherapy (mono) or in combination (combo) with carboplatin (CP) incorporating pharmacodynamics (PD) studies.
1527OTop-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod.
A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors.
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Grant Support: Dr Shuhang received a grant from 2016 ASCO Conquer Cancer Foundation (LIFe grant, no. 10092).
Potential Competing Interests: Dr. Mansfield reports funding to institution for participation on advisory boards for Abbvie, Genentech, and BMS. He also reports research funding to institution from Verily and Novartis. The other authors report no competing interests.
The Thematic Review on Neoplastic Hematology and Medical Oncology will continue in an upcoming issue.
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