Expert Practice Advice
Managing Extensive Stage Small Cell Lung Cancer

Patient case:

A 68-year-old woman, former smoker with mild chronic obstructive pulmonary disease, presented with cough, dyspnea, hemoptysis, fatigue, and a weight loss of 6 kg (13 lb) over the last 3 months. On the physical exam there was some wheezing at auscultation in the left lower lobe and palpable left supraclavicular node (1 cm in size). Laboratory exams (CBC and blood biochemistry) were all normal. Chest X-ray showed a left upper lobe (LUL) mass and hilar mass. Excision biopsy of the supraclavicular lymph node revealed poorly differentiated small cell lung cancer (SCLC) with positive staining for thyroid transcription factor-1 (TTF-1), chromogranin, synaptophysin and CD56 neural cell adhesion molecule (NCAM). Staging CT scan of the chest, abdomen, and pelvis showed a 6.5 cm LUL mass, bilateral hilar adenopathy and multiple liver metastases of up to 3 cm. A staging MRI of the brain was negative for metastases. This patient has extensive stage (ES) SCLC and her Eastern Cooperative Oncology Group performance status (ECOG PS) at diagnosis was 1.

SCLC is an aggressive cancer characterized by neuroendocrine high-grade features, rapid tumor growth, early metastatic spread and a poor prognosis. It is strongly associated with tobacco exposure. It accounts for about 15% of all lung cancers. Patients typically present with cough, dyspnea or hemoptysis. These symptoms are often accompanied by anorexia, weight loss and fatigue. Imaging usually reveals a centrally located lung mass and often bulky mediastinal lymph node involvement. Around two-thirds of SCLC patients present with extensive stage disease at diagnosis. The most common metastatic sites are contralateral lung, brain, liver, adrenal glands, bone and bone marrow. SCLC is often associated with paraneoplastic syndrome, including neuroendocrine (e.g. SIADH and Cushing syndrome), and neurologic paraneoplastic syndromes, which are caused by autoantibodies (e.g. Lambert–Eaton syndrome, encephalomyelitis and sensory neuropathy syndromes).1

What is the standard of care for a patient with newly diagnosed ES SCLC?

For decades, platinum-based chemotherapy was the gold standard front-line therapy. Platinum-based chemotherapy involves four to six cycles of cisplatin or carboplatin plus etoposide (EP) in Europe and US,2,3,4 and platinum plus irinotecan in Japan.4,5 In general, carboplatin is preferred over cisplatin as it was shown to have a similar efficacy and better toxicity profile with less nephrotoxicity, ototoxicity and neuropathy, although hematologic toxicity is higher.3

Unfortunately, high responses to chemotherapy are usually followed by relapse within 1 year. However, with the introduction of immunotherapy, the treatment paradigm for ES SCLC has changed. Multiple randomized phase III trials have demonstrated significant benefits of adding an PD-L1/PD-1 immune checkpoint inhibitor to first-line chemotherapy in patients with newly diagnosed ES SCLC.6-12 The addition of either of two PD-L1 inhibitors (atezolizumab or durvalumab) to EP, with continuation of immunotherapy as maintenance, improved overall survival (OS) by approximately 2 months (IMpower133,6 CASPIAN7,8). The most common immunotherapy related adverse events (irAEs) observed in these trials were thyroid disease and rash, while other irAEs, including hepatic toxicity, pneumonitis and colitis, were rare. These findings led to the regulatory approval of both regimens in the US, Europe and many other countries around the world. Similar improvements were seen with the addition of the anti-PD-1 inhibitor serplulimab to chemotherapy (ASTRUM 00512), and this regimen is approved in China. Benefit was seen regardless of PD-L1 expression and tumor mutational burden (TMB).6,7,9,12 Nevertheless, only about 10% of patients experience durable benefit with chemo-immunotherapy.6-12

Is there a role for consolidation chest radiotherapy (RT) and prophylactic cranial irradiation (PCI) in ES SCLC?

Based on the results that show improved 2-year survival with chest RT in a post-hoc analysis of the CREST study, consolidation chest RT may be an option, particularly for selected patients with a disease response to initial therapy and with residual disease confined to the chest. 13,14 However, the role of chest RT in the chemo-immunotherapy era is unclear and is being investigated in clinical trials. The role of PCI in patients with ES SCLC in era of MRI is controversial. While a European phase III study15 showed a survival benefit with PCI, a more recent Japanese phase III study16 demonstrated similar survival with MRI surveillance or PCI, and thus many institutions prefer using MRI surveillance over PCI. Clinical trials to evaluate both approaches after in the chemo-immunotherapy era are underway.

Patient's course of disease:

The patient started with the EP plus atezolizumab regimen. All her symptoms improved and CT evaluation after 4 cycles showed partial response in lung and liver, and she continued maintenance atezolizumab. During this period, she was followed up with CT scans and brain MRI surveillance every 3 months. While on maintenance therapy, surveillance imaging at 8 months revealed progression of liver metastases and new metastases in the right suprarenal gland, but no brain metastases. Atezolizumab maintenance was stopped. As her relapse was likely chemosensitve based on an 8 month interval since her last dose of platinum-based doublet, and her PS was 1, she was retreated with EP chemotherapy. At evaluation after 2 cycles of chemotherapy, her disease was stable, but progressed after 4 cycles of chemotherapy. She was then offered to participate in a clinical trial.

What are the treatment options for relapsed ES SCLC?

Most patients with ES SCLC relapse or progress following or during first-line therapy. Although second-line therapy may induce responses in 10 – 30% of patients, these are usually short-lived with a median survival of around 6 – 10 months.17 The likelihood of response is highly dependent on the time from initial chemotherapy to relapse and duration to response with initial therapy. Relapse > 90 days after the last exposure to first-line chemotherapy in patients who achieved a complete or partial response is called ‘’sensitive’’, whereas relapse < 90 days after the last exposure to first-line chemotherapy or failure to respond to the first-line chemotherapy is termed ‘’resistant’’ or ‘’refractory.’’ 17

If the patient has a good PS at progression, a clinical trial is preferred, if available.

Standard second-line options include topotecan (oral or intravenous), lurbinectedin, and for patients with chemosensitive relapse, rechallenge with a first-line platinum regimen (usually EP) 18 if their PS allows. Lurbinectedin is a novel alkylating agent (analog of trabectedin) that binds to the minor groove of DNA and inhibits transcription in tumor cells. It received accelerated approval for second-line use based on a response rate of 35% with a duration of response of around 5 months and OS of 9 months in a single-arm phase II study.19 It has less hematologic toxicity than topotecan, but a higher frequency of transaminitis. The phase III ATLANTIS trial of lurbinectedin plus doxorubicin versus topotecan or CAV (cyclophosphamide, doxorubicin, vincristine) failed to improve survival; however, the dose of lurbinectedin in combination was substantially lower than for monotherapy.20 

After progression on second-line therapy, inclusion in a clinical trial should also be considered. Otherwise, if the condition of the patient allows, third-line treatments may include agents not previously given (either topotecan or lurbinectedin), or other agents with modest activity (e.g. taxanes, irinotecan, temozolamide, oral etoposide, or gemcitabine).17 The use of immune checkpoint inhibitors, such as pembrolizumab and nivolumab, in a late-line setting is unclear after progression on first-line immune checkpoint inhibitors.1

Can patients with a PS 2 receive second-line therapy?

Patients with an ECOG PS 2 were included in clinical trials, but initial dose reduction or the addition of growth factor support could be considered. In addition, the FDA recently approved trilaciclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 to decrease the incidence of chemotherapy-induced myelosuppression in patients when administered prior to an EP-containing regimen or topotecan-containing regimen. Trilaciclib induces a transient, reversible G1 cell cycle arrest of proliferating hematopoietic stem and progenitor cells in bone marrow, thus protecting them from damage by chemotherapy (myelopreservation).19

In contrast with NSCLC, where molecular testing and targeted therapy is standard of care, no targeted treatment is available for SCLC and there is a high unmet need for personalized biomarker-driven therapy.

SCLC subtypes hold promise for future biomarker-driven personalized treatment

Advances in genomics and the development of diverse mouse- and patient-derived models have led to a better understanding of the biological diversity of SCLC. Genomic profiling studies of SCLC have shown extensive chromosomal rearrangements and a high mutational burden, and confirmed a functional loss of the two key tumor suppressor genes, TP53 and RB1 in almost all SCLCs. Amplifications or overexpression of MYC family genes were also frequent, as well as inactivating mutations in NOTCH family genes, PTEN loss, PI3K mutations and FGFR1 amplification, as well as mutations affecting epigenetic regulators.20,21

Recent studies1,21,22 have demonstrated that SCLCs display both intra-and inter-heterogeneity, and can be divided into four biologically distinct subtypes: neuroendocrine SCLC-A and SCLC-N and non-endocrine SCLC-P and SCLC-I. These subtypes were defined based on the differential expression of master transcription factors (ASCL1, NEUROD1, and POU2F3) and for SCLC-I by low/absent expression of all three transcription factors and an inflamed gene signature.21,22 Each subtype was found to be associated with distinct therapeutic vulnerabilities. For instance, SCLC-I, which has an immune-inflamed phenotype, may derive the greatest benefit from the addition of immunotherapy to chemotherapy. This was validated in a subtype-specific retrospective analysis of IMpower133 survival data, where a notable OS benefit was seen for the SCLC-I subtype relative to other subtypes with chemotherapy plus immunotherapy, but not with chemotherapy plus placebo.22 Subtyping analyses from the CASPIAN trial support these findings.23 The other subtypes each have distinct vulnerabilities, including to PARP inhibitors (SCLC-A), Aurora kinase inhibitors (SCLC-N), or BCL-2 inhibitors (SCLC-A). In addition, each subtype was found to be associated with unique protein expression patterns, which could be potential drug targets and predictive biomarkers.1 For example, Delta-like ligand 3 (DLL3) is highly expressed in the SCLC-A subtype and may be predictive for DDL3 targeting therapy, such as bispecific T engager antibodies. Schlafen-1 protein (SLFN1) has also been found most differentially expressed in the SCLC-A subtype, indicating a potential benefit from platinum-based chemotherapy and PARP inhibitors. The SCLC-N subtype expresses higly somatostatin receptor 2 (SSTR2), a known target for somatostatin analogs, and SCLC-I has high expression of Bruton tyrosine kinase, which is targetable with BTK inhibitors such is ibrutinib.1,22,24

In addition, subtype-switching during treatment (tumor plasticity) appears to be an important mechanism of acquired resistance and may have therapeutic implications.25 However, identifying resistance requires repeat biopsy at progression, which may be challenging but possible with liquid biopsy (cfDNA/ctDNA); this would enable monitoring the evolution of the disease.26

Taken together, a better understanding of the complex biology and identification of molecular subtypes with specific therapeutic vulnerabilities has opened new horizons and hope for personalized treatment strategies and improved outcomes in SCLC.

References:

  1. Rudin C, et al. Nat Rev Dis Primers. 2021;7(1):3.
  2. Pujol JL, et al. Br J Cancer. 2000;83:8-15.
  3. Rossi A, et al. J Clin Oncol. 2012;30(14):1692-1698.
  4. Lara PN, et al. J Clin Oncol. 2009;27:2530-2535.
  5. Noda K, et al. N Engl J Med. 2002;346:85-91.
  6. Liu SV, et al. J Clin Oncol. 2021;39(6):619-630.
  7. Paz-Ares L, et al. Lancet. 2019;394(10212):1929-1939.
  8. Paz-Ares L, et al. ESMO Open. 2022;7(2):100408.
  9. Rudin CM, et al. J Clin Oncol. 2020;38(21):2369-2379.
  10. Rudin C, et al. WCLC 2022; OA12.06.
  11. Wang J, et al. Lancet Oncol. 2022;23(6):739-747.
  12. Cheng Y, et al. ASCO 2022; Abstract 8505. 
  13. Slotman BJ, et al. Lancet 2015;385(9962):36-42.
  14. Slotman BJ, et al. Transl Lung Cancer Res. 2015;4(3):292-294.
  15. Slotman et al. N Engl J Med. 2007;357:664-672.
  16. Takahashi T, et al. Lancet Oncol. 2017;18(5):663-671.
  17. Dingemans AC, et al. Ann Oncol. 2021;32(7):839-853.
  18. Baize N, et al. Lancet Oncol. 2020;21(9):1224-1233.
  19. Weiss J, et al. Clin Lung Cancer. 2021;22:449.
  20. George J, et al. Nature. 2015;524(7563):47-53. 
  21. Rudin CM, et al. Nat Rev Cancer. 2019;19:289-297.
  22. Gay CM, et al. Cancer Cell. 2021;39(3):346-360.e7.
  23. Xie M, et al. AACR 2022; Abstract CT024.
  24. Zhang B, et al. Am Soc Clin Oncol Educ Book. 2021 Mar;41:1-10.
  25. Sutherland KD, et al. Genes Dev. 2022;36:241-258.
  26. Mondelo-Macía P. Biomedicines. 2021:9:48.