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Molecular characteristics of SCLC

Presented by
Dr Simon Ekman, Karolinska University Hospital, Sweden
ELCC 2019
The majority of patients with small cell lung cancer (SCLC) are diagnosed with advanced disease and have a poor prognosis. There is a scarcity of new therapeutic agents with clinical efficacy for the treatment of SCLC. The targets that are currently being studied, are based on the molecular biology of SCLC. Thus, there is a need to identify molecular subtypes of SCLC, as defined by transcriptional regulators. Furthermore, there is a need for novel predictive biomarkers.

SCLC is a neuro-endocrine tumour with high-grade features. It represents approximately 12-15% of total new lung cancer diagnosis. There is a strong association with tobacco use; only 2% of these patients are never-smokers. The majority (70%) of cases present with advanced disease at diagnosis. Although response rates with first-line chemotherapy are high (approximately 75%), SCLC is characterised by rapid emergence of resistance, poor long-term survival rates (15-20% after two years and <2% after five years), and median OS of 10-12 months. In addition, few advances in treatment have been made for this patient population (see Table) [1]. “So, there is a lot of work to be done”, Dr Simon Ekman (Karolinska University Hospital, Sweden) started his lecture. “Some examples include chemotherapy in the first- and second-line setting and the development of hyperfractionated radiotherapy.”

Table: Treatment of SCLC in the last decades [1]

Recently, a lot of new insights have been attained in the molecular characteristics of lung cancer. While NSCLCs contain multiple oncogenic driver-mutations, in SCLCs most mutations are located in tumour suppressor genes, which are more difficult to target [2,3].

There is a high mutational rate (8.62 mutations/Mb) and multiple signalling pathways are affected. In nearly all tumours, there is an inactivation of the tumour suppressors TP53 and RB1. Other important genetic aberrations in SCLC include amplifications of MYC family genes (e.g. FGFR1, IRS2, SOX2, loss of CDKN2A) and inactivation mutations in NOTCH family genes in 25%. Only in rare cases, there are actionable mutations in kinase genes, such as BRAF, KIT, and PIK3CA[3].

SCLC is one of the tumours with higher tumour mutational burden across different histologies. Furthermore, a number of para-neoplastic syndromes can exist in SCLC patients. For example, 0.5-3.0% of SCLC patients develop Lambert-Eaton syndrome, which involves an immune response to tumour antigens and nerve cells. Those patients have a better prognosis, presumably due to the anti-tumour immune response [4].
DLL3: role and target

Recently, the molecular subtypes of SCLC, defined by key transcription regulators, were summarised [5]. The authors propose a subtyping in four different types: SCLC-A, -N, -P, and -Y. Type A is the most common one, defined by a higher expression of ASCL1 and DLL3. It seems difficult to treat these pathways. In their view, we should focus on DLL3, which is an atypical inhibitory Notch ligand. DLL3 is induced by a key neuroendocrine transcription factor, called ASCL1, and is expressed on both cancer stem and tumour cells, but not normal adult tissue. In contrast, DLL3 is abundantly expressed on SCLC cells, namely on >85% [6].

An antibody-drug conjugate against DLL3 has been developed (rovalpituzumab tesirine; Rova-T, SC16LD6.5). “A phase 1 study in patients with relapsed or refractory lung cancer showed response rates of 16%”, Dr Ekman said. “In patients with high DLL3 expression, the response rate was 31%.” A subsequent phase 2 study showed that in the same patient population, a fixed dose of Rova-T resulted in an overall response rate of 18%, which was quite similar in DLL3-high patients. The median OS was 5.6 months [7]. These data led to the phase 3 TAHOE study evaluating Rova-T in the second-line setting. Unfortunately, in December 2018, there was a recommendation to stop this trial prematurely due to shorter OS in the Rova-T arm compared with the control arm. Another phase 3 trial evaluating the maintenance treatment with Rova-T after platinum doublet chemotherapy, is ongoing.
PARP and biomarkers

Currently, there is a lot of focus on the possibility of PARP inhibition for the treatment of SCLC. However, a trial evaluating veliparib showed no significant survival benefit in the experimental arm.

For the future, there is definitely a need for predictive biomarkers for SCLC [8]. “We really need to select patients, to increase the likelihood of a response. We are really looking at SCLC as one disease to an entity with different molecular subtypes, defined by differences in gene expression or the presence of biomarkers.”

  1. Alvarado-Luna G, Morales-Espinosa D. Transl Lung Cancer Res. 2016;5:26-38.
  2. Jordan EJ, et al. Cancer Discov. 2017;7:596-609.
  3. George J, et al. Nature. 2015;524:47-53.
  4. Alexandrov LB, et al. Nature. 2013;500:415-21.
  5.  Rudin CM, et al. Nat Rev Cancer. 2019 Mar 29.
  6.  Saunders LR, et al. Sci Transl Med. 2015;7:302ra136.
  7. https://clinicaltrials.gov/ct2/show/NCT02674568
  8. Sen T, et al. Transl Lung Cancer Res. 2018;7:50-68.

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