Small Cell Lung Cancer (SCLC) – Deadliest Lung Cancer

Introduction

Just some brief information (numbers) on small cell lung cancer (SCLC) before I jump into treatments for advanced SCLC.

  • 20% of all lung cancers
  • 95% are cigarette smokers (remaining I strongly believe is caused by second hand smoke (SHS) or environmental tobacco smoke (ETC)
  • 90% of the tumor is located centrally
  • 70-80% are extensive/ advanced stage, 20-30% are limited stage
  • Metastasis is early and frequent, with spread mainly to mediastinal lymph nodes, liver, bones, brain (25 – 30%), and adrenal glands.
  • Average/ median overall survival with extensive disease is 2 to 4 months without treatment, and 6 to 12 months with treatment (let’s see later whether this can be improved).
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Small cell lung cancer causing superior vena cava obstruction

Treatments for advanced/ extensive SCLC

Chemotherapy

Chemotherapy is the standard first-line (etoposide and cisplatinand second-line (topotecan) therapy for SCLC.

The effect of chemotherapy is rapid as the tumor is very sensitive to the chemotherapy (and radiotherapy).

The changes in the lung tumor size is apparent after just one cycle of chemotherapy and can ‘disappear’ after few cycles of chemotherapy (complete response can be up to 40%!). Unfortunately, the tumor can recur back just as fast after awhile.

In first line setting, the average/ median overall survival for advanced SCLC was around 39 weeks (68 weeks for patients who had complete response, 40 weeks for those achieving a partial response and 17 weeks only for those who had no response or whose disease progressed on treatment. (JCO, WK Evans, ‎1985)

Screen Shot 2018-08-01 at 12.56.56 AM.png
A first-line therapy study conducted in 1985 for SCLC. The whole world is still using the same regime (etoposide/ cisplatin), after more than 30 years! (JCO, WK Evans, ‎1985).

The standard second-line treatment for SCLC is also with chemotherapy (topotecan), which offers an average/ median overall survival of around 25 weeks.

Screen Shot 2018-08-01 at 1.13.20 AM.png
Second-line treatment study showing topotecan single agent is as effective as three chemotherapy regiment (CAV). Note the year (1999), 20 years ago!

In 2012, temozolomide was found to have activity against SCLC with added benefit of CNS penetration against brain metastasis.

Platinum sensitive relapsed SCLC are patients who responded well to first-line treatment but showed evidence of disease relapse or progression > 90 days after completion of the first-line treatment.

In a phase 2 study using temozolomide against relapsed sensitive or refractory SCLC

  • Overall response rate was 23% and 13% in relapsed sensitive and refractory SCLC, respectively.
  • Average/ median overall survival was 5.8 months
Screen Shot 2018-08-01 at 9.38.22 PM.png
Average/ median overall survival in (B) relapsed sensitive SCLC (6 months) and (D) refractory SCLC (5.8 months).

Another study, JCOG0605, showed that combination chemotherapy (cisplatin, etoposide, irinotecan) is more effective than topotecan alone.

  • Average/ median overall survival, 18.2 vs 12.5 months.
  • It’s a bit odd to add two similar agents (etoposide, cisplatin) that was used earlier in first-line setting with a new agent (irinotecan) for second-line treatment.
  • Not to mention also the increased side effects of 3 chemotherapy agents vs just 1 effective agent, albeit slightly shorted survival duration.
  • Will I try this regime? Hm, results did show good results and patients might benefit if they are fit enough.
Screen Shot 2018-08-01 at 2.10.22 PM.png
JCOG0605 (Lancet Oncology, K Goto, ‎2016)

Immunotherapy

CHECKMATE-032 (nivolumab + ipilimumab cs nivolumab) in advanced SCLC after failure of 1 or 2 prior therapies.

  • Overall response rate higher in combination immunotherapy (28% vs 11%)
  • Results showed better average/ median overall survival for combination immunotherapy, especially in high tumor mutational burden (TMB).
  • One year survival rate in combination immunotherapy in high TMB vs low TMB was 62.4% and 19.6%.
Screen Shot 2018-08-01 at 1.29.56 AM.png
CHECKMATE-032 (Antonia, WCLC, 2017)

KEYNOTE-158 (pembrolizumab in advanced SCLC after progression or intolerance to standard therapy, after failure of 1 or 2 prior therapies).

  • Overall response rate was higher in PD-L1 positive patients as compared to overall population, 36% and 19%, respectively.
  • Average/ median overall survival for PD-L1 positive patients was 15 months while 1-year survival rate was 53%
Screen Shot 2018-08-01 at 1.43.24 AM.png
KEYNOTE-158 (HC Chung, ASCO, 2018)

Notch family ligand DLL3 (Delta-like protein 3)

Rovalpituzumab tesirine (Rova-T) is a delta-like protein 3 (DLL3) targeted antibody-drug conjugate. More studies (NCT03061812, NCT0303511) are currently in progress.

TRINITY study (phase 2, third-line treatment, Rova-T in DLL3-expressing , relapsed/ refractory SCLC)

  • Overall response rate was 12.4%.
  • Average/ median overall survivor was 5.6 months.
Screen Shot 2018-08-01 at 2.01.11 AM.png
TRINITY study (DP Carbone, ‎2018)

PARP inhibitor

PARP inhibitor was tested against recurrent SCLC in a phase 2 trial (temozolamide + veliparib vs temozolamide alone) with some interesting findings (MC Pietanza, ‎2018)

  • Objective response rate was higher in the combination arm, 39%
  • The biomarker of PARP inhibitor is SLFN11 expression
  • Average/ median overall survival in combination arm and SLFN11 expression is 12.2 months
Screen Shot 2018-08-01 at 1.38.32 PM.png
The Lancet Oncology, MC Pietanza, ‎2018

Aurora kinase A inhibitor

Aurora kinase A plays important role in mitosis (cell division).

In an umbrella trial (one trial with many different tumor sites), alisertib, an aurora kinase A inhibitor for treatment of SCLC after failure of 1 or 2 prior therapies

The subset results for SCLC did showed some activities but with significant (53%) Grade 3-4 side effects (B Melichar, ‎2015).

  • Objective response rate was 21%
  • Average duration of response was 4.1 months

Finally

SCLC is not a disease with long survival despite newer treatments available currently.

However, SCLC is a disease that prevention can play a major role in.

  • Primary prevention: preventing risk factors.
    • SCLC is a disease that’s caused solely by cigarette smoking and exposure to cigarette smoking. Hence, SCLC is preventable by smoking cessation and avoiding second hand smoke (SHS).
  • Secondary prevention: early detection/ diagnosis
    • Those who are at risk  (smoked at least 15 cigarettes a day for more than 25 years or ten cigarettes a day for more than 30 years and were current smokers, or had quit smoking less than 10 years ago; as per Nelson trial, Lancet Oncology 2016) might want to consider low-dose CT for lung cancer screening, which enable lung cancer to be detected at earlier stage.

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