15 % of all lung cancer patients in the US have small-cell carcinoma. SCCs are diagnosed mostly in the lung (SCLC) and rarely in other organs such as cervix prostate, liver, pancreas, GI tract or liver. It is an aggressively and fast growing neuroendocrine cancer with early development of metastases. The short double time combined with missing cell size control might be the reason why the cells are small with very little cytoplasm.
70 % of SCLC patients present with already extensive stage disease that has spread beyond lung and close lymph nodes (ES-SCLC) in contrast to limited stage SCLC (LS-SCLC) that is confined to the primary tumor and surrounding lymph nodes.
SCLC can occur in combination with other types of lung cancer like squamous cell or adenocarcinoma. In case of combined SCLC, the recommendation is to treat the cancer as if it was a pure SCLC since it is progressing more rapidly and requires fast and if possible aggressive therapeutic actions.
Treatment options are very limited for SCLC and there is a great need to develop new therapeutic strategies. Median survival is 6-12 months.
LS-SCLC can be treated with a combination of chemotherapy and radiation. ES-SCLC is treated with chemo combinations. Radiotherapy can be added for palliative purposes to treat dyspnea or pain. Response rates are relatively high (45-75 % CR for LS and 15-30 % CR for ES-SCLC) but of short duration: 5-year survival is 1-5 % and 20 % for patients with ES- and LS-SCLC, respectively. Almost all patients relapse and their tumors become resistant to whatever therapy has been used. SCLC is a very poor prognosis type of cancer with only two approved lines of therapies. No third line drug thus far.
Research has not progressed in the past 2-3 decades for SCLC therapy until recently. Drugs that are approved are mostly chemotherapeutics such as etoposide, doxorubicin, topotecan, bendamustine, vinorelbine, methotrexate and the mTor inhibitor everolimus. One reason that explains the difficulty to develop innovative therapies against SCLC is the lack of known targetable drivers. P53, RB1, PTEN, NOTCH receptor and MYC are known to be mutated, inactivated or amplified but difficult to target. The need for new therapies and the fact that almost all SCLC patients are heavy current or former smokers led to testing immune-therapy in this indication. PD-1 and PD-L1 targeting antibodies as monotherapy or in combination with anti CTLA-4 antibodies are currently studied in phase 1 and 2 trials. Preliminary data presented at the annual ASCO (American Society of Clinical Oncology) meeting in Chicago in 2015 and 2016 are encouraging however not mature enough to draw final conclusions. Synergy between two immunotherapeutics (IO + IO) or between an IO and chemo (IO + CT) need to be assessed as far as efficacy and safety is concerned and also the optimal dosing schedule and line of treatment determined. Recent data from ASCO 2016 showed that IO + IO may lead to higher response rate and longer duration of response (18 months and beyond) in some patients compared to mono IO; however, toxicities are more frequent especially immune-related adverse events. The choice of the right biomarker remains a question as well.
A recent state of the art review by Cristea and Sage (JTO 2016) analyzed the potential of several known oncogenic drivers to be playing a role in SCLC. However, while oncogenes like EGFR, the RAF pathway, FGFR, IGFR and c-KIT can be found affected in some SCLC patients, the inactivation of their pathways paradoxically provides cancer cell with a growth advantage possibly due to missing feedback loops. Cristea and Sage therefore propose that their inhibitors e.g. a RAF inhibitor would not be effective as monotherapy but possibly in combination with immunotherapy, HSP90 or Bcl-2 inhbitors. Preclinical study results should be collected before going into humans.
One therapeutic approach that has not been discussed in this review concerns a DLL3 (delta-like protein 3 – suppresses Notch receptor signaling) targeted antibody drug conjugate. DLL3 is used to transfer a toxic agent into SCLC cells that overexpress specifically DLL3 in contrast to other (healthy?) tissues. Hypothesis-generating data from a phase 1 study with 74 SCLC patients has been presented at ESMO 2015 and ASCO 2016
In this phase 1 study, patients with high DLL3 expression (at least 50% overexpression using tissues samples) had better clinical benefit than low expressers: >30% overall response rate and >80% disease control rate. Interestingly, a trend could be seen that patients who received this ADC as third line might have a more pronounced benefit than 2nd line patients. But these data need to be confirmed in randomized phase 2/3 trials that are currently ongoing. DLL3 ADC therapy does induce side effects: 38% of patients suffered grade 3 sides effects e.g. skin reactions, thrombocytopenia, fatigue, pleural and serosal effusions.
Taken together, even in one of the hardest to treat types of lung cancer, SCLC, there is hope for patients to make progress with new innovations.
- World Cancer Report 2014
- Cristea S. and Sage J. (2016) Is the canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC? JTO Volume 11 No. 8: 1233-1241.
- Oral Abstract ASCO 2016: Safety and efficacy of single-agent SC16LD.6.5, a delta-like protein 3 (DLL3)-targeted antibody-durg conjugate (ADC) in recurrent or refractory SCLC.” Presented by Dr. Rudin from the MSKCC