An Update on Small Cell Lung Cancer

There are approximately 2700 new cases of lung cancer in Ireland each year with small cell lung cancer accounting for 13-15%. Most patients present with extensive stage disease, which is defined as spread of disease beyond what can be reasonably covered in a single radiation field. For the last three decades treatment options for these patients have been limited to platinum based chemotherapy. 5 year survival rates remained stubbornly low at 5%, with 1 year survival rates of 25.7% in Ireland over the period 2004- 2007. This has changed in the last five years with the addition of immunotherapy now becoming the standard of care in the extensive stage setting.

There were several challenges associated with improving outcomes for people with small cell lung cancer. It often presents with rapid onset of symptoms and at a late stage, and although usually initially sensitive to platinum based chemotherapy it relapses quickly. It also occurs almost exclusively in those with a heavy smoking history and if a patient’s baseline health is poor, they may be unable to tolerate second or third line treatment.

On a molecular level it is very different to non-small cell lung cancer. It is characterised by a high mutation load, high mitotic index and rapid proliferation rate. While the identification of targetable driver mutations has revolutionised care for many with metastatic non-small cell lung cancer (NSCLC), small cell is largely driven by loss of function mutations such as p53 and Rb deletions which are less amenable as drug targets.

Immunotherapy is particularly effective in malignancies with a high tumour mutational burden (TMB) such as melanoma, and in treatment for NSCLC a higher TMB score is associated with a longer duration of response compared to those with a lower score. Immunotherapy should have been a natural option for small cell lung cancer given its high TMB, but the benefit was slow to be proven. One reason may be that with the high burden of disease and rapidity of progression, the time needed to mount an effective anti-tumour response (often 6 months with immunotherapy) may exceed the overall survival of these patients. Alternatively, there may be other immunologic mechanisms by which small cell lung cancer evades immune surveillance that are not as easily targeted. Initial trials in the first line setting were not encouraging. One phase II trial, NCT02359019, found no benefit in overall survival for maintenance Pembrolizumab after initial platinum chemotherapy in patients with extensive stage disease. There was also a negative phase III trial, NCT01450761, which showed no benefit in overall survival for the addition of Ipilimumab to standard chemotherapy.

However in 2018 a trial emerged which showed benefit of upfront immunotherapy in combination with chemotherapy in the setting of treatment-naive extensive stage small cell lung cancer. In IMPower 133, 403 patients with extensive stage small cell lung cancer were randomised to receive an induction phase of either four cycles of carboplatin and etoposide alone, or with the addition of Atezolizumab, an immune checkpoint inhibitor. Following this they entered a maintenance phase to receive either placebo or Atezolizumab four weekly until progression of disease or unacceptable toxicity. The median overall survival was 12.3 months in the Atezolizumab group compared to 10.3 months in the placebo group At 18 months, 34.0% of the Atezolizumab-chemotherapy compared with 21.0% of the standard treatment group were alive. Toxicities were similar in both groups, although with increased immune-related adverse events in the Atezolizumab group.

The CASPIAN trial was a similar phase III trial published in November 2019. It randomised 805 patients to receive either platinum based standard of care treatment or with the addition of Durvalumab, followed by a phase of either maintenance Durvalumab or placebo. Durvalumab is an immune checkpoint inhibitor monoclonal antibody which blocks the interaction of programmed death ligand 1. Immune mediated toxicities included rash, thyroid dysfunction, type 1 diabetes and pneumonitis. The overall survival in the Durvalumab group was 13 months compared to 10.3 months in the chemotherapy alone group. While three months may seem a small benefit, the durability of response is seen in the 3 year survival data. The 36-month overall survival rate was 17.6% in the Durvalumab group versus 5.8% in the control group – in other words, triple the amount of patients who received Durvalumab were alive at three years.

At present the only immunotherapy reimbursed in small cell lung cancer in Ireland is Atezolizumab. Globally, further trials are ongoing to investigate the role of immunotherapy monotherapy, dual agent immunotherapy regimes, and immunotherapy in the limited stage setting. There are also novel agents under development such as PARP inhibitors and antibody-drug conjugates such as sacituzumab-govotecan. It may be several years before these are translated in to standard clinical practice in Ireland, particularly because of the high costs associated with these drugs, however they represent exciting developments after many years of stagnation in the treatment for small cell lung cancer.