Immunotherapy Atezolizumab Has Transformed First-Line Treatment of Small Cell Lung Cancer

Small cell lung cancer (KHAK), is a neuroendocrine tumor accounting for around % 15 of all lung cancers, almost all caused by smoking. Small cell lung cancer cells, compared with non-small cell lung cancer cells, grow and divide more quickly and undergo earlier metastasis . Small cell lung cancer is usually at stage 4 (advanced) at diagnosis, and fewer drugs and drug types are available for its treatment than for other lung cancers. Indeed, for 40 years there has been no change in first-line (initial) treatment of advanced small cell lung cancer, and median overall survival in this group is around 10 months. Also, although KHAK responds at a high rate to both chemotherapy and radiotherapy , despite treatment, within months cancer recurrence occurs.

The IMpower133 Study Testing the Efficacy of the Immunotherapy Atezolizumab in First-Line Treatment of Small Cell Lung Cancer

Small cell lung cancer has a high tumor mutation rate, raising the question of whether immunotherapies might work in this cancer. In addition, blocking PD-1 and PD-L1 signaling had previously been shown to activate the immune system's T cellsagainst small cell lung cancer cells in previous clinical trials, and on 17 August 2018, for use alone in "second"-line KHAK treatment, another immune checkpoint inhibitor , nivolumab, FDA approval had received. This raised the question, "In advanced KHAK, first-line treatment: can immunotherapies work here too?" To answer this question, the standard first-line treatment, carboplatin + etoposide doublet chemotherapy was studied with the addition of atezolizumab in IMpower133, a phase-3 clinical trial published on 6 December 2018 in NEJM.

Note: Atezolizumab (Tecentriq) had previously received FDA approval in 2016 for urothelial (bladder and urinary tract) cancer treatment at line 2 and for second-line non-small cell lung cancer, and in 2017 for first-line urothelial cancer. This double-blind, placebo -controlled phase 3 study enrolled 403 previously untreated patients with advanced small cell lung cancer. Patients were to receive treatment every 21 days for 4 cycles and were randomly assigned in equal proportions to two groups. One received standard doublet chemotherapy plus atezolizumab, while the other received standard treatment plus placebo; treatment continued until unacceptable adverse effects or disease progression. The primary endpoints were progression-free survival and overall survival.

Results

• A total of 201 patients were randomly assigned to the atezolizumab group and 202 to the placebo group.
• At a median follow-up of 13.9 months, median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group. Adding atezolizumab to standard treatment reduced the risk of death by % 30.
• Median progression-free survival was 5.2 months and 4.3 months, respectively. Atezolizumab reduced the risk of progression by % 23.

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• Regarding adverse effects, the safety profile of atezolizumab plus carboplatin and etoposide was consistent with previously reported clinical studies, and no new adverse effects were observed.
• The following findings were noteworthy in the study's subgroup analysis:

• Patients older than 65 benefited more from atezolizumab,
• Adding atezolizumab to standard treatment, in patients with brain metastases , their survival did not extend,
• Tumor mutation burden above 16 was associated with greater benefit from atezolizumab.

In conclusion, adding atezolizumab to chemotherapy in first-line treatment of advanced small cell lung cancer provides significant benefits in both overall and progression-free survival compared with chemotherapy alone. The "few months" gained in the study may initially seem brief, but considering that first-line KHAK treatment has not changed for nearly 40 years, these are important findings with the potential to change clinical practice. A benefit in overall survival, not just progression-free survival, is also valuable. Immunotherapies have this characteristic: those who benefit have a prolonged duration of response. Thus, even if the proportion benefiting is small, the benefit may last several years. We may see a more pronounced increase in survival when the long-term results are announced.