Immunotherapy Success in Small Cell Lung Cancer Has Completely Changed the Treatment Strategy

On 18 March 2019, the United States Food and Drug Administration (FDA) approved atezolizumab immunotherapy (brand name Tecentriq) for first-line treatment of adults with advanced small cell lung cancer, in combination with carboplatin and etoposide chemotherapy.

The approval is based on a randomized, multicenter, double-blind trial in patients who had not previously received chemotherapy for advanced disease and had an ECOG performance status of 0, involving 403 patients with small cell lung cancer, randomized (1: 1), and placebo -controlled in a phase-3 clinical trial called IMpower133.

Small cell lung cancer (SCLC) is a neuroendocrine tumor accounting for approximately % 15 of all lung cancers, almost all of which are caused by smoking.

Small cell lung cancer cells, compared with non-small cell lung cancer cells, grow and divide faster and have the ability to metastasize earlier.

Small cell lung cancer is usually at stage 4. at diagnosis, and fewer types and numbers of drugs are available than for other lung cancers. Indeed, for 40 years, the first-line (initial) treatment of advanced small cell lung cancer had not changed, and median overall survival in this group is approximately 10 months. Moreover, although SCLC has high response rates to both chemotherapy and radiotherapy , despite treatment, within months patients experience cancer recurrence .

The IMpower133 Study

The high tumor mutation rate in small cell lung cancer raised the question of whether immunotherapies might work in this cancer. In addition, suppressing PD-1 and PD-L1 signaling could activate the immune system’s T cells against small cell lung cancer cells, as shown in previous clinical trials; on 17 August 2018, for use alone as “second”-line SCLC treatment, another immune checkpoint inhibitor , nivolumab, received FDA approval . This prompted the question: “In advanced SCLC, first-line treatment—could immunotherapies work here too?” To answer this, the standard first-line dual chemotherapy of carboplatin + etoposide was supplemented with atezolizumab in the IMpower133 phase-3 clinical trial, assessing its efficacy; the trial was published on 6 December 2018 in NEJM.

Note: Atezolizumab (Tecentriq) had previously received FDA approvals in 2016 for 2. line urothelial (bladder and urinary tract) cancers and second-line non-small cell lung cancer (NSCLC), in 2017 for first-line urothelial cancers, in December 2018 for first-line non-squamous NSCLC, and in March 2019 for first-line triple-negative breast cancer (see the history of immunotherapies)

This double-blind, placebo -controlled phase 3 trial enrolled 403 previously untreated patients with advanced small cell lung cancer. Patients were randomly assigned equally to two groups to receive treatment every 21 days for 4 cycles. One group received standard dual chemotherapy plus atezolizumab; 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.

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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 with atezolizumab and 10.3 months with placebo. 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.
• Regarding adverse effects, the safety profile of atezolizumab plus carboplatin and etoposide was consistent with previously reported clinical trials, and no new adverse effects were observed.
• The subgroup analysis highlighted the following findings:
1. Patients older than 65 benefited more from atezolizumab,
2. Adding atezolizumab to standard treatment, in patients with brain metastases , survival was not prolonged,
3. Tumor mutational burden above 16 was associated with greater benefit from atezolizumab.

In IMpower133, the most common effects seen in ≥ % 20 of patients receiving atezolizumab were adverse effects, fatigue, asthenia (weakness, lack of strength), nausea, alopecia (hair loss), constipation , and loss of appetite.

For patients with small cell lung cancer, the recommended atezolizumab dose is every 3 weeks over 60 minutes intravenously (into a vein) at 1200 mg. When given on the same day, atezolizumab should be administered before chemotherapy. If the first infusion is tolerated, all subsequent infusions may be given over 30 minutes.

In conclusion , the standard first-line treatment for advanced small cell lung cancer has changed with this FDA approval based on IMpower133 results showing that immunotherapy prolonged overall survival.