Maintenance immunotherapy fails to improve survival in extensive-stage small cell lung cancer (SCLC), according to late-breaking results from the CheckMate 451 study to be presented today at the European Lung Cancer Congress 2019 (ELCC). 

Around 60–70 percent of patients with SCLC have extensive disease at the time of diagnosis, meaning it has spread beyond a single lung and nearby lymph nodes and cannot be treated with radiotherapy.

Most patients respond to chemotherapy, but the duration of the response is usually short, and their cancer grows within a short period of time.

The standard approach after chemotherapy is to wait until the tumour grows before intervening.

This study examined whether acting earlier, by giving maintenance immunotherapy after successful chemotherapy, would improve overall survival.

The study enrolled 834 patients with extensive-stage SCLC whose cancer did not progress after four cycles of chemotherapy.

Patients were randomly allocated in a 1:1:1 ratio to combination immunotherapy with nivolumab and ipilimumab, nivolumab alone, or placebo.

Patients were treated for two years or until cancer progression, death, or unacceptable toxicity.

Compared to placebo, overall survival was not significantly prolonged with combination immunotherapy (the primary endpoint) or with nivolumab alone.

Study author Professor Taofeek Owonikoko, Co-Chair of the Clinical and Translational Review Committee, Winship Cancer Institute of Emory University, Atlanta, US, said the finding was “a big disappointment”.

But he added: “There was some indication that compared to placebo, it took longer for the cancer to progress in patients who received either combination immunotherapy or nivolumab alone. This was not the primary endpoint of the study so we cannot make definitive conclusions, but it shows that this strategy could be promising, especially in patients who are responsive to immunotherapy. The challenge will be how to select and identify those patients since patients who began maintenance therapy sooner after completion of chemotherapy did appear to derive greater benefit.”

Adverse event rates were 86 percent with nivolumab plus ipilimumab, 61 percent with nivolumab, and 50 percent with placebo.

Rates of discontinuation due to toxicity were 31 percent with combination immunotherapy, 9 percent with nivolumab, and less than 1 percent with placebo.

Treatment-related deaths occurred in seven (2.5 percent) patients on nivolumab plus ipilimumab, one patient on nivolumab and one patient on placebo.

Commenting on the results, Dr Pilar Garrido, co-chair of this year’s ELCC Congress, said: “This appears to be the end of the story for maintenance immunotherapy in unselected SCLC patients. A previous smaller study was also negative. Although the progression-free survival results seem positive, the design of the study means they cannot be considered because the primary endpoint was negative. On top of that, there is concern about deaths and stopping treatment because of toxicity."

Garrido, who is head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said there are specific challenges related to translational research in small cell lung cancer.

“SCLC is a ‘recalcitrant’ disease and research in this field is particularly challenging, for several reasons, including the rapid pace at which the disease progresses and the limited availability of tissue,” noted Garrido.

Although there are some positive data, the final role of immune checkpoint inhibitors will be shaped by the results of ongoing trials.

Predictive biomarkers will be crucial for identifying SCLC patients with small cell lung cancer who could be treated with immune checkpoint inhibitors and should be assessed within prospective studies to better understand the complexity of the immune response.

As for whether there could be a subset who responds to maintenance treatment, Garrido concluded: “The study is negative and with the information available it seems difficult to say. The commitment with high quality research is key because we desperately need new options for our SCLC patients.”

Source: European Lung Cancer Congress 2019