IMpower133 displays potential of first-line atezolizumab in extensive stage SCLC
The addition of atezolizumab to standard of care (SOC) carboplatin and etoposide appears to improve overall survival (OS) and progression-free survival (PFS) in patients with extensive stage small cell lung cancer (ES-SCLC), setting in place a potential new SOC, according to the IMpower133* trial findings.
“There is no doubt that IMpower133 is the first study in over 20 years to demonstrate improvement in overall outcome by the addition of atezolizumab to standard chemotherapy for which we’re observing an improvement in OS and PFS,” said Professor Tony Mok from The Chinese University of Hong Kong who presented the findings at the European Society of Medical Oncology (ESMO) Asia Presidential Symposium.
In this trial, 403 systemic treatment-naïve patients (median age, 64 years) with measurable ES-SCLC and ECOG performance score 0–1 received intravenous carboplatin (AUC 5 mg/mL/min on day 1) plus etoposide (100 mg/m2 on days 1–3) with or without intravenous atezolizumab (1,200 mg on day 1) for four 21-day cycles. Responders followed up with a maintenance phase of either atezolizumab or placebo until disease progression or unacceptable toxicity, during which time eligible patients underwent prophylactic cranial irradiation (PCI).
Patients who received atezolizumab demonstrated greater OS compared with those who received placebo (median, 12.3 vs 10.3 months, hazard ratio [HR], 0.70; p=0.0069) as well as PFS (median, 5.2 vs 4.3 months, HR, 0.77; p=0.017). [ESMO Asia 2018, abstract LBA1]
OS and PFS were better in patients without brain metastases (HR, 0.68 and 0.75, respectively), with little effect seen in patients with brain metastases (HR, 1.07 and 0.98, respectively).
While objective response rate was similar between atezolizumab and placebo recipients (60.2 percent vs 64.4 percent), duration of response was slightly longer with atezolizumab (median, 4.2 vs 3.9 months) with a higher 12-month event-free rate (14.9 percent vs 6.2 percent).
The adverse event (AE) profile was comparable between groups with 56.6 and 56.1 percent of atezolizumab and placebo recipients, respectively, experiencing grade 3–4 treatment-related AEs. Haematological toxicities occurred at a similar rate between groups, though atezolizumab recipients experienced more immune-related AEs (eg, rash, hepatitis) than placebo recipients.
Subgroup analyses of PCI recipients
Seventeen and 18 patients who received atezolizumab and placebo, respectively, had brain metastases at time of enrolment, and had received either surgery or radiotherapy pre-enrolment. Among patients who developed brain metastases during treatment, three and four atezolizumab and placebo recipients, respectively, received thoracic radiotherapy and six and five, respectively, received brain or CNS** radiotherapy (excluding PCI).
Twenty-two patients without brain metastases in each group underwent PCI. Definitive thoracic radiation was not permitted during the trial.
“PCI has been shown to reduce the incidence of brain metastases in patients with ES-SCLC who have responded to systemic therapy but is associated with neurological AEs [with] NCCN*** and ESMO guidelines recommending that only patients who respond to first-line treatment and have a reasonable good performance score be considered for PCI,” said Mok.
However, recent data has shown the lack of apparent OS benefit with PCI compared with observation, he said. [Lancet Oncol 2017;18:663-671]
Among patients who underwent PCI or palliative thoracic radiation, the most common CNS-related adverse events were headache (n=8 and 3 in the atezolizumab and placebo groups, respectively) and aesthenia (n=5 and 2), which were also the most common CNS-related AEs in the overall safety population (n=24 and 23 reporting headaches in the atezolizumab and placebo groups, respectively, and n=25 and 20 with aesthenia). Two atezolizumab recipients who underwent PCI experienced dizziness; this AE was not reported in placebo recipients who underwent PCI. One atezolizumab recipient who underwent PCI withdrew from the study due to a CNS-related AE (aesthenia).
These findings suggest a possibility for CNS-related toxicity in atezolizumab recipients who underwent PCI. However, a majority of the CNS-related symptoms may not have been PCI-related, as the numbers reduced when assessing symptom incidence after PCI, and as such, some symptoms may have occurred pre-PCI. A causal relationship could not be determined due to the small number and timing of events, said Mok.
According to study discussant Dr Pilar Garrido from Hospital Universitario Ramón y Cajal in Madrid, Spain, there is a need for prospective information about the best way to manage patients with brain metastases in the era of immunotherapy.
“We [also] need predictive biomarkers not only to identify the patients most likely to benefit from immunotherapy, but also to identify those with a major risk of developing toxicities,” she said.