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The eagerly anticipated clinical trial results from IMpower133 were reported recently in the by Stephen Liu, MD, director of both Thoracic Oncology and Developmental Therapeutics at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., and colleagues.

The study investigated the efficacy of a combination of atezolizumab with standard carboplatin/etoposide therapy in treatment-naïve extensive-stage small-cell lung cancer (ES-SCLC) patients. In the treatment arm, maintenance atezolizumab was continued after four cycles of initial therapy, until disease progression or toxicity.

Compared with placebo plus carboplatin/etoposide, there was improvement in median overall survival (OS) (12.3 vs 10.3 months), median progression-free survival (PFS) (5.2 vs 4.3 months), and median duration of response (DOR) (4.2 vs 3.9 months) with the atezolizumab combination therapy.

Interestingly, there was not an improved objective response rate with the combination atezolizumab with chemotherapy. There were also fewer patients enrolled with brain metastasis in this study, and so clear conclusions about the use of immunotherapy combinations in ES-SCLC patients with CNS disease remain uncertain.

Nevertheless, the toxicity was similar between the arms, with immune-related adverse events consistent with atezolizumab exposure requiring corticosteroids in 20% of patients. The infusion-related incidence of pneumonitis, however, was similar between arms.

Regarding the PDL-1 subgroup analysis, although the PDL-1 >5% subgroup seemed to derive a substantial OS benefit, there were some confounding factors which merit some discussion. As there were limited numbers of patients with PDL-1 expression of >5%, the cutoffs had to be set at 1% and 5%.

Indeed, it was also reported that only 34% of the study population was included in the overall PDL-1 analysis.

Also, PDL-1 expression in patients with ES-SCLC in this trial was observed more frequently on immune cells rather than tumor cells, which is different from what we observed in NSCLC. Therefore, when evaluating the PDL-1 subgroups as a whole, the authors were unable to conclude with certainty that there was a proportional degree of response with higher PDL-1 expression.

With regards to the tumor mutational burden (TMB) subgroup analysis, both TMB-high and TMB-low subgroups showed an OS benefit; however, TMB high and PDL-1 high did not perfectly correlate. As we have learned from other trials in both NSCLC and ES-SCLC, it is generally thought that TMB and PDL-1 are not interchangeable and may represent very distinct patient populations. Therefore, we still lack a useful biomarker or PDL-1 status to help drive treatment decisions in SCLC.

Despite its limitations, this was the first trial in decades to show an overall survival and duration-of-response benefit in treatment-naïve patients with ES-SCLC.

Further investigations are certainly warranted to evaluate the use of immunotherapy in this advanced cancer.

Hardeep Phull, MD, is a hematologist/oncologist at Sharp Healthcare & Sharp Rees-Stealy in San Diego.

Read the study here and an interview about it here.