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Atezolizumab Plus Chemotherapy Improves Outcomes in Small Cell Lung Cancer


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ATEZOLIZUMAB (TECENTRIQ), an anti–program cell death ligand 1 (PD-L1) antibody, combined with carboplatin/ etoposide as first-line treatment for extensive-stage small-cell lung cancer (SCLC) improved overall and progression-free survival and may represent a new standard of care, according to experts at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer.1 However, the survival gain was modest, and the high cost of immunotherapy may not lead to widespread adoption of this option.

At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group vs 10.3 months in the placebo arm, representing a 30% reduction in the likelihood of death (hazard ratio [HR] = 0.70, P = .007). These findings were published in The New England Journal of Medicine to coincide with the IASLC presentation.2

Stephen V. Liu, MD

Stephen V. Liu, MD

“IMpower133 is the first trial in more than 20 years to show a clinically meaningful improvement in overall survival compared with the current standard of care in first-line extensive-stage SCLC,” stated senior study author Stephen V. Liu, MD, of Georgetown University, Washington, DC. “These findings suggest that atezolizumab/carboplatin/etoposide represents a new standard for the first-line treatment of extensive-stage SCLC.”

“Over the past 2 decades, there has been little progress in the first-line treatment of extensive-stage SCLC. With the current standard—platinum plus etoposide—outcomes remain poor, with a median overall survival of about 10 months,” Dr. Liu said. “New treatments are needed. Preclinical and clinical evidence suggests possible synergy between immunotherapy and chemotherapy, which led to the design of IMpower133,” he added.

IMpower133 Details

THE RANDOMIZED, placebo-controlled, double-blind phase III study enrolled 403 patients with measurable extensive-stage SCLC not previously treated. Enrollment took place at 106 sites in 21 countries. Patients with treated, asymptomatic brain metastases were allowed. Baseline characteristics were well balanced between the two treatment arms. Twenty-two patients in each group received prophylactic cranial irradiation.

“IMpower133 is the first trial in more than 20 years to show a clinically meaningful improvement in overall survival compared with the current standard of care in first-line extensive-stage SCLC.”
— Stephen V. Liu, MD

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Study participants were randomly assigned 1:1 to receive 4 cycles of carboplatin/etoposide with either 1,200 mg of atezolizumab on day 1 of each cycle or placebo, followed by maintenance therapy with atezolizumab or placebo according to previous randomization until disease progression or toxicity. Continuation of treatment was allowed after disease progression if there was evidence of clinical benefit. Tissue samples were requested, but not mandated, for all patients.

At 13.9 months of follow-up, a clear separation of curves was evident for the co-primary endpoint of overall survival or investigator-assessed progression-free survival. More patients in the atezolizumab arm were alive at 1 year than in the placebo arm: 51.7% vs 38.2%.

Atezolizumab also improved progression-free survival; the median progression-free survival was 5.2 months and 4.3 months, respectively, representing a 23% improvement favoring the addition of immunotherapy (HR = 0.77; P = .02). “There was a doubling of 12-month progression-free survival with atezolizumab: 12.6% vs 5.4%, respectively,” Dr. Liu stated.

Subgroup Analysis

THE BENEFIT of atezolizumab was consistent across key subgroups, including sex, age (< 65 years or older), Eastern Cooperative Oncology Group score (0 vs 1), presence of liver metastases, and level of tumor mutation burden. There was no difference in overall or progression-free survival between the two treatment arms in patients with treated brain metastases, but these numbers were too small to interpret, Dr. Liu explained.

The objective response rate was similar in both arms (60.2% for atezolizumab vs 64.4% for placebo), but about 3 times more patients in the atezolizumab arm had an ongoing response at the time of data cutoff: about 15% vs 4% for placebo. Blood tumor mutation burden did not identify patients more likely to respond to the immunotherapy combination. About 50% of patients in each arm received subsequent therapy.

Safety

THE SAFETY profiles of all three drugs were similar to what has been previously reported, Dr. Liu continued. There were no new safety signals. The frequency of adverse events, including hematologic events, was similar in both arms, except immune-related adverse events were more common in patients who received atezolizumab.

Adverse events associated with any of the components of the treatment regimen occurred in 94.9% of the atezolizumab group and 92.3% of the placebo group. Hematologic events were the most frequent events associated with the treatment regimen. Deaths occurred in three patients in each treatment group.

Immune-related adverse events were reported in 39.9% of the atezolizumab arm and 24.5% of the placebo arm. Rash and hypothyroidism were the most common immune-related adverse events.

“Both groups got the same median number of chemotherapy doses, suggesting that atezolizumab does not interfere with the ability to give four cycles of standard chemotherapy,” he said. ■

DISCLOSURE: IMpower133 was funded by F. Hoffmann-La Roche, Ltd. Dr. Liu is a consultant/advisor with AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, Heron, Lilly, Pfizer, Regeneron, Taiho, and Takeda; and has received institutional research grants from AstraZeneca, Bayer, Blueprint, Clovis, Corvus, Esanex, Genentech, Lilly, Lycera, Merck, Molecular Partners, OncoMed, Pfizer, and Threshold.

REFERENCES

1. Liu SV, Mansfield AS, Szczesna A, et al: IMpower133: Primary PFS, OS, and safety in a PH1/3 study of 1L atezolizumab + carboplatin + etoposide in extensive-stage SCLC. 2018 World Conference on Lung Cancer. Abstract PL02.07. Presented September 25, 2018.

2. Horn L, Mansfield AS, Szczesna A, et al First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. September 25, 2018 (early release online).


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