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Sacituzumab govitecan plus pembrolizumab missed both survival goals in EVOKE-03

Adding the antibody-drug conjugate sacituzumab govitecan to pembrolizumab did not significantly delay progression or extend life in untreated metastatic non-small cell lung cancer with high PD-L1 expression, the phase 3 EVOKE-03 trial reported at the World Conference on Lung Cancer in Seoul. Median progression-free survival was 11.8 months with the combination and 7.7 months with pembrolizumab alone, short of its statistical bar, and overall survival was 21.5 against 22.8 months. Responses were more frequent, and so were severe side effects.

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Progression-free survival was longer but not by enough

The EVOKE-03 trial, also filed as KEYNOTE-D46, asked whether pairing sacituzumab govitecan, an antibody-drug conjugate that delivers a chemotherapy payload to tumour cells, with the checkpoint inhibitor pembrolizumab beats pembrolizumab alone as first-line treatment for metastatic non-small cell lung cancer in which at least 50 percent of tumour cells express PD-L1. The answer presented at the IASLC 2026 World Conference on Lung Cancer in Seoul, the annual meeting of the International Association for the Study of Lung Cancer, was no on both primary endpoints. By independent central review, median progression-free survival was 11.8 months with the combination and 7.7 months with pembrolizumab alone; the hazard ratio of 0.81 came with a range of 0.66 to 1.00 and fell short of the prespecified significance threshold. At the interim analysis of overall survival, medians were 21.5 months with the combination and 22.8 months with pembrolizumab alone, a hazard ratio of 1.07 with a range of 0.85 to 1.35. Giannis Mountzios of the Henry Dunant Hospital Center in Athens, who presented the trial, said the combination gave numerically longer progression-free survival and a higher response rate but did not reach statistical significance on the primary endpoint, and that overall survival was not significantly improved at this analysis.[1]

Responses came more often among the 620 people treated

EVOKE-03 is an open-label phase 3 study, and the 620 people in it had previously untreated metastatic non-small cell lung cancer, PD-L1 expression on at least 50 percent of tumour cells and no EGFR, ALK or ROS1 alterations. One arm received sacituzumab govitecan at 10 mg/kg intravenously on days 1 and 8 plus pembrolizumab at 200 mg on day 1 of each 21-day cycle; the other received pembrolizumab alone. The two primary endpoints were progression-free survival by independent central review and overall survival. Where the combination did better, confirmed responses reached 55.6 percent of its arm against 43.7 percent of the pembrolizumab arm, disease control 83.3 percent against 73.1 percent, and the median response lasted 21.4 months against 21.3 months, so responses came more often without lasting longer.[1]

Severe side effects more than tripled with the combination

Treatment-related adverse events occurred in 93.2 percent of patients on the combination and 65.4 percent on pembrolizumab alone, and grade 3 or higher events in 55.7 percent against 16.5 percent. The most common events in the combination arm were anaemia, hair loss, neutropenia, diarrhoea and nausea, a profile the presenters described as consistent with the known profiles of the two drugs, with no new toxicities from combining them. Mountzios concluded that, despite the numerical gain in progression-free survival and the higher response rate, the pairing did not reach statistical significance against pembrolizumab alone in untreated PD-L1-high disease and did not improve overall survival at the interim analysis, findings he said carry information for how treatment strategies in this group are evaluated. The results were reported as a conference presentation; a journal publication does not yet exist.[1]

References

  1. News sourceIASLCEVOKE-03: sacituzumab govitecan plus pembrolizumab missed its primary PFS bar↩1↩2↩3
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