Selumetinib adds no benefit to docetaxel in KRAS-mutant advanced NSCLC
medwireNews: Adding selumetinib to docetaxel does not improve progression-free survival (PFS) over docetaxel alone in patients with previously treated, advanced, KRAS-mutant non-small-cell lung cancer (NSCLC), phase III trial data show.
During the SELECT-1 trial, which was conducted at 202 sites across 25 countries, 510 patients with disease progression following first-line therapy were randomly assigned to receive the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib, or placebo, in combination with docetaxel.
At the time of data analysis, patients in both groups had received a median of four treatment cycles. Disease progression had occurred in 88% of patients, overall, and 68% had died.
There was no significant difference in PFS between the groups, at 3.9 months with selumetinib plus docetaxel and 2.8 months with docetaxel alone. And results were similar in exploratory analyses based on KRAS mutation subtype.
Overall survival was also similar between the two groups, at 8.7 and 7.9 months, respectively.
By contrast, the researchers found that objective response was significantly better with selumetinib plus docetaxel than with docetaxel alone (20.1 vs 13.7%), but the response duration was shorter (2.9 vs 4.5 months).
Diarrhea and nausea were the most common adverse events in both groups, followed by rash with selumetinib plus docetaxel and fatigue with docetaxel alone. Grade 3 or worse adverse events were more common in the selumetinib group, where they were reported by 67% of patients, compared with 45% in the group that only received docetaxel.
Writing in JAMA, Pasi Jänne (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and colleagues note that their findings “differ from those observed in a prior smaller randomized phase 2 trial with the same design,” which showed that selumetinib plus docetaxel significantly improved PFS compared with docetaxel alone.
They say that the differences are unlikely to be due to study design or geography because both were conducted at multiple sites worldwide, but may be caused by “differences in the distribution of concomitant genomic alterations, alongside KRAS mutations.”
Commenting on the findings in an accompanying editorial, Jacob Kaufman (Duke University, Durham, North Carolina, USA) and Thomas Stinchcombe (Duke Cancer Institute, Durham, North Carolina, USA) say: “The oncology community will be left seeking an explanation for these nonsignificant trial results and wondering what next investigational path should be pursued in this population.”
They add: “Although selumetinib demonstrated little suggestion of benefit in SELECT-1, it may be premature to conclude that other [MEK inhibitors] will be ineffective given differences in their inhibitory mechanism.”
Kaufman and Stinchcombe conclude: “The development of a targeted therapy is critical to the future management of patients with KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations.”
By Laura Cowen
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