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Selumetinib fails to improve PFS in KRAS–mutant advanced NSCLC
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The addition of selumetinib to docetaxel did not improve PFS among patients with KRAS–mutant non–small cell lung cancer, according to results of the SELECT-1 clinical trial.
“KRAS mutations represent the largest genomically defined subset of lung cancer,” Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, and colleagues wrote. “There remains a great need to develop effective therapies of this subset of patients and the findings from the present study further highlight this.”
Because directly targeting KRAS is challenging, research efforts have focused on inhibiting KRAS effector proteins downstream. Selumetinib (AZD6244/ARRY-142886; AstraZeneca/Array BioPharma) is a potent, highly selective MEK1/2 inhibitor, a target downstream from KRAS.
A previous phase 2 trial showed the addition of selumetinib to docetaxel significantly improved PFS and objective response rate in patients with KRAS–mutant NSCLC.
To confirm this benefit, Jänne and colleagues evaluated data from 510 patients (mean age, 61.4 years; women, 41%) with KRAS–mutant NSCLC and disease progression following first-line anticancer therapy. Researchers randomly assigned patients to receive docetaxel 75 mg/m2 via IV on day 1 of every 21-day cycle with 75 mg selumetinib twice daily (n = 254) or placebo (n = 256). Patients also received prophylaxis with granulocyte colony–stimulating factor.
PFS served as the primary endpoint. Secondary objectives included OS, objective response rate, safety and tolerability.
At the time of data cutoff, 88% of patients experienced a progression event (n = 447) and 68% of patients had died (n = 346).
Patients treated with selumetinib demonstrated a longer median PFS (3.9 months vs. 2.8 months; HR = 0.93; 95% CI, 0.77-1.12) and longer median OS (8.7 months vs. 7.9 months; HR = 1.05; 95% CI, 0.85-1.3), but the differences did not reach statistical significance.
Researchers observed a higher ORR among patients assigned selumetinib (20.1% vs. 13.7%; OR = 1.61; 95% CI, 1-2.62).
More patients treated with selumetinib experienced grade 3 or worse adverse events (67% vs. 45%), including serious adverse events (49% vs. 32%) and adverse events leading to hospitalization (46% vs. 30%).
Selumetinib use had no significant effect on the time to symptom progression (HR = 0.9; 95% CI, 0.73-1.11) or symptom improvement rates (OR = 1.17; 95% CI, 0.74-1.86).
The lack of improved PFS from the regimen will likely leave oncologists and clinicians left with many questions, Jacob Kaufman, MD, PhD, internal medicine resident in the department of medicine at Duke University, and Thomas E. Stinchcombe, MD, medical oncologist and instructor in the department of medicine at Duke Cancer Institute, wrote in a related editorial.
“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,” Kaufman and Stinchcombe wrote.
Next-generation therapies will most likely be more potent and specific for the oncogenic driver, which will “improve efficacy and reduce off-target toxicities,” they added. – by Melinda Stevens
Disclosures: Jänne reports grants or fees from Ariad, Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Merrimack and Roche, as well as stock ownership in Gatekeeper Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures. Kaufman and Stinchcombe report no relevant financial disclosures.
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