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Selumetinib plus docetaxel fails to extend survival in KRAS–mutant NSCLC
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COPENHAGEN, Denmark — The addition of selumetinib to second-line docetaxel did not improve outcomes among patients with KRAS–mutant non–small cell lung cancer, according to phase 3 study results presented at the European Society for Medical Oncology Congress.
“Hence, it is not a treatment approach that should be adapted moving forward, and there remains a desperate need and an opportunity to develop new treatments for this subset of NSCLC patients,” Pasi A. Janne, MD, PhD, translational thoracic medical oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, said in a press release.
Selumetinib (AZD6244/ARRY-142886; AstraZeneca/Array BioPharma) is a potent, highly selective MEK1/2 inhibitor that inhibits an effector protein downstream from KRAS. This process was thought to mitigate KRAS–mediated signaling in KRAS mutation–positive cancers.
A phase 2 trial showed the addition of selumetinib to docetaxel significantly improved PFS and objective response rate in patients with KRAS–mutant NSCLC.
Janne and colleagues conducted the randomized, double blind SELECT-1 trial to confirm this potential benefit.
The analysis included 510 patients with KRAS–mutant NSCLC. Researchers assigned 254 patients to 75 mg selumetinib twice daily plus docetaxel 75 mg/m2 via IV on day 1 of every 21-day cycle. The other 256 patients received placebo plus docetaxel. Patients also received prophylaxis with granulocyte colony stimulating factor.
Secondary objectives include OS, objective response rate, safety and tolerability.
At the time of data cutoff, 447 patients (88%) had progressed and 346 (68%) had died.
Patients assigned selumetinib achieved 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 also reported a higher objective response rate in the selumetinib group (20.1% vs. 13.7%; OR = 1.61; 95% CI, 1-2.62), but the difference was not statistically significant.
Selumetinib-treated patients experienced higher rates of grade 3 or higher adverse events (67% vs. 45%), serious adverse events (49% vs. 32%) and adverse events leading to hospitalization (46% vs. 30%).
“Dr. Janne and colleagues should be congratulated for performing a well-designed genotype-driven trial; however, the preclinical rationale for studying this combination specifically in KRAS–mutant NSCLC was weak at best,” Alex Adjei, MD, PhD, director of the early cancer therapeutics program and global oncology at Mayo Clinic in Rochester, Minnesota, said in a press release.
“Selumetinib and other MEK inhibitors are not effective in KRAS–mutant NSCLC cell lines and, while there are preclinical data that demonstrate cytotoxic synergy between selumetinib and other MEK inhibitors combined with docetaxel in a number of tumor types — including NSCLC — such synergy is independent of KRAS status,” Adjei, who was not involved in the study, added.
A prior randomized phase 2 trial showed the addition of another MEK inhibitor, trametinib (Mekinist, Novartis), to docetaxel failed to yield benefit in patients with KRAS–mutant NSCLC compared with those who had KRAS wild-type disease, Adjei noted.
“Furthermore, the phase 2 study on which this phase 3 trial design was based had a very small sample size,” Adjei said. “Historically, such small randomized phase 2 studies have led to negative phase 3 trials.” – by Mark Leiser
For more information: Janne PA, et al. Abstract LBA47_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: AstraZeneca provided funding for this study. Janne 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 abstract for a list of all other researchers’ relevant financial disclosures.