CHICAGO – The oral investigational MEK inhibitor selumetinib has crossed a clinical hurdle in the treatment of KRAS-mutated non–small cell lung cancer, but it was not without a cost in terms of toxicity.
When compared with docetaxel alone in a phase II trial of 87 patients with locally advanced or metastatic disease, second-line treatment with selumetinib plus docetaxel significantly improved all secondary outcomes:
• Progression-free survival went from 2.1 months to 5.3 months (hazard ratio, 0.58; 1-sided P value = .013).
• Response rate went from 0% to 37.2% (two-sided mid P value less than .0001).
• The percent alive and progression free at 6 months rose from 15.8% to 37.1% (one-sided P = .0158).
• The change in tumor size at 12 weeks favored selumetinib by –26% (one-sided P = .004).
The primary end point of overall survival was increased as well from 5.2 months to 9.4 months with selumetinib plus docetaxel, albeit not significantly (HR, 0.80; 1-sided P = .206).
Dr. Pasi Jänne
"This is the first prospective study to demonstrate a clinical benefit for patients with KRAS-mutant non-small cell lung cancer or even perhaps for KRAS-mutant patients of any cancer," lead author Dr. Pasi Jänne said at the meeting.
The results were met with enthusiasm because KRAS is the most frequently mutated oncogene in non–small cell lung cancer outside Asia, but currently there is no targeted therapy for this subset of patients. In addition, these patients fail to derive the same benefit from chemotherapy and do not respond to epidermal growth factor receptor (EFGR) targeted therapies.
Selumetinib is a selective inhibitor of MEK 1/2, a critical downstream effector protein of KRAS signaling. When used as monotherapy, it has shown clinical activity in second-/third-line NSCLC, but was not superior to pemetrexed (J. Thorac. Oncol. 2010;5:1630-6).
Invited discussant Dr. Joel Neal of Stanford (Calif.) University also heralded selumetinib plus docetaxel as the first clinically validated strategy for KRAS-mutant NSCLC, but called the toxicity significant.
"The ideal targeted therapy is probably a little less toxic and maybe potentially even more effective," he said.
Four of the 44 patients (9%) treated with selumetinib plus docetaxel died as the result of a serious adverse event, and 21, or 47.7% were hospitalized from an adverse event.
Adverse events led to dose reductions of selumetinib in 34% of patients and dose interruptions in 45.5%.
Grade 3/4 peripheral edema (2.3%), dermatitis acneiform (6.8%) and febrile neutropenia (18.2%) were all increased in selumetinib patients, and were absent in controls.
Some disease-related adverse events were improved with the addition of selumetinib, said Dr. Jänne of the Dana Farber Cancer Institute in Boston. Grade 3/4 decreased appetite was absent in patients treated with the combination vs. 2.4% of controls) and there was less fatigue of all grades (27.3% vs. 33.3%) or grade 3/4 (0% vs. 7.1%).
Dr. Neal pointed out that the response rate in unselected second- or third-line non–small cell lung cancer trials is generally 9%, and ranges from 57% to 70% when targeted agents such as erlotinib (Tarceva) and crizotinib (Xalkori) are used against the correct molecular alteration.
"This trial falls somewhere in between, which is still very impressive," he said.
The 5.3 month progression-free survival with selumetinib also falls between the 2-3 months reported in unselected trials and the 9 months or better in selected trials.
Selumetinib’s overall survival time of 9.4 months surpasses that of 7-8 months in unselected trials, but falls short of the astounding overall survival times of roughly 24 months for crizotinib in patients with an anaplastic lymphoma kinase (ALK) rearrangement and 27 months for erlotinib in those with an EGFR mutation.
As for whether KRAS is truly an actionable target in non–small cell lung cancer, Dr. Neal said it probably depends on the agent.
"With selumetinib and docetaxel, I’d say probably; this looks very promising," he said.
Dr. Joel Neal
The answer was a more equivocal "possibly" for other targeted therapies such as the selective MET inhibitor tivantinib plus erlotinib or the investigational MEK inhibitor GSK 1120212.
Both men observed that the clinical activity of selumetinib plus docetaxel could be affected by dosing order (Br. J. Cancer 2012;106:858-66) and other passenger mutations such as p53, which was recently shown in a mouse model to be more sensitive to the combination than the LKB1 mutation (Nature 2012;483:613-7).
Patients in the phase II trial were randomized to docetaxel 75 mg/m2 administered every 21 days plus twice-daily selumetinib 75 mg or placebo. The selumetinib arm received a median of five cycles and the control arm, four cycles.