Currently, there are no approved therapies for KRAS-mutant non–small cell lung cancer (NSCLC), and few clinical trials have been performed specifically in this setting. In a recent article in Lancet Oncology, Pasi A. Jänne, MD, PhD, Scientific Director, Belfer Institute for Applied Cancer Science, and Associate Professor of Medicine, Harvard Medical School, and colleagues at the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, reported results of a phase II study showing promising activity of the oral MEK inhibitor selumetinib plus docetaxel in patients with KRAS-mutant NSCLC.1 Selumetinib inhibits MEK1/MEK2 downstream from KRAS, with preclinical studies indicating that it inhibits KRAS-mutant tumor growth and exhibits a synergistic antitumor effect in combination with docetaxel. A phase II study of monotherapy showed little activity of selumetinib in an unselected pretreated population of NSCLC patients.
Study Details
In this study, 87 patients were randomly assigned to receive selumetinib at 75 mg twice daily plus docetaxel at 75 mg/m2 on day 1 of a 21-day cycle (n = 44) or docetaxel alone (n = 43). There were slight imbalances between the selumetinib and placebo groups in some baseline characteristics. For the selumetinib and placebo groups, 52% and 53% of patients were female, median ages were 59.5 and 59 years, 89% and 88% were current (16% and 26%) or past smokers, 52% and 51% had an ECOG performance status of 1, 68% and 53% had adenocarcinoma (14% and 23% had bronchoalveolar adenocarcinoma), and 89% and 98% had stage IV disease.
All patients had received at least one prior treatment regimen (surgery, radiotherapy, or neoadjuvant or adjuvant chemotherapy), and 11% and 14% had two or more. All had prior chemotherapy, including platinum compounds in 98% and 100%, taxanes in 39% and 30%, and vinca alkaloids/analogs in 9% and 21%; 27% and 26% had prior surgery, and 27% and 53% had prior radiotherapy. Best response to prior chemotherapy was complete response in 2% and partial response in 36% of the selumetinib group and complete response in 2% and partial response in 16% of the placebo group.
Median treatment durations were 117 days (range, 7–435 days) in the selumetinib group and 68 days (range, 7–463 days) in the placebo group. The median numbers of docetaxel cycles were 5 (1–9) and 4 (1–12). One patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumors were not confirmed to be KRAS-mutation positive. The relative dose intensity of docetaxel was 86% in the selumetinib group and 91% in the placebo group. Selumetinib dose reduction and dose interruption occurred in 36% and 55% of patients, respectively. Poststudy chemotherapy was used in 44% of selumetinib patients and in 55% of placebo patients.
Significant Improvements in Secondary Endpoints
Although there was no significant difference between the two groups in median overall survival (the primary endpoint of the study), selumetinib treatment was associated with significant improvements in progression-free survival, objective response rate, and patient-reported outcomes.
Median overall survival was 287 days in the selumetinib group and 157 days in the placebo group, representing a nonsignificant 20% reduction in risk for death with selumetinib treatment (hazard ratio [HR] = 0.80, 80% confidence interval [CI] = 0.56–1.14, P = .21). Median progerssion-free survival was 5.3 months in the selumetinib group and 2.1 months in the placebo group, representing a significant 42% reduction in risk for progression (HR = 0.58, 80% CI = 0.42-0.79, P = .014).
Objective response was significantly more common with selumetinib plus docetaxel than with docetaxel alone (37% vs 0%, P < .0001). All responses were partial responses. Median duration of response was 182 days.
Outcomes on the patient-reported Lung Cancer Specific Symptom Questionnaire—Lung Cancer Subscale (LCS) also showed benefit of selumetinib treatment. More selumetinib patients had improvement on the LCS (44% vs 24%, P = .029), and median time to deterioration in LCS score was longer in the selumetinib group (186 vs 49 days, P = .0002).
Toxicity Increased with Combination
Adverse events were more common with selumetinib treatment. The most common adverse events of any grade in the selumetinib group were neutropenia, diarrhea, nausea, vomiting, peripheral edema, rash, and stomatitis, all of which were more common than in the placebo group. Dyspnea, exertional dyspnea, musculoskeletal chest pain, arthralgia, fatigue, and myalgia were more common in the placebo group. Grade 3 or 4 adverse events occurred in 82% of patients in the selumetinib group vs 67% of patients in the placebo group. The most common grade 3 or 4 adverse events were neutropenia (67% vs 55%), febrile neutropenia (18% vs 0%), dyspnea (2% vs 12%), and asthenia (9% vs 0%).
Serious adverse events occurred in 59% of selumetinib patients and 31% of placebo patients; the most common were febrile neutropenia (14% vs 0%), pneumonia (9% vs 0%), neutropenia (7% vs 7%), and respiratory failure (7% vs 5%). Serious adverse events resulted in death in 9% vs 7% of patients, with none of the events being deemed related to study drugs. Adverse events led to hospitalization in 48% of selumetinib patients and 19% of placebo patients. In the selumetinib group, adverse events led to discontinuation of selumetinib in 18% of patients and discontinuation of docetaxel in 14%. In the placebo group, adverse events led to discontinuation of placebo in 12% of patients and discontinuation of docetaxel in 17%.
The authors concluded, “Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC.”
They noted that the finding of apparent synergy of selumetinib plus docetaxel in this setting, while consistent with preclinical findings with the combination, stands in contrast to the findings of previous studies in NSCLC indicating no additional benefit when a targeted agent is added to chemotherapy. In this regard, the authors stated, “Additional studies are therefore needed to understand why the combination studied here displays synergistic activity and whether this finding will also be recorded with other agents targeting MAPK signaling or other chemotherapies.”
The authors further noted, “Our study has potential therapeutic implications for other tumors in which KRAS mutations are particularly prevalent, such as colorectal and pancreatic cancers. In both cases, selumetinib monotherapy has shown no clinical benefit versus chemotherapy. Whether addition of selumetinib to chemotherapy agents commonly used in these diseases, which do not include docetaxel, will result in enhanced clinical benefit when combined remains to be established and should be tested in prospective clinical trials.” ■
Disclosure: The phase II selumetinib study was funded by AstraZeneca. Among the study investigators, Dr. Pasi A. Jänne has received consultancy fees from AstraZeneca, Roche, Genentech, Pfizer, Boehringer Ingelheim, and Sanofi, and other remuneration from Lab Corp. Dr. Alice T. Shaw has received consultancy fees from Pfizer, Ariad, Novartis, Chugi, and Daiichi-Sankyo, and received research funding from AstraZeneca and Novartis. Dr. Johan Vansteenkiste’s institute has received research funding from AstraZeneca. Dr. Carlos Barrios has received consultancy fees from Pfizer, Roche, and GlaxoSmithKline and has received research funding from AstraZeneca. Drs. Ian Smith and Paul Smith and Ms. Lynda Grinsted are employees and stockholders of AstraZeneca. Dr. Victoria Zazulina is a former employee of AstraZeneca. Drs. Jose R. Pereira, Gaëlle Jeannin, Fabio A. Franke, and Lucio Crinò reported no potential conflicts of interest.
Reference
1. Jänne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomized, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38-47, 2013.
