Discussion
blurred vision, nausea, DLTs, dyspepsia, diarrhea, toxicity, Gastrointestinal AEs, visual impairment, vomiting, vitreous floaters, urticaria, rash, pruritus, Treatment-related, dermatitis
MYOCARDIAL INFARCTION, SOLID TUMORS, EYE DISORDERS, URTICARIA, DERMATITIS
Combination therapy with the investigational ERK inhibitor MK-8353 and the MEK inhibitor selumetinib was tolerable at the 2 lower dose combinations evaluated (MK-8353 50 mg + selumetinib 25 mg and MK-8353 100 mg + selumetinib 50 mg). However, treatment with MK-8353 150 mg plus selumetinib 75 mg had unacceptable toxicity, with 50% of patients experiencing DLTs affecting the eyes and gastrointestinal system. Dose escalation was therefore stopped according to mTPI algorithm. The MTD (and therefore the recommended phase 2 dose) for the combination was MK-8353 100 mg plus selumetinib 50 mg. There were no responders at the dose levels assessed.In a previous phase 1 study of patients with advanced solid tumors, no eye disorders occurred at the MTD of MK-8353 (400 mg twice daily), but visual impairment (n = 3), blurred vision (n = 2), and vitreous floaters (n = 1) occurred among 6 patients treated with the highest dose (800 mg twice daily) [Gastrointestinal AEs were reported at the MTD of MK-8353 monotherapy (400 mg twice daily [n = 7]) in the aforementioned phase 1 study, including nausea (n = 4), diarrhea (n = 2), dyspepsia (n = 2), and vomiting (n = 2) [The other DLT observed in our study was grade 3 urticaria (n = 1, MK-8353 100 mg plus selumetinib 50 mg). In the phase 1 study of MK-8353, maculopapular rash (n = 3), macular rash (n = 1), pruritus (n = 1), and urticaria (n = 1) occurred at the MTD (400 mg twice daily) [Treatment-related cardiovascular AEs, which may be related to MEK inhibitors [On both day 1 and day 4 of cycle 1, the CPrevious clinical experience with the combination of an ERK inhibitor and MEK inhibitor is limited. In a phase 1 study, DLTs occurred in 1/3 patients with advanced solid tumors treated with the ERK inhibitor GDC-0994 200 mg plus the MEK inhibitor cobimetinib 40 mg once daily (grade 3 diarrhea) and 2/6 patients treated with GDC-0994 200 mg plus cobimetinib 80 mg once daily (grade 3 myocardial infarction, grade 3 rash and acneiform dermatitis) [In our study, toxicity resulted in both study selumetinib and MK-8353 being administered at doses below their single-agent dose level which may have resulted in limited pathway inhibition [In summary, the combination of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib did not demonstrate antitumor activity at tolerable doses. These findings are consistent with those from other studies that have evaluated combinations of MEK and ERK inhibitors in patients with advanced solid tumors.