Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in <i>KRAS</i>-Mutant Metastatic Colorectal Cancer

<div><p></p><p>This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in <i>KRAS</i>-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m² followed by weekly 250 mg/m²) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in <i>KRAS</i>-mutant metastatic colorectal cancer patients.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT01032291" target="_blank">NCT01032291</a></p></div

TEAEs suspected by the investigator to be related to study drug, occurring in ≥2 patients, sorted by overall incidence.

a<p>All grade ≥3 TEAEs related to study drug were grade 3. Grade 3 events related to lenalidomide: fatigue (7; 2 events in 2 patients each), neutropenia (2), anorexia, hypokalemia, general physical health deterioration, diarrhea, increased gamma-glutamyltransferase, and decreased blood potassium. Grade 3 events related to cetuximab: rash (4; 3 events in 1 patient), fatigue (4; 2 events in 1 patient), hypersensitivity (3; 2 events in 1 patient), diarrhea (2), urticaria, general physical health deterioration, tachycardia, dyspnea, and hypertension.</p

Reasons for discontinuation.

<p>One patient in the lenalidomide monotherapy group of phase IIb discontinued on investigator's decision due to lack of efficacy, mentioned as “other” in the figure.</p

Baseline characteristics phase IIa and IIb.

a<p><i>KRAS</i> mutations as determined by Genoptix Medical Laboratory.</p>b<p><i>KRAS</i> mutation found in local laboratory.</p><p>Abbreviations: ECOG PS: Eastern Cooperative Oncology Group performance status; n.a.: not applicable.</p

Study design and enrollment in patient groups.

<p>Study was terminated before the expansion part of phase IIb. *One patient was randomized to the lenalidomide monotherapy group but discontinued before taking any study drug and was therefore excluded from the analyses. AE, adverse event; ITT, intention to treat; PD, progressive disease.</p

Median treatment duration, cumulative dose, dose intensity, and relative dose intensity.

a<p>Treatment duration = [(the study treatment end date)−(the first study drug start date)+1]/7.</p>b<p>Cumulative dose = total doses taken during treatment phase.</p>c<p>Dose intensity = cumulative dose/treatment duration.</p>d<p>Relative dose intensity = dose intensity/planned dose intensity×100.</p