Second-generation ALK Inhibitor: Ceritinib
To overcome resistance to crizotinib, more potent ALK inhibitors were developed. The second-generation ALK inhibitor, ceritinib, was granted accelerated approval by the FDA in 2014, and other second- and third-generation inhibitors are currently being evaluated.
Ceritinib is 20-fold more potent than crizotinib for ALK inhibition, which includes several resistance-conferring mutations including Leu1196Met, Gly1269Ala, Ile1171Thr, and Ser1206Tyr. Results of the phase 3 ASCEND-5 trial (ClinicalTrials.gov Identifier: NCT01828112) suggest that ceritinib can indeed overcome crizotinib resistance.3
“To definitively establish ceritinib as a standard option in the crizotinib-resistant setting, we performed this randomized trial comparing ceritinib with standard of care, single-agent chemotherapy in ALK-positive patients who had failed prior crizotinib and platinum-based chemotherapy,” Alice Shaw, MD, PhD, of the Massachusetts General Hospital in Boston and one of the ASCEND-5 investigators, told Cancer Therapy Advisor.
The multicenter, international, open-label trial randomly assigned 231 patients with ALK-rearranged stage IIIB or IV NSCLC to receive ceritinib or chemotherapy with pemetrexed or docetaxel. All patients had progressed during treatment with chemotherapy and crizotinib. Patients were allowed to crossover to ceritinib if they progressed during chemotherapy.
The overall response rate was substantially higher with ceritinib at 39.1% (95% CI, 30.2-48.7%) compared with 6.9% (95% CI, 3.0-13.1%) with chemotherapy. The disease control rate was 76.5% with ceritinib and 36.2% with chemotherapy.
During a median follow-up of 16.5 months, ceritinib treatment significantly prolonged PFS to 5.4 months (95% CI, 4.1-6.9) compared with 1.6 months (95% CI, 1.4-2.8) with chemotherapy (HR, 0.49; 0.36-0.67; P < .0001).
Though OS data were not mature as half of the required events had not yet occurred, at the time of the interim analysis, death occurred among 42% of patients receiving ceritinib and 43% of patients receiving chemotherapy (HR, 1.0; 95% CI, 0.67-1.49; P = .50).
All subgroup analyses, including age, sex, race, performance status, disease burden, smoking history, and previous response to crizotinib, favored ceritinib. Patients with brain metastases at baseline (57% and 59%, respectively) also had improved PFS with ceritinib compared with chemotherapy, suggesting that ceritinib has CNS activity.
Gastrointestinal (GI) toxicities, including diarrhea (72%), nausea (66%), and vomiting (52%), occurred more frequently with ceritinib than chemotherapy. “Encouraging data have been presented that suggest that ceritinib at a dose of 450 mg per day with food has similar exposure to ceritinib 750 mg fasted and significantly reduces GI toxicity,” the authors noted.
Despite the high rate of GI toxicities, the discontinuation rate of ceritinib due to adverse events was 10%. Patient-reported outcomes were also higher than chemotherapy. “Its greater antitumor activity compared with chemotherapy led to improved scores for disease-related symptoms, a significantly longer time to symptom deterioration, and greater benefit in overall health status,” Dr Shaw said.
The median time to symptom deterioration was 18.0 months with ceritinib compared with 4.4 months with chemotherapy. According to questionnaire data, scores for the composite of pain, dyspnea, and cough were similar between the 2 arms. Yet individual scores for dyspnea, cough, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, and others favored ceritinib. The investigators noted that the questionnaire analysis “was often noninterpretable because of low numbers of patients remaining in the chemotherapy group.”