Clinical Trials

The Phase I single-arm study investigated the maximum tolerated dose, safety, pharmacokinetics and preliminary antitumor activity of LDK378 in 130 patients, including 122 patients with ALK+ NSCLC. Of 114 ALK+ NSCLC patients treated with LDK378 at 400 mg or higher per day, 80 had progressed during or following treatment with crizotinib, and 34 patients with ALK+ NSCLC were crizotinib-naïve. The maximum tolerated dose observed in the study was 750 mg per day.

 

* On June 2, 2014, Novartis announced data showing Zykadia™ (ceritinib, previously known as LDK378) shrank tumors in patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), including those who had received previous treatment with an ALK inhibitor as well as patients receiving one for the first time. Results were also observed in patients with ALK+ NSCLC who entered the study with brain metastases. The study is being presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Among a combined population of 246 NSCLC patients, ceritinib achieved an overall response rate (ORR) of 58.5% and a median progression-free survival (PFS) of 8.2 months. Of these, 124 patients entered the trial with brain metastases and achieved an ORR of 54.0% and a median PFS of 6.9 months. The most common adverse events, occurring in more than half of patients, were diarrhea, nausea, vomiting, abdominal pain and fatigue.

Approximately 2-7% of patients with NSCLC harbor the ALK gene rearrangement, which causes cancer growth. These patients are candidates for treatment with a targeted ALK inhibitor. Patients with ALK+ NSCLC are often younger than the average NSCLC patient, and in many cases have never smoked.

The study presented at ASCO served as the basis for the FDA approval of Zykadia™ in April 2014, which followed the FDA's Breakthrough Therapy designation, and occurred less than three and a half years after the first patient entered a clinical trial. Additional ongoing regulatory reviews are currently underway in the European Union, Argentina and Switzerland.

The 246 patients with ALK+ NSCLC in this Phase I single-arm study received ceritinib 750 mg daily and had a 7-month median duration of follow-up. Of these, 166 (67%) had received at least two prior regimens and 163 (66%) had been previously treated with an ALK inhibitor. Findings from the study showed that patients treated with ceritinib achieved an ORR of 58.5% [95% CI, 52.1-64.8%] and a median PFS of 8.2 months [95% CI, 6.7-10.1 months]. The median duration of response was 9.7 months [95% CI, 7.0-11.4 months], with a median time to first response of 6 weeks after starting treatment. Among 163 patients receiving 750 mg of ceritinib daily and who were previously treated with the commonly prescribed ALK inhibitor crizotinib, ORR was 54.6% [95% CI, 46.6-62.4%] and PFS was 6.9 months [95% CI, 5.4-8.4 months]. In 83 patients who had not received prior treatment with an ALK inhibitor, ORR was 66.3% [95% CI, 55.1-76.3%] and PFS had not been reached (NR) at the time of data cutoff as the majority of patients were still receiving treatment with ceritinib.

In the 124 patients who started the study with brain metastases, ceritinib achieved an ORR of 54.0% [95% CI, 44.9-63.0%] and a median PFS of 6.9 months [95% CI, 5.4-8.4 months]. Tumor shrinkage was seen in 50.0% of patients [49 of 98 patients; 95% CI, 39.7-60.3%] with brain metastases who had received previous ALK inhibitor therapy, while 69.2% of patients [18 of 26 patients; 95% CI, 48.2-85.7%] with brain metastases who were not previously treated with an ALK inhibitor achieved tumor shrinkage following treatment with ceritinib.Discontinuation of treatment due to adverse events occurred in 10% of patients.

Among 255 patients treated with ceritinib, including 246 patients with NSCLC and nine patients with other types of cancer, 150 (59%) required at least one dose reduction. The most frequent adverse events (incidence >50%) among 255 patients were diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%) and fatigue (52%). The most common lab abnormalities (incidence >50%) were decreased hemoglobin (84%), increased ALT (80%), AST increased (75%) and increased creatinine (58%). The most common Grade 3/4 lab abnormalities (incidence >10%) were increased ALT (27%), increased AST (13%) and increased glucose (13%).

This study is part of the ongoing Novartis clinical trial program in this patient population. Several major studies evaluating treatment with ceritinib are being conducted in more than 300 study centers across more than 30 countries. Two Phase II single-arm clinical trials in previously treated and treatment-naïve ALK+ NSCLC patients, (www.clinicaltrials.gov identifiers NCT01685060 and NCT01685138), are fully enrolled and ongoing. In addition, two Phase III clinical trials comparing ceritinib with chemotherapy in treatment-naïve and in previously-treated patients, (www.clinicaltrials.gov identifiers NCT01828099 and NCT01828112), are ongoing and actively recruiting patients worldwide[5],[6],[7],[8].

* On March 26, 2014, Novartis has announced that The New England Journal of Medicine (NEJM) published clinical trial results showing LDK378 (ceritinib) achieved an overall response rate (ORR, including complete response [CR] and partial response [PR]) of 58% and a median progression-free survival (PFS) of seven months in adults with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) who received 400 mg or higher of LDK378 per day. The study evaluated 114 ALK+ NSCLC patients treated with LDK378, including patients who had progressed during or following treatment with a commonly prescribed ALK inhibitor called crizotinib and those who had not received prior treatment with an ALK inhibiton.

The study results published in NEJM demonstrated a median PFS of 7.0 months [95% CI; 5.6-9.5 months] in patients with ALK+ NSCLC treated with LDK378 at doses of 400 mg to the maximum tolerated dose of 750 mg per day. The study also reported an ORR of 59% [95% CI; 47-70%] in patients taking LDK378 at 750 mg per day. The responses observed demonstrated LDK378 is active in patients with advanced ALK+ NSCLC, including those who were previously treated with crizotinib, with or without new mutations in the ALK gene.

The most frequent adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase levels (35%). Preliminary data from this publication were first presented at the 2013 American Society of Clinical Oncology annual meeting. The study is ongoing with more data to become available. 
These data served as the basis for the first regulatory filing for LDK378. The FDA designated LDK378 as a Breakthrough Therapy, which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint. Several major studies evaluating treatment with LDK378 are being conducted in more than 300 study centers across more than 30 countries. Currently, two Phase II clinical trials (NCT01685060 and NCT01685138) are fully enrolled and ongoing. In addition, two Phase III clinical trials (NCT01828099 and NCT01828112) are ongoing and are actively recruiting patients worldwide to further evaluate LDK378 in patients with ALK+ NSCLC.

(Shaw A, et al. Ceritinib in ALK-Rearranged Non-Small-Cell Lung Cancer. N Engl J Med. 2014;370(13):1189-97)

* On June 3, 2013, Novartis has announced data on its investigational compound LDK378 showing a marked clinical response in 78 patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who had progressed during or after crizotinib therapy or had not been previously treated with crizotinib.

The results from the study showed an overall response rate (including complete response [CR] and partial response [PR]) of 60% in patients with ALK+ NSCLC taking LDK378 (750 mg/day), which includes patients who had progressed during or after crizotinib therapy (overall response rate of 59%) and those who were crizotinib-naïve (overall response rate of 62%). In addition to the 78 patients treated at 750 mg/day, an additional 36 patients were treated with LDK378 at 400-750 mg/day. The study is continuing to enroll patients and evaluations are ongoing. Of 114 patients evaluable for response, 79 had progressed during or following treatment with crizotinib, and 35 patients with NSCLC were crizotinib-naïve.

In the 78 patients with ALK+ NSCLC who received LDK378 at 750 mg/day, the overall response rate was 60% (47 patients had partial responses). In the 114 patients treated with LDK378 at 400 mg/day or higher, the overall response rate was 58% (1 patient had a complete response and 65 patients had partial responses).

The median duration of response for patients treated at 400 mg/day or higher (n=66) was 8.2 months (95% confidence interval [CI], 6.9-NE), with a median progression-free survival of 8.6 months (95% CI; 5.7-9.9). The six month duration of response rate at 750 mg/day was 61% (95% CI; 34.9-78.8).
This pivotal trial will serve as the basis for the first regulatory filing, anticipated in early 2014.

The most frequent adverse events (regardless of relationship to LDK378) were nausea (73%), diarrhea (72%), vomiting (58%) and fatigue (41%). The most frequent Grade 3/4 adverse events were alanine aminotransferase increased (19%), aspartate aminotransferase increased (10%) and diarrhea (8%).

\"These results confirm that LDK378 has activity in patients with ALK+ NSCLC, including those who have progressed on crizotinib, as well as those who haven\'t taken crizotinib,\" said lead investigator Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer Center, Boston. \"LDK378 may become another standard targeted therapy for these ALK-positive patients.\"

Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study, highlighted as a Trials in Progress poster at ASCO, focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib. The second study examines LDK378 in patients who are crizotinib-naïve. In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide.