Novartis breakthrough therapy LDK378 shows a marked clinical response in patients with ALK+ non-small cell lung cancer

Novartis today 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[1]. The trial will be featured as an oral presentation (abstract #8010; Monday, June 3) at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

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%)[1]. 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. 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.”

In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies[2].

“LDK378 is representative of the Novartis targeted research approach to identify key disease pathways and those specific patients affected by the disease,” said Hervé Hoppenot, President, Novartis Oncology. “Based on these data showing the potential of LDK378, we are developing a robust clinical program to move it forward as quickly as possible.”

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 (presented on Saturday, June 1 from 8:00 – 11:45 AM; abstract #TPS8119). 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.

Non-small cell lung cancer is the most common type of lung cancer accounting for 85-90% of all cases[3]. Approximately 3-8% of patients with NSCLC have the ALK gene mutation[1]. There are limited treatment options for patients with ALK+ NSCLC, who tend to be non-smokers and younger than NSCLC patients without an ALK translocation[4].

About the study

The Phase I single-arm study investigated the maximum tolerated dose, safety, pharmacokinetics and preliminary antitumor activity of LDK378 in 114 patients with ALK+ NSCLC (78 patients taking LDK378 at 750 mg/day and 36 additional patients taking 400-750 mg/day). Of 114 patients evaluable for response, 79 had progressed during or following treatment with crizotinib, and 35 patients with NSCLC were crizotinib-naïve[1].

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).

About LDK378

LDK378 is a selective inhibitor of a cancer target called anaplastic lymphoma kinase or ALK. Because it is an investigational compound, the safety and efficacy profile of LDK378 has not yet been established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of this compound. Because of the uncertainty of clinical trials, there is no guarantee that LDK378 will ever be commercially available anywhere in the world.

References

1. Shaw A, et al. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. Abstract #8010. 49th American Society of Clinical Oncology (ASCO) Chicago, IL.
2. US Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. Available at: http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm. Accessed May 30, 2013.
3. American Cancer Society. Lung Cancer – Non-Small Cell Detailed Guide. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed May 30, 2013.
4. Shaw A, et al. Targeting Anaplastic Lymphoma Kinase in Lung Cancer. Clin Cancer Res 2011;17:2081-2086.