Date: 2015-05-31
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Clovis Oncology (USA - CO)
Product: rociletinib (CO-1686)
Action
mechanism: kinase inhibitor. Rociletinib is an oral, potent, mutant-selective inhibitor of epidermal growth factor receptor (EGFR) under investigation for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). Rociletinib targets the activating mutations of EGFR (L858R and Del19), while also inhibiting the dominant acquired resistance mutation, T790M, which develops in approximately 60 percent of patients treated with first- and second-generation EGFR inhibitors, while sparing wild-type, or “normal” EGFR at anticipated therapeutic doses. Accordingly, it has the potential to treat NSCLC patients with EGFR mutations both as a first-line or second-line treatment with a potentially reduced toxicity profile. Rociletinib was granted Breakthrough Therapy designation by the FDA in May 2014. Clovis announced on August 3 that it submitted its New Drug Application (NDA) regulatory filing to the FDA and submitted its Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) through the centralized procedure for rociletinib for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy.
Disease: non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On May 31, 2015, Clovis Oncology announced updated findings from its Phase 2 clinical study of rociletinib (CO-1686), the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. These data from the TIGER-X trial are being presented in an oral presentation (Abstract #8001) at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago. Data presented are from the TIGER-X trial of 456 mutant EGFR NSCLC patients treated with rociletinib tablets at each of the efficacious dose groups studied (all doses BID): 500mg (n=119), 625mg (n=236), 750mg (n=95) and 1000mg (n=6) doses. Efficacy data from 243 centrally confirmed tissue T790M-positive patients, 35 centrally confirmed tissue T790M-negative patients and 147 plasma T790M-positive patients were also presented. The study is being conducted at sites in the U.S., Europe and Australia, with greater than 80 percent of study participants enrolled at U.S. sites. Patients enrolled in trial were heavily pretreated prior to receiving rociletinib. Eighty-two percent of patients across all doses had immediately progressed on TKI therapy prior to rociletinib treatment. The median number of previous lines of therapy across patients at all doses was two. Seventy-two percent of patients had an ECOG performance score of one or higher. Additionally, patients with stable CNS metastases were allowed in the trial. Forty-one percent of study participants had a history of CNS metastases, consistent with the study population being drawn largely from U.S. academic centers where more advanced patients are often referred for continuing management of progressive disease after standard therapy. Data from this study, combined with data from the TIGER-2 study, will form the U.S. New Drug Application (NDA) and E.U. Marketing Authorization Application (MAA) submission packages in July. Evidence of Activity: A total of 243 centrally confirmed tissue T790M-positive patients were evaluable in the four dose subgroups (all doses BID): 500mg (n=48), 625mg (n=114), 750mg (n=77) and 1000mg (n=4). At the recommended dose of 500mg, a 60 percent ORR and a 90 percent DCR was observed, and across all doses, a 53 percent ORR and an 85 percent DCR was observed. At the time of analysis, a median PFS of 10.3 months was observed in 163 heavily pretreated centrally confirmed tissue T790M-positive patients without a history of CNS metastases, while a median PFS of 8 months was observed in 270 heavily pretreated centrally confirmed tissue T790M-positive patients, of whom 40 percent had a history of CNS metastases. Clinical benefit was durable with some patients on drug for over two years without disease progression. These data continue to mature. A total of 147 evaluable plasma T790M-positive patients were treated with rociletinib; in those treated with 500mg, a 57 percent ORR and an 80 percent DCR has been observed to date, and at all doses, a 53 percent ORR and an 82 percent DCR has been observed, which is highly consistent with the comparable tissue outcomes data. These data suggest that T790M plasma testing may be an alternative to tissue testing. Rociletinib activity was also observed in 35 evaluable T790M-negative patients treated at all doses. A 37 percent ORR has been observed, in a range of 32 to 39 percent across doses studied. Eighty-six percent of these patients were treated with rociletinib directly after TKI therapy, so a TKI re-treatment effect cannot be the driver of this activity. Safety and Tolerability: The data presented at ASCO continue to demonstrate rociletinib is well tolerated. In the 500mg dose group, the most common treatment-related AEs reported in greater than 10 percent of all patients included hyperglycemia, diarrhea and nausea. Across all doses, most AEs were grade 1 or 2 in severity. The only common grade 3 treatment-related AE was hyperglycemia, which was observed in 17 percent of patients treated with rociletinib 500mg (20/119), 24 percent of patients treated with the 625mg dose (56/236), 36 percent of patients treated with the 750mg dose (34/95) and 33 percent of patients treated with the 1000mg dose (2/6). Most AEs appear to be dose dependent. Hyperglycemia was readily managed with commonly prescribed oral agents and grade 3 hyperglycemia rates have decreased over time as routine monitoring was standardized in the clinical program for rociletinib. Specifically, prior to September 2014, grade 3/4 hyperglycemia was observed in 22 percent of patients treated with rociletinib at 500mg. After September 2014, by which time routine monitoring had been implemented, grade 3 hyperglycemia was observed in only eight percent of such patients. No interstitial lung disease (ILD) was observed in the 500mg dose group. Across all doses, 1.5 percent (7/456) of patients developed ILD, and continuation of treatment with rociletinib was possible with the addition of steroid cover in recent cases. There have been no fatal cases of ILD. No paronychia or stomatitis was observed and any observed rash was minimal. Treatment-related AEs leading to drug discontinuation were observed in 2.5 percent of cases at the recommended dose of 500mg, and in four percent of overall cases. Recommended Dose: TIGER-X is a large study designed to evaluate the safety and efficacy of rociletinib in three different doses, 500mg BID, 625mg BID and 750mg BID. Based on results from all dose groups, the 500mg dose clearly emerged as the best dose for patients based on its activity and safety profile. As a result, the recommended dose for rociletinib is 500mg BID and all ongoing rociletinib studies will use this dose. The presentation, titled “Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients” was presented on Sunday, May 31, during the Oral Abstract Session titled “Lung Cancer: Non-Small Cell Metastatic”, from 8:00 to 11:00am Central Time (Abstract 8001). In addition to the TIGER-X trial, Clovis is currently enrolling several studies in EGFR-mutant NSCLC: TIGER-1 is a randomized Phase 2/3 registration study versus erlotinib in newly-diagnosed patients. TIGER-2 is a global registration study underway in both T790M-positive and T790M-negative patients directly after progression on their first and only TKI therapy. TIGER-3 is a randomized, comparative study versus chemotherapy in both T790M-positive and T790M-negative patients with acquired TKI resistance. In addition, a Phase 1 study of rociletinib in Japan has completed enrollment and a Phase 2 study in Japanese patients, agreed upon with Japanese regulatory authorities, is expected to initiate in the second half of 2015.
Multiple combination studies planned to initiate in the second half of 2015, including inhibitors of PD-L1, PD-1 and MEK.
