Clovis Oncology (CLVS) announced today updated findings from the Phase 1 portion of its ongoing Phase 1/2 clinical study of CO-1686, the Company’s novel, oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M. Interim results from the Phase 1 dose-escalation portion of this Phase 1/2 study are being presented today in an oral presentation by Dr. Heather Wakelee at the 4th European Lung Cancer Conference (ELCC) in Geneva.
“These data are completely consistent with what I have seen personally in my own patients,” said Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at Paris University XI and cancer specialist at Gustave Roussy Institute and the European lead investigator for the Phase 1/2 study of CO-1686. “CO-1686 provides meaningful and long-term benefit for patients who until now have had limited, if any, options. I am very enthusiastic about participating in the continued development of this agent.”
“One of the issues with oncogene-targeted therapies is that while initial response rates can be promising, these responses can be short-lived,” said Patrick J. Mahaffy, President and CEO of Clovis Oncology. “In contrast, as CO-1686 Phase 1 data extend and mature, we see both a consistency of response rate that is very encouraging as well as an impressive initial duration of clinical benefit. Patients in general benefit from, and stay on, CO-1686 for a prolonged period of time. We are also pleased that we can deliver this long-term benefit with very good tolerability. Given the observed durability of clinical benefit we are increasingly optimistic about the potential of CO-1686 not only to deliver impressive response rates, but also meaningful progression-free survival in both first- and second-line patients.”
The Phase 1 dose escalation portion of the study is being conducted in the United States, France and Australia in patients with metastatic or unresectable recurrent NSCLC and a documented EGFR mutation. Patients were not required to be T790M positive for the Phase 1 portion of the study but had to have progressed on prior EGFR-directed tyrosine kinase inhibitor (TKI) therapy (prior chemotherapy was also allowed).
Approximately one hundred patients have been treated with CO-1686 to date across all dosing cohorts in the Phase 1 portion of the trial. Emerging data from the first 62 patients treated with CO-1686 at efficacious doses (comprising patients treated with 900mg BID of freebase or any dose of the hydrobromide salt (HBr) formulation) were presented today at ELCC. Of these 62 patients, 22 are centrally-confirmed T790M positive, 12 are centrally-confirmed T790M negative, seven have as yet unknown T790M status and the remaining are non-evaluable, primarily because they have not yet had their first scan.
Patients on study were heavily pretreated prior to receiving CO-1686; 73 percent of patients across all doses had immediately progressed on TKI therapy prior to CO-1686 treatment. The median number of previous lines of therapy across patients at all doses was three; the median number of previous TKI lines was two.
Evidence of Activity
In the 22 evaluable T790M positive patients across efficacious dose levels, 14 RECIST partial responses (PRs) have been observed to date, for a 64 percent objective response rate (ORR). Ten of the 14 patients (71 percent) started CO-1686 therapy immediately following progression on a prior TKI. Twenty of the 22 evaluable T790M positive patients, or 91 percent, have experienced stable disease or a PR.
In a broader population of 29 evaluable T790M positive and T790M currently unknown patients, 15 RECIST PRs have been observed to date, for a 52 percent response rate. Twenty-six of the 29 evaluable 790M positive and T790M currently unknown patients, or 90 percent, have experienced stable disease or a PR. These data will be updated if and as the T790M status of the unconfirmed patients are centrally determined.
The median duration of response cannot yet be estimated in the T790M positive patients. However, PFS greater than six months has been observed in evaluable T790M positive heavily-pretreated patients and the median has not yet been reached. In contrast, PFS in T790M negative patients is shorter, with a median of three months.
Five of nine evaluable patients, or 56 percent, dosed initially with 900mg BID of freebase and now on the HBr formulation remain on drug with continuing PRs, and 35 of the 43 total patients dosed with the HBr formulation, or 81 percent, remain on drug.
Safety and Tolerability
CO-1686 is well-tolerated, with only one patient who discontinued treatment with CO-1686 due to adverse events. There was no evidence of systemic wild-type EGFR inhibition. The most common adverse events were hyperglycemia, nausea, diarrhea, decreased appetite and vomiting, and these were mostly grade 1 in severity. The most common grade 3 adverse event was hyperglycemia, which was observed in 19 percent of patients. Hyperglycemia, when observed and requiring treatment, is typically asymptomatic and managed with a commonly prescribed single oral agent.
Presentation Details
The presentation, titled “Phase 1 evaluation of CO-1686, an irreversible, mutant-selective inhibitor of EGFR mutations (activating and T790M)”, was presented on Thursday, March 27, during the session titled “Advanced Disease with Targeted Agents” from 9:00 -10:30am.
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