【medical-news】【资讯翻译】ASCO2012：研究发现非小细胞肺癌中具有“神奇反应”的新突变位点
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ASCO: 'Dramatic' Responses Noted in NSCLC
http://www.medpagetoday.com/MeetingCoverage/ASCO/33093
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CHICAGO -- More than half of a small group of patients with metastatic non-small cell lung cancer (NSCLC) responded to a drug that homes in on a previously untargeted mutation, investigators reported here.
Eight of 14 patients had objective responses and four others had stable disease when treated with crizotinib (Xalkori). The drug targets an ROS1 mutation that occurs in 1% to 2% of NSCLC.
The most common adverse event was mild visual disturbance, which occurred in almost all patients. Overall, the side effects were consistent with what has been observed in other clinical evaluations of crizotinib, Alice T. Shaw, MD, PhD, said here at the American Society of Clinical Oncology meeting.
"ROS1 rearrangement defines a distinct subset of non-small cell lung cancer," said Shaw, of Massachusetts General Hospital in Boston. "Crizotinib demonstrates marked antitumor activity in patients with advanced ROS1-positive non-small cell lung cancer. These results validate ROS1 as a therapeutic target in lung cancer."
Some patients had dramatic responses, associated with symptomatic improvement within days of starting treatment and substantial resolution of tumor burden within a few weeks, she added.
Crizotinib inhibits MEK and ALK in addition to ROS1, which was only recently identified as a specific molecular subset of NSCLC. The drug has approval for locally advanced or metastatic ALK-positive NSCLC.
Although its link to NSCLC is new, ROS1 is not, having been discovered more than 20 years ago. However, the normal function of ROS1 remains poorly understood, said Shaw. At the cellular level, ROS1 activates signaling pathways shared by other receptor tyrosine kinases.
Chromosomal rearrangement is the primary mechanism of ROS1 activation in cancer. The oncogenic form of ROS1 is thought to activate downstream signaling pathways associated with malignant transformation.
Originally developed as a cMET inhibitor, crizotinib subsequently demonstrated inhibitor activity against several other tyrosine kinases, including ROS1. In preclinical studies, crizotinib showed substantial activity against ROS1-driven cancer cells, providing the rationale for the phase I clinical trial reported by Shaw.
By means of fluorescence in-situ hybridization assay, investigators identified patients with ROS1-positive metastatic NSCLC and initiated treatment at the standard dose of 250 mg BID identified from a previous study of patients with ALK-positive tumors.
Shaw said 15 patients have been treated to date, 12 remain on therapy, and 14 were evaluable for treatment response. All the patients had adenocarcinoma histology, all but one were nonsmokers, and 12 patients had received one or more prior treatments for metastatic disease.
The cohort had an objective response rate of 57.1% and a median treatment duration of 25.7 weeks. The disease control rate was 79%, including the four patients who had stable disease for 8 weeks or longer.
In addition to mild visual impairment, the most common adverse events (≥10% of patients) were transient elevations in liver enzymes, diarrhea, hypophosphatemia, peripheral edema, dysgeusia, nausea, vomiting, elevated alkaline phosphatase, neutropenia, and sinus bradycardia.
The results added another piece to the mutation puzzle of NSCLC, which includes MEK, ALK, FGFR1, PTEN, PIK3CA, and DDR2. Altogether, 63% of squamous-cell lung cancers harbor mutations that can be targeted for treatment, according to another study reported at ASCO (ASCO 2012. Abstract 7505).
During a discussion of Shaw's presentation, Gregory Riely, MD, PhD, spoke of the ongoing transformation of NSCLC from a single entity into a heterogeneous disease associated with multiple genetic mutations and profiles, as well as the implications for clinical practice.
"We can't solely identify these patients by smoking history, ethnicity, age. We really, really, need to test all patients," said Riely, of Memorial Sloan-Kettering Cancer Center in New York.
Citing the "dramatic" response rate in the trial, Riely said he intends to begin using crizotinib in any patient who can be confirmed as ROS1 positive.
"I hope insurance companies will cover this," he said. "It is clear these data are correct."
http://www.medpagetoday.com/MeetingCoverage/ASCO/33093
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翻译时请参照版规 【版务】科技动态版版规及加分细则（ 2014-02-21 更新）
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CHICAGO -- More than half of a small group of patients with metastatic non-small cell lung cancer (NSCLC) responded to a drug that homes in on a previously untargeted mutation, investigators reported here.
Eight of 14 patients had objective responses and four others had stable disease when treated with crizotinib (Xalkori). The drug targets an ROS1 mutation that occurs in 1% to 2% of NSCLC.
The most common adverse event was mild visual disturbance, which occurred in almost all patients. Overall, the side effects were consistent with what has been observed in other clinical evaluations of crizotinib, Alice T. Shaw, MD, PhD, said here at the American Society of Clinical Oncology meeting.
"ROS1 rearrangement defines a distinct subset of non-small cell lung cancer," said Shaw, of Massachusetts General Hospital in Boston. "Crizotinib demonstrates marked antitumor activity in patients with advanced ROS1-positive non-small cell lung cancer. These results validate ROS1 as a therapeutic target in lung cancer."
Some patients had dramatic responses, associated with symptomatic improvement within days of starting treatment and substantial resolution of tumor burden within a few weeks, she added.
Crizotinib inhibits MEK and ALK in addition to ROS1, which was only recently identified as a specific molecular subset of NSCLC. The drug has approval for locally advanced or metastatic ALK-positive NSCLC.
Although its link to NSCLC is new, ROS1 is not, having been discovered more than 20 years ago. However, the normal function of ROS1 remains poorly understood, said Shaw. At the cellular level, ROS1 activates signaling pathways shared by other receptor tyrosine kinases.
Chromosomal rearrangement is the primary mechanism of ROS1 activation in cancer. The oncogenic form of ROS1 is thought to activate downstream signaling pathways associated with malignant transformation.
Originally developed as a cMET inhibitor, crizotinib subsequently demonstrated inhibitor activity against several other tyrosine kinases, including ROS1. In preclinical studies, crizotinib showed substantial activity against ROS1-driven cancer cells, providing the rationale for the phase I clinical trial reported by Shaw.
By means of fluorescence in-situ hybridization assay, investigators identified patients with ROS1-positive metastatic NSCLC and initiated treatment at the standard dose of 250 mg BID identified from a previous study of patients with ALK-positive tumors.
Shaw said 15 patients have been treated to date, 12 remain on therapy, and 14 were evaluable for treatment response. All the patients had adenocarcinoma histology, all but one were nonsmokers, and 12 patients had received one or more prior treatments for metastatic disease.
The cohort had an objective response rate of 57.1% and a median treatment duration of 25.7 weeks. The disease control rate was 79%, including the four patients who had stable disease for 8 weeks or longer.
In addition to mild visual impairment, the most common adverse events (≥10% of patients) were transient elevations in liver enzymes, diarrhea, hypophosphatemia, peripheral edema, dysgeusia, nausea, vomiting, elevated alkaline phosphatase, neutropenia, and sinus bradycardia.
The results added another piece to the mutation puzzle of NSCLC, which includes MEK, ALK, FGFR1, PTEN, PIK3CA, and DDR2. Altogether, 63% of squamous-cell lung cancers harbor mutations that can be targeted for treatment, according to another study reported at ASCO (ASCO 2012. Abstract 7505).
During a discussion of Shaw's presentation, Gregory Riely, MD, PhD, spoke of the ongoing transformation of NSCLC from a single entity into a heterogeneous disease associated with multiple genetic mutations and profiles, as well as the implications for clinical practice.
"We can't solely identify these patients by smoking history, ethnicity, age. We really, really, need to test all patients," said Riely, of Memorial Sloan-Kettering Cancer Center in New York.
Citing the "dramatic" response rate in the trial, Riely said he intends to begin using crizotinib in any patient who can be confirmed as ROS1 positive.
"I hope insurance companies will cover this," he said. "It is clear these data are correct."
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