Σάββατο, 24 Δεκεμβρίου 2016

ICOTINIB ACTIVE FOR EGFRm+ NSCLC WITH BRAIN METASTASES

For patients with non–small cell lung cancer (NSCLC) with brain metastases, progression-free survival (PFS) was significantly improved with treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in comparison with standard whole-brain irradiation (WBI) with or without chemotherapy, results from a phase 3 clinical trial show.
The results come from the BRAIN or CTONG 1201 clinical trial, presented here at the 17th World Conference on Lung Cancer (WCLC), which used the first-generation EGFR TKI icotinib (Conmana, Beta Pharma). Icotinib was developed in China.
Brain metastases, which are seen in approximately 40% of NSLC patients, have a major impact on quality of life and survival. Nevertheless, the number of patients with such metastases included in prospective trials of novel therapies is relatively small.
Yi Long Wu, MD, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China, who presented the study, said that there were several key take-home messages from the findings.
"First, the BRAIN data represent the first phase 3 results comparing an EGFR TKI with WBI," he said.
"The second is that icotinib improved intracranial PFS and overall PFS in EGFR mutant NSCLC patients with brain metastases, and with a favorable response rate and disease control rate, icotinib was superior to WBI with or without chemotherapy," he said.
Dr Wu concluded that "icotinib should be used in first-line treatment for advanced EGFR-mutant NSCLC with brain metastases."
Invited discussant Jacek Jassem, MD, PhD, Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland, said that the study was "well designed and well executed."
He continued: "In patients with multiple brain metastases from EGFR-mutated NSCLC, icotinib is clearly superior and safer compared to up-front whole-brain radiotherapy," although he noted that the findings would probably not apply to "any cytotoxic agent."
"This is, potentially and likely, a practice-changing study," Dr jassem commented, but he noted that data on quality of life, neurotoxicity, and the secondary use of whole-brain radiotherapy "are not yet available."
He added: "There are some pending questions, such as the efficacy of gefinitinb and erlotinib vs whole-brain radiotherapy, and the efficacy EGFR TKIs in non–East Asian populations. We all know that EFGR TKIs are particularly active in East Asian patients."
Another outstanding question is that of the up-front use EGFR TKIs in conjunction with the deferral of neurosurgery or radiosurgery in patients with limited brain metastases. In addition, there is the "important question of the efficacy of third-generation EGFR TKIs, such as osimertinib," Dr Jassem said.
Finally, he noted that EGFR-mutated and, specifically, T790M-positive brain metastases also need to be studied, as does the role of other TKIs, such as anaplastic lymphoma kinase TKIs, in lieu of WBI.
Nevertheless, Dr Jassem said that the study "clearly shows, also in the context of other studies, that perhaps we will use [WBI] more sparingly in the future, not only in EGFR-mutated patients but also in other settings." 
Study Details
Dr Wu began his presentation by noting that WBI has been the standard of care for NSCLC patients with brain metastases and is recommended in guidelines from the National Comprehensive Cancer Network. He pointed out, however, that median PFS with WBI is just 4 to 6 months, with disease control rates of 52%.
Although EGFR TKIs have achieved impressive results in patients with advanced NSCLC with EGFR mutations, no prospective, randomized clinical trials have examined the efficacy of the drugs in patients with brain metastases.
Dr Wu and colleagues therefore recruited 176 patients with advanced NSCLC with at least three brain metastases who had an EGFR mutation and were EGFR TKI-naive. Life expectancy had to be at least 12 weeks, and the patients had good Eastern Cooperative Oncology Group (ECOG) performance status (0-1).
Patients were randomly allocated to receive icotinib 125 mg three times daily (n = 85) or a standard regimen of WBI with or without chemotherapy (n = 73, with 18 withdrawing consent). Patients who experienced disease progression were switched to the opposite arm and continued to be followed.
The two treatment groups were well matched in terms of baseline characteristics. The majority of participants had exon 18 or exon 12 (L858R) EGFR mutations. Approximately 16% of patients in both groups had symptoms related to their brain metastases.
Intracranial PFS was significantly longer with icotinib than with WBI, at 10.0 months vs 4.8 months (hazard ratio [HR], 0.56; = .014). Rates of intracranial PFS at 6 months were 72.0% with icotinib vs 48.0% with WBI; rates at 12 months were 47.0% and 43.0%, respectively.
Overall PFS was also significantly greater with icotinib than with WBI, at 6.8 months vs 3.4 months (HR, 0.44; < .001). PFS rates at 6 months were 55.0% with icotinib vs 22.0% months with WBI; PFS rates at 12 months were 19.0% and 9.0%, respectively.
Crucially, the improvements in intracranial and overall PFS were largely seen across all subgroups.
Overall survival did not improve with icotinib, however, at a median of 18.0 months vs 20.5 months with WBI (HR, 0.93; = .734). There were no subgroups in which icotinib offered a significant survival benefit.
The intracranial and overall response rates to therapy were significantly better with icotinib than with WBI, at 67.1% vs 40.9% and 55.0% vs 11.0%, respectively (< .001 in both cases).
A similar pattern was seen for intracranial disease control rates, at 84.7% for icotinib vs 67.1% for WBI (= .014), and for overall disease control rates, at 78.8% vs 54.8% (= .001).
Treatment-related toxicities were significantly reduced with icotinib, with 8.2% of patients experiencing grade 3 adverse events vs 21.9% for WBI (= .015); 0.0% and 13.7%, respectively, experienced grade 4 adverse events (= .001).
The most common adverse events with icotinib were rash (27.1%), arthralgia (21.2%), and decreased appetite (16.5%). The most common adverse events with WBI with or without chemotherapy were fatigue (37.0%), rash, (31.5%) and arthralgia (31.5%).
Speaking at a press conference after the presentation, Dr Wu told Medscape Medical News that although the study was carried out in an East Asian population, icotinib "would be expected to have similar results in non-Asian patients."
However, Tony S. K. Mok, MD, chairman, Department of Clinical Oncology, Faculty of Medicine, the Chinese University of Hong Kong, pointed out that "the pharmacokinetics of icotinib in non-Asians has never been studied".
No funding for the study has been disclosed. Dr Wu has received grants/research support and honoraria or consultation fees from AstraZeneca and Roche, among other companies. Dr Jassem has received grants/travel support from Roche and Boehringer-Ingelheim and honoraria or consultation fees from AstraZeneca and Roche, among others.
17th World Conference on Lung Cancer (WCLC). Abstract PL03.05, presented December 6, 2016.

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