新たな分子標的薬はGIST患者の予後を改善する （Abstract # LBA10008）

Regorafenibは承認標的治療に対する耐性のために進行した消化管間質腫瘍に対し有効である
Regorafenib effective for gastrointestinal stromal tumors that progress due to resistance to approved targeted therapies
第48回American Society of Clinical Oncology学会で発表された第3相国際トライアルの結果、新たな経口分子標的薬regorafenibは、イマチニブやスニチニブを含む他の使用可能な治療オプションに対する耐性のために進行した消化管間質腫瘍（GIST）患者の予後を改善しうることが示された。研究者らは転移性および/または手術不能なGIST患者199人をregorafenibまたはプラセボと疾患の症状を緩和する最良の支持療法を併用する群に無作為に割り付けた。全ての患者が過去に少なくとも標準的なイマチニブおよびスニチニブ療法を受けていた。その結果、無増悪生存期間はregorafenibを用いて治療された患者（4.8か月）においてプラセボを用いた患者（0.9か月）よりも4倍長かった。疾患が悪化した場合にはプラセボ群患者はregorafenib治療に変更することが許可されていた；全体で85%の患者がregorafenib内服に変更することができた。このトライアルデザインのために、全生存期間は両群間で統計学的な差を認めなかったが、治療の過程でregorafenibを早期に開始した患者において有意ではないが好ましい傾向がみられた。この薬剤の忍容性は全般的に良好で、副作用はGISTに対する他の承認分子標的薬と同等であった。
Full Text

Results of an international Phase III trial presented at the American Society of Clinical Oncology's 48th Annual Meeting demonstrate that the new targeted oral drug, regorafenib, can improve outcomes for patients with gastrointestinal stromal tumors (GIST) that progress due to resistance to other available treatment options, including imatinib and sunitinib.

The researchers found that progression-free survival was four times longer among patients receiving regorafenib than among those receiving placebo.  All patients also received best supportive care to alleviate the symptoms of their disease.

"If approved, regroafenib will fulfill an urgent unmet need for patients with GIST who have exhausted all other treatment options," said George Demetri, M.D., Director of the Ludwig Center and Sarcoma Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston. "Targeted therapy has revolutionized treatment for this rare cancer, but we've been on the hunt for additional effective treatments for the 85 percent of patients whose cancer eventually develops resistance to the only two available therapies. Regorafenib appears to target GIST tumors in a different and possibly more powerful way than the current FDA-approved therapies, making it a potentially significant new option to help patients."

Like other approved "smart drugs" for GIST, regorafenib targets abnormalities in cancer cell signaling pathways driven by an enzyme called KIT. Although initially suppressed by targeted therapies such as Gleevec, new mutations eventually evolve which lead to drug-resistant forms of the KIT enzyme, allowing the cancer to grow despite continuing the drugs which initially worked. Regorafenib appears to inhibit the cancer-promoting signals in a unique way, working even in patients whose cancers have developed resistance to the other treatments.

In this study, researchers randomized 199 patients with metastatic and/or inoperable GIST patients to either regorafenib or placebo plus best supportive care. All had undergone prior treatment with at least standard imatinib and sunitinib therapy. Progression-free survival was significantly longer among patients treated with regorafenib (4.8 months), compared with placebo (0.9 months). If the disease worsened, patients on placebo were allowed switch to regorafenib treatment; in all, 85 percent of patients were able to cross over to receive regorafenib. Because of this trial design, there was no statistical difference in overall survival between the two arms, although a non-significant trend was noted in favor of patients who started regorafenib earlier in the course of care. The drug was well-tolerated overall, with side effects similar to other approved targeted agents for GIST.