Gefitinib改善EGFR突變肺癌病患之存活
作者：Roxanne Nelson
出處：WebMD醫學新聞
December 23, 2009 —又有一篇研究顯示，上皮細胞生長因子受體(EGFR)突變的亞洲肺癌病患，對於gefitinib (商品名Iressa，AstraZeneca藥廠)之初步治療反應良好。最新的研究中，gefitinib的無惡化存活時間優於以白金製劑為基礎的標準合併化療。
這篇線上登載於12月21日Lancet Oncology期刊的研究，由日本名古屋愛知癌症中心醫院的Tetsuya Mitsudomi醫師發表，是177名病患的研究結果。接受gefitinib之病患的無惡化存活時間中位數為9.2個月(95% 信心區間[CI]為8.0 - 13.9個月)，使用白金雙重化療者為6.3個月(95% CI，5.8 - 7.8個月；風險比[HR]為0.489；95% CI，0.336 - 0.710；P < . 0001)。
研究作者寫道，還不清楚gefitinib延長無惡化存活時間是否等同於延長整體存活，他們將繼續仔細監控這些病患，以確認長期效果。
之前已經有兩篇類似的gefitinib對於有EGFR突變之肺癌病患有效的研究報告，兩篇的研究對象都是亞洲人，曾由Medscape Oncology報導。一篇西班牙研究也提出使用erlotinib的類似研究發現。這得以獲致肺癌病患應篩檢EGFR突變的建議，有這些突變的病患應優先使用標靶製劑而非化療。
【Gefitinib改善無惡化存活時間】
最新的這篇研究中，Mitsudomi醫師等人試圖確認gefitinib作為經EGFR突變篩檢之肺癌病患的第一線治療時，是否提供優於白金雙重化療的存活利益。
這個開放標籤、第3期研究，在2006年3月31日至2009年6月22日間，於日本的36個中心納入177名病患，全部病患都無化療經驗、75歲以下、診斷為第IIIB/IV期非小細胞肺癌或術後復發、有EGFR突變者(不論是外顯子19消失或L858R點突變)。
這些病患被隨機分派接受gefitinib (口服250 mg/天；n = 88人)，或cisplatin (靜脈注射80 mg/m?)加docetaxel (靜脈注射60 mg/m?)、每21天給藥一次，進行3-6循環(n = 89人)。試驗初步終點為無惡化存活時間，根據修改後的治療意向對象進行存活分析。
大部份為腺癌病患，71名(41.3%)病患為術後復發疾病，54名(31.4%)病患有抽菸史。追蹤期間中位數為81天(範圍74-1253天)。
整體而言，相較於cisplatin加docetaxel，使用gefitinib治療的病患有顯著較長的無惡化存活期間(HR為0.489；95% CI為0.336 - 0.710；P < .0001)。兩個次組中，gefitinib組的無惡化存活期間比cisplatin加docetaxel組長，不過，相較於術後復發的病患，並不顯著。
有可測量之病灶的病患，其客觀反應率方面，接受gefitinib之病患(62.1%)顯著優於接受cisplatin加docetaxel的病患 (32.2%)。gefitinib組的疾病控制率(93.1%)也優於化療組(78%)，整體差異為15.5% (95% CI為2.7 - 27.6；P = .020)。
兩組都有副作用，化療組比較常有骨髓抑制、掉髮與疲勞；而gefitinib組比較常有皮膚毒性、肝功能不佳、腹瀉。整體而言，除了肝功能不佳之外，不常有等級3以上的毒性。
作者們指出，至今，gefitinib組有17件死亡、化療組有10件，gefitinib之HR為1.638 (95% CI為0.75 - 3.58)。整體存活期間的資料還不充足，正持續追蹤。
研究作者寫道，我們的研究指出，EGFR基因檢測是可行的，當可以執行時即應進行，這些結果強力認為，出現EGFR突變可用以確認臨床效果，而非根據病患的臨床背景，這個觀念將可導出以分子為基礎的個人化肺癌治療。
【新的EGFR抑制劑】
哈佛大學與達那-法柏癌症研究治療中心的研究者，確認了一類新的EGFR激酶抑制劑，他們希望它可以比現有的製劑改善更多臨床效果且耐受更佳。
Gefitinib或erlotinb的臨床效果，受限於後天的藥物阻抗性之發生，例如gatekeeper T790 residue (T790M)之突變，如同12月24/31日版Nature期刊中的一篇報告，所有臨床阻抗性病患中，半數有T790M。
在一個實驗研究中，哈佛大學醫學院醫學副教授Pasi A. J?nne博士等人藉由篩檢針對EGFR T790M的不可逆激酶抑制劑庫存，辨識共價嘧啶EGFR抑制劑。於試管內檢測時，這些產物的抗EGFR T790M強度是現有製劑的30-100倍，抗野生型EGFR的強度則是小100倍。
這些物質之一、WZ4002，於肺癌老鼠進行研究，2週效果癌劑顯示腫瘤明顯復原，根據作者表示，治療後進行肺組織評估，確認腫瘤結節明顯解決。
他們寫道，這些發現認為，WZ4002可以用於EGFR突變NSCLC(非小細胞肺癌)病患的初步治療，產生病況惡化的時間可以比目前以gefitinib治療的效果更久。
West Japan Oncology Group支持Lancet Oncology期刊的研究。多位研究作者宣告接受AstraZeneca、Chugai、Sanofi-Aventis和/或 Boehringer-Ingelheim等之演講費和/或獎金。
國家健康研究中心、國家癌症研究中心、Cecily and Robert Harris基金會、Uniting Against Lung Cancer、Flight Attendant醫學研究中心、Hazel and Samuel Bellin研究基金、Damon Runyon基金會癌症研發獎等支持Nature期刊的研究。
Lancet Oncology. 線上發表於2009年12月21日。
Gefitinib Improves Survival in Lung Cancer Patients with EGFR Mutations
By Roxanne Nelson
Medscape Medical News
December 23, 2009 — Another clinical trial has shown that Asian patients with lung cancer and epidermal growth-factor receptor (EGFR) mutations respond well to initial treatment with gefitinib (Iressa; AstraZeneca). In the latest study, gefitinib conferred superior progression-free survival time vs standard treatment with platinum-based combination chemotherapy.
The results, from a study in 177 patients, are reported by Tetsuya Mitsudomi, MD, from Aichi Cancer Center Hospital, Nagoya, Japan, in the December 21 online issue of Lancet Oncology.
Patients who received gefitinib had a median progression-free survival time of 9.2 months (95% confidence interval [CI], 8.0 - 13.9 months) vs 6.3 months (95% CI, 5.8 - 7.8 months; hazard ratio [HR], 0.489; 95% CI, 0.336 - 0.710; P < . 0001) for those treated with platinum doublet chemotherapy.
"It is not yet known whether the prolonged progression-free survival conferred by gefitinib will translate into prolonged overall survival," the study authors write, adding that they will continue to carefully monitor these patients to determine the long-term effects.
Two previous trials have already reported a similar finding of gefitinib efficacy in patients with lung cancer and EGRF mutations, both conducted in Asian populations, as previously reported by Medscape Oncology. A similar finding has also been reported for erlotinib from a Spanish study. This has led to suggestions that patients with lung cancer should be screened for EGRF mutations and that patients with these mutations should be treated with targeted agents first instead of chemotherapy.
Gefitinib Improves Progression-Free Survival Time
In this latest study, Dr. Mitsudomi and colleagues sought to determine if gefitinib offered a survival advantage vs platinum doublet chemotherapy, when used as a first-line treatment in patients with lung cancer selected by EGFR mutation.
The open label, phase 3 study enrolled 177 patients between March 31, 2006, and June 22, 2009, from 36 centers in Japan. All participants were chemotherapy naive, 75 years or younger, and had been diagnosed with stage IIIB/IV non–small-cell lung cancer or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).
The patients were randomly assigned to receive either gefitinib (250 mg/day orally; n = 88) or cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 intravenously; n = 89), administered every 21 days for 3 to 6 cycles. The primary endpoint of the trial was progression-free survival time, and survival analysis was conducted with the modified intent-to-treat population.
The majority of patients had adenocarcinoma, 71 patients (41.3%) had postoperative recurrent disease, and 54 (31.4%) of the patients had a history of smoking. The median follow-up period was 81 days (range, 74 - 1253 days).
Overall, patients treated with gefitinib had significantly longer progression-free survival duration vs cisplatin plus docetaxel (HR, 0.489; 95% CI, 0.336 - 0.710; P < .0001). In both subgroups, progression-free survival time in the gefitinib group was longer vs the cisplatin-plus-docetaxel group, although it was not significant for patients with postoperative recurrence.
The objective response rate in patients with measurable disease was significantly higher among patients receiving gefitinib (62.1%) vs patients receiving cisplatin plus docetaxel (32.2%). The disease control rate was also higher in the gefitinib group (93.1%) vs the chemotherapy group (78%), with an overall difference of 15.5% (95% CI, 2.7 - 27.6; P = .020).
Both groups experienced adverse events, with myelosuppression, alopecia, with fatigue reported more frequently in the chemotherapy group, whereas skin toxicity, liver dysfunction, and diarrhea were more frequently reported in the gefitinib group. Overall, grade 3 or higher toxicities were infrequent except for liver dysfunction.
Thus far, there have been 17 events (deaths) in the gefitinib group vs 10 events in the chemotherapy group — with an HR for gefitinib of 1.638 (95% CI, 0.75 - 3.58), the study authors note. The data for overall survival duration are still immature, and follow-up is ongoing.
"Our study indicates that EGFR genetic testing is feasible and should be done when possible," write the study authors. "These results strongly suggest that the presence of EGFR mutations, and not the clinical background of patients, determines clinical efficacy, and this knowledge should lead to molecularly based, personalized treatment of lung cancer."
Novel EGFR Inhibitor
A novel structural class of EGFR kinase inhibitors has been identified by researchers from Harvard University and the Dana-Farber Cancer Institute in Boston, Massachusetts, and they are hopeful that it may prove to be more clinically effective and better tolerated than the agents currently available.
The clinical efficacy of gefitinib or erlotinib is limited by the development of acquired drug resistance, such as by mutation of the gatekeeper T790 residue (T790M), as noted in an article that appears in the December 24/31 issue of Nature. The T790M has been identified in half of all clinically resistant patients.
In an experimental study, Pasi A. Janne, MD, PhD, an associate professor of medicine at Harvard University Medical School, and colleagues, identified covalent pyrimidine EGFR inhibitors by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These products were found to be 30- to 100-fold more potent against EGFR T790M than currently available agents, as well as 100-fold less potent against wild-type EGFR, when tested in vitro.
One of the substances, WZ4002, was tested in mouse models of lung cancer, and a 2-week efficacy study showed significant tumor regressions. Further histologic evaluation of the lungs after treatment confirmed a significant resolution of the tumor nodules, according to the authors.
"These findings suggest that WZ4002 could also be used as initial therapy for patients with EGFR-mutant NSCLC [non–small-cell lung cancer] and may ultimately lead to a longer time to disease progression than currently achieved with gefitinib," they write.
The Lancet Oncology study was supported by the West Japan Oncology Group. Several of the study authors have received lecture fees and/or honoraria from AstraZeneca, Chugai, Sanofi-Aventis, and/or Boehringer-Ingelheim.
The Nature study is supported by grants from the National Institutes of Health, National Cancer Institute Lung, the Cecily and Robert Harris Foundation, Uniting Against Lung Cancer, the Flight Attendant Medical Research Institute, the Hazel and Samuel Bellin Research Fund, and the Damon Runyon Foundation Cancer Innovation Award. The study authors have disclosed no relevant financial relationships.
Lancet Oncology. Published online December 21, 2009.
