来源：盛诺一家
研究显示，曲妥珠单抗联合拉帕替尼对有长期治疗史的转移癌患者有效，不需要加入任何化疗。
在有长期治疗史的患者人群中，临床试验结果非常好，并且与结直肠癌的HER2靶点有关。尽管该试验结果只适用于一小部分亚组患者，但这仍然是一个突破性的进展。
曲妥珠单抗的靶点是HER2/neu受体，拉帕替尼的靶点是HER2/neu和EGFR通路。
该II期临床试验纳入了27例KRAS基因第2外显子野生型、HER2阳性、难治性（包括西妥昔单抗或帕尼单抗难治）结直肠癌患者，研究时间从2012年至2015年。该研究的中位随访时间为94周，其中8例患者（30%）出现了客观缓解，包括1例完全缓解。治疗的中位有效时间为9.5个月。12例患者疾病稳定。无进展生存期为4-8月，中位无进展生存期为5.2个月，支持临床前研究结果，提示曲妥珠单抗联合帕妥珠单抗对HER2阳性结直肠癌患者治疗效果优于化疗。
该研究中出现了6例（22%）三级不良事件，包括疲劳（4例）、皮疹（1例）和胆红素浓度升高（1例）。未出现四级不良事件、药物相关严重不良事件或死亡。
该临床试验的作者认为，该研究结果可能会改变HER2阳性结直肠癌患者的日常临床护理方法，也可能会提高曲妥珠单抗和拉帕替尼方案的治疗优先级，甚至可能能够让患者不需要接受化疗。
该联合治疗方案看起来对免疫组化HER2 3+的肿瘤效果好于HER2 2+的肿瘤，但即便是在HER2低表达的患者中，接受该方案的效果也要好于不接受治疗的患者。因此，HER2 2+或3+的患者，可考虑使用HER2靶向治疗。
该研究还显示，应当更早考虑使用抗HER2治疗结直肠癌。对于西妥昔单抗治疗无效的患者，即便是肿瘤为KRAS野生型，使用抗HER2挽救治疗效果仍很好，所以曲妥珠单抗联合方案似乎更适合在EGFR抗体之前使用。而目前正在进行的一项研究氟尿嘧啶联合曲妥珠单抗和帕妥珠单抗作为一线维持治疗的临床试验（NCT02291289）显示，曲妥珠单抗联合方案甚至可以作为一线治疗方案。
该研究的作者认为，目前可以进行一项III期试验来获取更多更明确的数据。
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Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial
Summary
Background
We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer.
Methods
HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33.
Findings
Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events.
Interpretation
The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer.
Funding
Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.
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原文链接：
http://www.oncotherapynetwork.com/possible-%E2%80%98breakthrough%E2%80%99-treating-refractory-her2-positive-metastatic-crc
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2816%2900150-9/fulltext
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