Background

Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 “hyper”-amplified (≥ 8 copies) tumors.

Methods

We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates, in a selected subgroup of HER2 “hyper”-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials.

Results

Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody–drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting.

Conclusion

These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-“hyper”-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

中文翻译：

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HER2驱动胃癌的个性化治疗策略

背景

曲妥珠单抗是唯一批准用于HER2扩增转移性胃癌 (GC)患者的靶向疗法。遗憾的是，在临床实践中，只有一小部分人从基于曲妥珠单抗的前期策略中获得了长期利益。为了推进精准肿瘤学，我们研究了不同 HER2 靶向策略在HER2 “超”扩增（≥ 8 拷贝）肿瘤中的治疗效果。

方法

我们通过临时临床前试验的设计，在选定的HER2 “超”扩增胃患者来源异种移植物 (PDX)亚组中，对使用单克隆抗体、酪氨酸激酶抑制剂和抗体-药物偶联物的 HER2 靶向进行了前瞻性评估。

结果

尽管HER2扩增水平很高，但曲妥珠单抗仅在 8 个 PDX 模型中的 2 个中引起部分反应。曲妥珠单抗加帕妥珠单抗或拉帕替尼的双重 HER2 阻断在 8 个模型中的 5 个（62.5%）中产生了完全和持久的反应，其中包括一个伴随HER2突变的肿瘤。在具有KRAS扩增的耐药 PDX 中，新型抗体药物偶联物曲妥珠单抗 deruxtecan（但不是曲妥珠单抗 emtansine）克服了KRAS介导的耐药性。我们还确定了一种 HGF 介导的非细胞自主机制，对抗 HER2 药物的继发性耐药，对 MET 共靶向有反应。

结论

这些临床前随机试验清楚地表明，在 HER2 驱动的胃肿瘤中，需要加强 HER2 治疗阻断以获得最佳疗效，从而在大多数情况下产生完全和持久的反应。我们的结果表明，选定的HER2 “超”扩增 GC 患者亚群可以从这种策略中受益匪浅。尽管临床试验的结果为阴性，但对于明显对 HER2 成瘾的癌症患者，应重新考虑双重阻断。