Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Canada.
Department of Pharmacy, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, M5G 2M9, Canada.
Target Oncol. 2022 May;17(3):271-281. doi: 10.1007/s11523-022-00884-z. Epub 2022 May 30.
Epidermal growth factor receptor (EGFR)- and human epidermal growth factor receptor (HER)2-targeted therapies are approved for the treatment of breast, gastric/gastrointestinal junction (GEJ), and non-small cell lung cancer (NSCLC) with specific molecular aberrations affecting HER family members. Over 10 % of other cancers harbor genomic aberrations affecting HER family members, but their role remains undefined.
The MOBILITY3 trial evaluated the antitumor activity of afatinib, an oral pan-HER tyrosine kinase inhibitor (TKI) in HER-aberrant tumors outside of the licensed indications.
In this single-center basket trial, patients with advanced solid tumors that harbor mutations and/or amplifications of any of the HER family members (EGFR, ERBB2, ERBB3, ERBB4) were enrolled. The EGFR-mutated NSCLC and HER2-positive breast cancers were excluded. Participants were treated with oral afatinib 40 mg daily until disease progression or unacceptable toxicity. Objective response rate (ORR) and progression-free survival (PFS) were primary and secondary endpoints, respectively.
The study enrolled 12 patients with 6 tumor types (NSCLC, sarcoma, salivary gland, gastric/GEJ, breast and pancreatic cancer). Objective response rate was 8 % (95 % CI 0.2-38%) and median PFS was 11.4 weeks (95% CI 4.6-33.3 weeks). All 3 patients with salivary gland cancers and 1 patient with ERBB2-mutant NSCLC had clinical benefit (stable disease or partial response lasting > 24 weeks). Due to slow accrual and a lower-than-expected response rate, trial recruitment was terminated before the target of 30 patients were enrolled.
In the MOBILITY3 study (NCT02506517), afatinib demonstrated modest activity in tumors that possess EGFR and ERBB2 aberrations. Clinical benefit seen in all 3 salivary gland cancers supports the growing evidence for the utility of HER-targeted therapies in the treatment of this specific tumor type.
表皮生长因子受体（EGFR）和人表皮生长因子受体（HER）2 靶向治疗药物已获批准，可用于治疗具有特定分子异常影响 HER 家族成员的乳腺癌、胃/胃食管交界处（GEJ）和非小细胞肺癌（NSCLC）。超过 10%的其他癌症存在影响 HER 家族成员的基因组异常，但它们的作用仍未确定。
MOBILITY3 试验评估了 afatinib（一种口服泛 HER 酪氨酸激酶抑制剂[TKI]）在 HER 异常肿瘤中的抗肿瘤活性，这些肿瘤超出了许可的适应症范围。
在这项单中心篮子试验中，招募了患有任何 HER 家族成员（EGFR、ERBB2、ERBB3、ERBB4）突变和/或扩增的晚期实体瘤患者。排除 EGFR 突变型 NSCLC 和 HER2 阳性乳腺癌患者。参与者接受口服 afatinib 40mg 每日治疗，直至疾病进展或不可接受的毒性。客观缓解率（ORR）和无进展生存期（PFS）分别为主要和次要终点。
该研究纳入了 12 名患者的 6 种肿瘤类型（NSCLC、肉瘤、唾液腺癌、胃/GEJ、乳腺癌和胰腺癌）。客观缓解率为 8%（95%CI0.2-38%），中位 PFS 为 11.4 周（95%CI4.6-33.3 周）。所有 3 名唾液腺癌患者和 1 名 ERBB2 突变型 NSCLC 患者均有临床获益（持续 >24 周的疾病稳定或部分缓解）。由于入组速度较慢且缓解率低于预期，在招募 30 名患者的目标之前，试验提前终止。
在 MOBILITY3 研究（NCT02506517）中，afatinib 在具有 EGFR 和 ERBB2 异常的肿瘤中表现出适度的活性。所有 3 例唾液腺癌患者均出现临床获益，这支持了 HER 靶向治疗在治疗这种特定肿瘤类型中的有效性的不断增加的证据。
