E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)
A number of strategies for overcoming trastuzumab resistance have been proposed and new agents are being actively studied in gastric cancers. These include clinical trials testing agents in gastric cancer already approved for HER2positive breast cancers.
Pertuzumab (Perjeta®, Genentech) is a human monoclonal antibody which binds to extracellular domain HER2. Unlike trastuzumab which binds at domain IV of the HER2 receptor, pertuzumab binds at domain II of the receptor and is thus able to disrupt HER2 heterodimerization and ligand-activated signaling with other HER family members, including EGFR, HER3, and HER4. The HER2-HER3 heterodimer is an effective activator of the PI3K signaling pathway; blockade of HER2-HER3 complexes likely represents the most relevant antitumor action of pertuzumab. In HER2+ breast cancer, pertuzumab in combination with trastuzumab and docetaxel demonstrated significant improvement in PFS compared to placebo, trastuzumab, and chemotherapy in advanced disease . In the neoadjuvant treatment of HER2+ breast cancer, the combination of pertuzumab, trastuzumab, and chemotherapy showed significantly increased pathological complete responses compared to other regimens, leading to FDA approval in both the advanced and neoadjuvant settings .
Yamashita-Kashima and colleagues investigated the antitumor activity of pertuzumab in combination with trastuzumab in HER2+ gastric cancer xenograft models. Their results demonstrated antitumor activity with pertuzumab monotherapy and more potent activity with the combination of pertuzumab and trastuzumab. In addition, the combination of the two agents reduced EGFR-HER3 heterodimerization and phosphorylation of these receptors and their downstream signaling factors .
The clinical efficacy of pertuzumab in breast cancer and the in vivo activity in HER2-positive gastric cancers lead to development of the international phase III JACOB study in HER2positive metastatic gastric or GEJ patients. This ongoing multicenter international study randomizes patients to receive pertuzumab or placebo in combination with trastuzumab, cisplatin, and fluoropyrimidine as first-line therapy . Target enrollment is 780 patients. The results of this study are eagerly awaited.
Antibody-drug conjugates are a way to deliver cytotoxic drugs directly to cancer cells. TDM-1 (Kadcyla, Genentech) is an antibody-drug conjugate of trastuzumab and emtansine, a microtubule inhibitor. In metastatic HER2-positive breast cancer patients previously treated with trastuzumab and a taxane, TDM-1 was shown to improve PFS by 3.2 months and OS by 5.8 months compared to patients treated with lapatinib plus capecitabine . This led to the FDA approval of the first antibody drug conjugate to show activity in breast cancer.
In preclinical gastric cancer models, TDM-1 has shown more effective tumor activity than trastuzumab . In combination with pertuzumab, TDM-1 has been shown to increase binding of TDM1-1 to HER potentially augmenting antibody-dependent cellular cytotoxicity and result in downstream HER2 signaling .
A multicenter adaptive phase II/III of TDM-1 is currently recruiting patients with HER2-positive advanced gastric cancer after progression on first line treatment. Patients will be randomized to one of three treatment arms: TDM-1 at 3.6 mg/kg every 3 weeks, TDM-1 at 2.4 mg/kg every week, or standard taxane chemotherapy (docetaxel or paclitaxel, per physician choice). After 100 patients in all three study arms have been treated for at least four cycles, the dose and schedule of trastuzumab will be determined and used in the second stage of the study, with overall survival as the primary endpoint .
Reversible EGFR/HER2 TKIs: Lapatinib
Lapatinib (Tykerb®, GlaxoSmithKline) is a reversible TKI of EGFR and HER2 that blocks activation by binding to the intracellular adenosine triphosphate (ATP) binding site of these kinases. Lapatinib has shown activity in HER2-positive breast cancer phase II and III clinical trials and causes response in some patients refractory to trastuzumab, suggestion that suppression of HER2 continues to be useful in this population [48, 49]. Modest activity was demonstrated with single-agent lapatinib in esophagogastric adenocarcinomas. In the Southwest Oncology Group (SWOG) 0413 trial, unselected patients showed a 9% confirmed partial response rate, and 23% had disease stabilization . HER2 overexpression was not required for participation in this study which affected the potential efficacy of the drug.
However, two large phase III trials of lapatinib indicated no signal of activity for lapatinib in confirmed HER2-positive gastric cancer patients. The LOGiC trial is a phase III trial of capecitabine and oxaliplatin with or without lapatinib in first-line advanced HER2 FISH amplified gastric and GEJ adenocarcinoma. The presented results show that the lapatinib arm did not meet its primary endpoint of overall survival (HR 0.91, 95% CI 0.73, 1.12, p = 0.35 in the lapatinib arm), but there were improvements in survival only in subgroups (Asian patients, HR 0.68; patients under 60 years of age, HR 0.69)  .
TyTAN is a completed open-label randomized phase III study comparing paclitaxel with paclitaxel plus lapatinib in patients with HER2 FISHamplified gastric cancer as a second-line therapy . In 261 East Asian patients, the median OS for the lapatinib plus paclitaxel group was 11.0 months compared to 8.9 months alone in the paclitaxel group, which was not statistically significant (HR 0.84, p = 0.2). In a preplanned subgroup analysis, in HER2 IHC3+ patients the median OS was 14.0 months in the lapatinib combination group compared to 7.6 months for paclitaxel alone (HR 0.59, p = 0.0176). In this study, patients were required to have HER2 amplified gastric cancer in order to be eligible; however this did not correlate with HER2 positivity by IHNC. 35% of patients had tumors classified as IHC0/1+, which may account for the survival benefit seen only in the subgroup of IHC 3+ patients.
Irreversible EGFR/HER2 TKIs: neratinib, afatinib
In vitro data suggest that second-generation irreversible inhibitors covalently bind HER2 and EGFR (unlike lapatinib, which compete with intracellular ATP in a reversible manner) in a highly selective fashion, which may be able to overcome trastuzumab resistance. In HER2-positive breast cancer patients with trastuzumab resistance, the reported efficacy profile seen with one such irreversible, dual EGFR/HER2 inhibitor (neratinib) compares favorably with the monotherapy experiences with anti-HER2 agents. Treatment with neratinib resulted in 16-week PFS rates of 59% and objective response rates of 24% in patients with prior trastuzumab treatment . In the phase II I-SPY 2 trial, neratinib produced a significantly improved pathological complete response at the time of surgery in patients with stage II/III HER2-positive, hormone receptor negative breast tumors, compared with a control group (55 versus 32%) . With these promising results, a phase III trial is currently underway, comparing neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive patients who have received two or more prior anti-HER2 regimens . There is an ongoing multicenter open-label phase 2 study of neratinib in patients with solid tumors with HER2, HER3, or EGFR mutations, which is open to patients with HER2-positive gastric cancer . Study accrual is ongoing.
Afatinib (Gilotrif®, Boehringer Ingelheim) is another irreversible inhibitor of EGFR, HER2, and HER4. In July 2013, the FDA approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors had specific EGFR gene mutations (exon 19 deletions or exon 21 (L858R) substitution mutations) as detected by an FDA approved test. Afatinib is currently in phase III development in EGFR positive non-small cell lung cancer, trastuzumab pretreated HER2 breast cancer, and head and neck squamous cell carcinoma.
There is preclinical data showing potent antitumor activity of single agent afatinib in an NCI-N87 HER2-positive esophagogastric cancer xenograft. Although the tumors were relatively refractory to trastuzumab, treatment with single agent afatinib led to dramatic tumor volume regression. The combination of afatinib with trastuzumab had even greater antitumor efficacy than either drug alone . These results are similar to the clinical experiences seen in breast cancer patients. Blackwell et al. showed that despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improves PFS and clinical benefit rate versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with HER2-positive metastatic breast cancer .
Simultaneous targeting of EGFR/HER2 kinase activity may be an effective strategy in patients with metastatic, trastuzumab resistant HER2-positive esophagogastric cancer via potent signaling inhibition. There is an ongoing phase II study of afatinib in combination with trastuzumab in metastatic HER2-positive trastuzumab refractory esophagogastric cancer . The first cohort of patients in the study was treated with afatinib alone. Preliminary results reported in these 14 patients showed promising activity, with one patient with confirmed partial response (PR), and three patients with disease stabilization . The second cohort of the study will receive the combination of afatinib and trastuzumab.
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