The targeting of pathways downstream of HER2 has also been considered,23 and other targets under assessment for HER2+ treatment-refractory breast cancer include signal transduction molecules implicated in HER2 resistance, such as PI3K, Akt, mTOR, and insulin-like growth factor 1 receptor (IGF1R), as well as heat shock protein 90 (Hsp90), telomerase, and vascular endothelial growth factor (VEGF).

Mediation of an interleukin (IL)-6 inflammatory loop, which has been implicated in HER2 overexpression and trastuzumab resistance, is also under consideration,56,57 and preclinical reports of trastuzumab therapy in combination with antimalarial agents suggest improved activity in trastuzumab-resistant breast cancers.58

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Availability of novel therapies that target different pathways and with unique mechanisms of action might improve outcomes in patients with trastuzumab-resistant disease.

HER-targeted therapies

The monoclonal antibody pertuzumab targets the HER2 receptor and prevents HER2 from coupling with other HER family members. Pertuzumab is approved for use in combination with trastuzumab and docetaxel in patients who have not received HER2-targeted therapy or chemotherapy for metastatic disease. The approval was based on the data from the CLEOPATRA study, which showed a significantly increased median PFS and OS, compared with trastuzumab in combination with docetaxel.59–62

Pertuzumab is under clinical investigation in patients with HER2-resistant breast cancer. In a phase 2, open-label, single-arm, two-stage study in 66 evaluable patients with advanced breast cancer who had no response to trastuzumab ( identifier NCT00301899), the ORR with pertuzumab therapy in combination with trastuzumab was 24% and the clinical benefit rate was 50% (8% had complete response, 17% had partial response, and 26% had stable disease for at least 6 months), with a median PFS of 5.5 months.63 In an ongoing phase 2 study of pertuzumab in combination with trastuzumab and chemotherapy ( identifier NCT01276041), the preliminary 6-month PFS was 81% (95% CI 67–91; based on data from 18 January 2013) in evaluable patients (53 patients enrolled; 36 evaluable at 6 months).64

A phase 2 study assessing pertuzumab in combination with eribulin and trastuzumab in patients with recurrent HER2+ breast cancer is currently recruiting ( identifier NCT01912963).

Therapies targeting downstream pathways—PI3K/Akt/mTOR inhibitors

mTOR is a serine/threonine kinase that is downstream of PI3K/Akt65 and integrates multiple signals from growth factors and hormones, thereby controlling cell growth, proliferation, and angiogenesis.66Overexpression of HER2 is associated with activation of the mTOR pathway, and hyperactivation of the pathway is associated with poor prognosis.67,68

Multiple upstream components of the mTOR pathway become dysregulated in breast cancer and are believed to be involved in oncogenesis, suggesting that mTOR inhibition has the potential to interfere with tumor progression at several levels and that targeting multiple pathways with different agents might be more effective than monotherapy strategies.66,69

Several clinical studies are investigating the potential of mTOR inhibitors to improve or overcome resistance to HER2-targeted therapy,66 including phase 3 data for everolimus.45,70

The phase 1b dose-escalation study of everolimus in combination with trastuzumab and paclitaxel in 33 patients with metastatic HER2+ breast cancer that progressed while on or after trastuzumab therapy reported an ORR of 44% and a disease control rate of 74%, with a median PFS of 34 weeks (95% CI 29.1–40.7) (J2101 study, identifier NCT00426556).71

The phase 2 portion of the trial in 55 evaluable patients with resistance to trastuzumab and a taxane reported clinical benefit and objective response rates of 36% and 22%, respectively, and a median PFS of 5.5 months (95% CI 4.99–7.69).72 The incidences of adverse events (AEs) were consistent with the safety profiles of the individual therapies. Grade 3/4 hematologic events included neutropenia (grade 3, 26%; grade 4, 4%), anemia (grade 3, 7%; grade 4, 0), and thrombocytopenia (grade 3, 6%; grade 4, 2%). Grade 3/4 non-hematological events included stomatitis (20%), diarrhea (6%), vomiting (6%), fatigue (6%), and pneumonia (6%). No grade 4 non-hematological events were reported.

A phase 1/1b study assessed dose-limiting toxicity (DLT) and overall tumor response of everolimus in combination with trastuzumab and vinorelbine in 50 patients with HER2+ advanced breast cancer who experienced disease progression or relapse while previously taking trastuzumab with or without chemotherapy (J2102 study, identifier NCT00426530).73

Patients received either daily (5 mg/d) or weekly (20 or 30 mg/wk) everolimus therapy in combination with vinorelbine (25 mg/m2 on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly), and, based on DLT findings, everolimus 5 mg/day was chosen as the optimal daily dose in combination with weekly trastuzumab and vinorelbine for further clinical development. Responses and disease stabilization in the 5 mg/day cohort were durable, and ORR was 20% and clinical benefit rate was 50%. Median PFS was 30.7 weeks in the 5 mg/day everolimus arm, 27.1 weeks in the weekly arm, and 30.7 weeks in the overall population.

In the extension phase of the study, in which patients were allowed to continue everolimus and vinorelbine could be discontinued, two additional patients achieved complete response, one achieved partial response, and the overall PFS was 41 weeks.74 In patients receiving everolimus 5 mg/day in combination with weekly trastuzumab and vinorelbine, neutropenia (grade 1/2, 10%; grade 3/4, 83%) was the most common hematological AE and stomatitis (grade 1/2, 70%; grade 3/4, 17%) was the most common non-hematological AE related to study treatment.

A post hoc analysis of these two phase 1/2 trials evaluated the efficacy of everolimus in patients pretreated with lapatinib.75 Among 101 evaluable patients, the ORR was 21% and 29%, disease control rate was 88% and 81%, and mean PFS was 29.0 and 36.1 weeks in those pretreated with lapatinib and those not pretreated with lapatinib, respectively, suggesting that the effect of everolimus in combination with trastuzumab and chemotherapy in patients with HER2+ metastatic breast cancer is independent of previous lapatinib therapy.75

BOLERO-3 is a phase 3, randomized, double-blind, placebo-controlled, multicenter, international clinical trial comparing the efficacy of everolimus in combination with vinorelbine and trastuzumab versus placebo in combination with vinorelbine and trastuzumab in 569 patients with HER2+ advanced breast cancer resistant to trastuzumab and who have previously been treated with a taxane.45,70

At the time of analysis (data cutoff: 15 March 2013), the median duration of follow-up was 20 months, and 61 patients were continuing the study treatment. The most common reason for discontinuation was disease progression, and fewer patients discontinued treatment because of disease progression in the everolimus arm than in the control arm (68% vs 78%), whereas more patients in the everolimus arm discontinued treatment because of AEs than in the control arm (10% vs 5%).