Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer

Moulder, Stacy L.; Wheler, Jennifer J.; Jiang, Yunfang; Bastida, Christel C.; Kurzrock, Razelle

doi:10.1093/annonc/mdt395

Cited by 26 publications

(17 citation statements)

References 29 publications

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“…These patients had all received prior trastuzumab and the majority prior lapatinib [43]. Despite failing prior concurrent or sequential trastuzumab and lapatinib treatment, these patients continued to achieve SD≥6months/PR/CR with the addition of bevacizumab to the treatment combination.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer

et al. 2014

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PURPOSE Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates. EXPERIMENTAL DESIGN Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types). Patients received lapatinib daily for 21 days, and bevacizumab and trastuzumab every three weeks. Correlates included HER2 extracellular domain levels (ECD) and single nucleotide polymorphisms (SNPs). RESULTS Ninety-four patients were treated (median = four prior systemic therapies). The most common related adverse events ≥ grade 2 were diarrhea (n=33, 35%) and hypertension (n=10, 11%). The recommended phase 2 dose was trastuzumab 6 mg/m2 (loading = 8 mg/m2) and bevacizumab 15 mg/kg every three weeks, with lapatinib 1250 mg daily (full FDA-approved dose of each drug). One patient (1%) achieved a complete response (CR); eight (9%), a partial response (PR) (includes breast (n=7, one of which was HER2 2+ by IHC) and salivary ductal carcinoma (n=1); and 14 (15%), stable disease (SD) ≥ 6 months (total SD≥6 months/PR/CR = 23 (25%). All patients with PR/CR received prior trastuzumab +/− lapatinib. SD≥6 months/PR/CR rate and time to treatment failure (TTF) correlated with elevated baseline HER2 ECD (N=75 patients tested) but not with HER2 SNPs. CONCLUSIONS Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy.

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Section: Discussionmentioning

confidence: 99%

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer

et al. 2014

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“…In the investigation of Azambuja et al [22], a combination of temozolomide and lapatinib was administered and showed a moderate efficacy in 16 heavily pretreated patients with multiple BM of breast cancer (PFS 2.6 months, 95% CI 1.82-3.37, stable disease rate 67%, progressive disease rate 33%). A combination of lapatinib, trastuzumab and bevacizumab showed promising results in the analysis of Falchook et al [23] in 10 patients with BM of breast cancer pretreated with trastuzumab and lapatinib. The HER2-reintroduction therapy in the combination with anti-vascular endothelial growth factor (VEGF) treatment showed a stable disease rate ( 6 months) and partial or complete remission in 60% of patients.…”

Section: Combination Of Lapatinib With Other Compoundsmentioning

confidence: 98%

Systemic Treatment Options for HER2-Positive Breast Cancer Patients with Brain Metastases beyond Trastuzumab: A Literature Review

et al. 2017

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Background: The incidence of brain metastases (BM) in breast cancer patients has increased. Many retrospective analyses have shown that first-line treatment with trastuzumab prolongs survival in patients with HER2-positive BM. In contrast, the evidence for other therapies targeting HER2 for patients with BM is rare. Methods: The aim of this review is to update the reader about current systemic treatment options in patients with HER2-positive metastatic breast cancer with BM who had already received trastuzumab. A literature search was performed in the PubMed database in June 2016. 30 relevant reports concerning the efficacy of trastuzumab emtansine (T-DM1), lapatinib and its combination with other cytotoxic agents, pertuzumab and novel HER2-targeting substances were identified. Results: There is limited but promising evidence for the use of T-DM1 and pertuzumab in the treatment of BM. Up to now, most reported studies used lapatinib as treatment of HER2-positive breast cancer with BM, a treatment with only a modest effect and a high toxicity profile. The combination of lapatinib with cytotoxic agents seems to result in better response rates. Conclusion: Further prospective investigations are needed to investigate the efficacy of the established and novel HER2-targeting agents on BM in HER2-positive breast cancer patients.

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“…To this end, we combined HER2-targeted drugs (trastuzumab and lapatinib) with an anti-VEGFR2 antibody and demonstrated a significant improvement in survival of mice bearing HER2+ tumors in their brain (Kodack et al, 2012). Moreover, a phase II clinical trial with dual HER2-blockade and bevacizumab showed encouraging results in heavily pretreated HER2+ breast cancer patients with brain metastases (Falchook et al, 2013). Whether this will translate into increased OS in brain metastasis patients in a phase III trial remains to be seen.…”

Section: Combining Antiangiogenic Agents With Drugs That Target Oncogmentioning

confidence: 99%

Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia

2014

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Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors’ blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiotherapy, chemotherapy, and immunotherapy. Here, I summarize lessons learned from pre-clinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.

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Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer

Cited by 26 publications

References 29 publications

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer

Systemic Treatment Options for HER2-Positive Breast Cancer Patients with Brain Metastases beyond Trastuzumab: A Literature Review

Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia

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