Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer

This study evaluated and compared the efficacy and tolerability of lapatinib and letrozole, with letrozole and placebo in post-menopausal women with hormone receptor positive (ER positive and/or PgR positive) advanced or metastatic breast cancer, who had not received prior therapy for advanced or metastatic disease.

Sex

Female

Minimum age

18 Years

Key inclusion criteria

1. Signed informed consent;
2. Subjects with histologically confirmed invasive breast cancer with stage IV disease at primary diagnosis or at relapse after curative-intent surgery;

   * Subjects with either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).
   * If the disease was restricted to a solitary lesion, its neoplastic nature was confirmed by cytology or histology.
3. Tumors that were ER+ and/or PgR+;
4. Post-menopausal female subjects ≥ 18 years of age.
5. ECOG Performance Status of 0 or 1;
6. Subjects who had archived tumor tissue available to compare tumor response with intra-tumoral expression of ErbB1 and ErbB2.
7. Adjuvant therapy with an aromatase inhibitor and / or trastuzumab was allowed; however, treatment was to stop more than 1 year prior (\>12 months) to the first dose of randomized therapy.
8. Subjects must have ended hormonal replacement therapy (HRT) at least 1 month (30 days) prior to receiving the first dose of randomized therapy.

Key exclusion criteria:

1. Pre-menopausal, pregnant, or lactating;
2. Received prior chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for advanced or metastatic disease;
3. Bisphosphonate therapy for bone metastases was allowed; however, treatment was to be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, was not permitted;
4. Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of randomized therapy (lapatinib or placebo);
5. Subjects with known history of/clinical evidence of CNS metastases or leptomeningeal carcinomatosis; and / or subjects on concurrent anti-cancer therapies other than letrozole; and / or who have not recovered from toxicities related to prior adjuvant therapy (surgery, radiotherapy, chemotherapy etc.)
6. Subjects with active or uncontrolled infection and/ or with history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure.

• BACKGROUNDJohnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28. PMID 19786658
• BACKGROUNDSchwartzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122-9. doi: 10.1634/theoncologist.2009-0240. Epub 2010 Feb 15. PMID 20156908
• BACKGROUNDSherrill B, Amonkar MM, Sherif B, Maltzman J, O'Rourke L, Johnston S. Quality of life in hormone receptor-positive HER-2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. Oncologist. 2010;15(9):944-53. doi: 10.1634/theoncologist.2010-0012. Epub 2010 Aug 26. PMID 20798196
• BACKGROUNDFinn RS, Press MF, Dering J, O'Rourke L, Florance A, Ellis C, Martin AM, Johnston S. Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2014 Feb 1;20(3):736-43. doi: 10.1158/1078-0432.CCR-13-1260. Epub 2013 Nov 6. PMID 24198242
• BACKGROUNDPrat A, Cheang MC, Galvan P, Nuciforo P, Pare L, Adamo B, Munoz M, Viladot M, Press MF, Gagnon R, Ellis C, Johnston S. Prognostic Value of Intrinsic Subtypes in Hormone Receptor-Positive Metastatic Breast Cancer Treated With Letrozole With or Without Lapatinib. JAMA Oncol. 2016 Oct 1;2(10):1287-1294. doi: 10.1001/jamaoncol.2016.0922. PMID 27281556
• DERIVEDWedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.