ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D

This was a four-arm (parallel group) randomized, open-label, multicenter Phase 3 study to investigate the use of a combination of Lapatinib and Trastuzumab, a sequence of Trastuzumab followed by Lapatinib, and Lapatinib alone, compared to Trastuzumab alone in the adjuvant treatment of Human Epidermal Growth Factor Receptor 2 (HER2) positive early breast cancer.

Sex

All

Minimum age

18 Years

Key Inclusion Criteria:

* Patients \>= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF \>= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =\< 1, were included.
* For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
* Approved, signed written informed consent obtained prior to any study specific screening procedures.

Key Exclusion Criteria:

* History of any prior (ipsi- and/or contralateral) invasive breast carcinoma, past (less than 10 years) or current history of malignant neoplasms, any clinically staged T4 tumor, or bilateral tumors.
* Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer;
* Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which had not been irradiated or would not be irradiated, or patients with supraclavicular lymph node involvement.
* Any prior anti-HER therapy, which includes agents that target other members of the HER family of receptors, e.g. gefitinib (Iressa)
* (Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support;
* Serious cardiac illness or medical conditions.
* Any of the following abnormal laboratory tests immediately prior to randomization:

  1. Serum total bilirubin \>1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\<2 x ULN) was allowed;
  2. Alanine amino transferase (ALT) or aspartate amino transferase (AST) \>2.5 x ULN;
  3. Alkaline phosphatase (ALP) \>2.5 x ULN;
  4. Serum creatinine \>2.0 x ULN;
  5. Total white blood cell count (WBC) \<2.5 x 10\^9/L;
  6. Absolute neutrophil count \<1.5 x 10\^9/L;
  7. Platelets \<100 x 10\^9/L.
* Women of childbearing potential and male patients with partners of childbearing potential, who are unable or unwilling to use adequate contraceptive measures during study treatment, and pregnant or lactating women.
* Concomitant use of CYP3A4 inhibitors or inducers.

• DERIVEDRediti M, Venet D, Joaquin Garcia A, Maetens M, Vincent D, Majjaj S, El-Abed S, Di Cosimo S, Ueno T, Izquierdo M, Piccart M, Pusztai L, Loi S, Salgado R, Viale G, Rothe F, Sotiriou C. Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial. Nat Commun. 2024 Nov 29;15(1):10402. doi: 10.1038/s41467-024-54621-3. PMID 39613746
• DERIVEDNader-Marta G, Debien V, Eiger D, Tsourti Z, Caparica R, Kassapian M, Napoleone S, Hultsch S, Korde L, Wang Y, Chumsri S, Pritchard KI, Untch M, Bellet-Ezquerra M, Dornelles Rosa D, Moreno-Aspitia A, Piccart M, Dafni U, de Azambuja E. Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study. Br J Cancer. 2022 Nov;127(10):1799-1807. doi: 10.1038/s41416-022-01963-8. Epub 2022 Sep 1. PMID 36050448
• DERIVEDMoreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, Korde L, Fumagalli D, Izquierdo MA, McCullough AE, Wolff AC, Pritchard KI, Untch M, Guillaume S, Ewer MS, Shao Z, Sim SH, Aziz Z, Demetriou G, Mehta AO, Andersson M, Toi M, Lang I, Xu B, Smith IE, Barrios CH, Baselga J, Gelber RD, Piccart-Gebhart M; ALTTO Steering Committee and Investigators. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur J Cancer. 2021 May;148:287-296. doi: 10.1016/j.ejca.2021.01.053. Epub 2021 Mar 23. PMID 33765513
• DERIVEDSonnenblick A, Agbor-Tarh D, de Azambuja E, Hultsch S, Izquierdo M, Liu M, Pruneri G, Harbeck N, Piccart M, Moreno-Aspita A, Granit RZ, Rouas G, Fahoum I, Sotiriou C. STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial. Int J Cancer. 2021 Mar 15;148(6):1529-1535. doi: 10.1002/ijc.33385. Epub 2020 Nov 23. PMID 33152119
• DERIVEDEiger D, Ponde NF, Agbor-Tarh D, Moreno-Aspitia A, Piccart M, Hilbers FS, Werner O, Chumsri S, Dueck A, Kroep JR, Gomez H, Lang I, Rodeheffer RJ, Ewer MS, Suter T, de Azambuja E. Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial. Br J Cancer. 2020 May;122(10):1453-1460. doi: 10.1038/s41416-020-0786-x. Epub 2020 Mar 16.