GlaxoSmithKline plc (GSK) announced that the phase III study of two anti-HER2 agents, lapatinib (Tykerb/Tyverb) and trastuzumab, did not meet the primary endpoint of improved disease free survival (DFS) compared to single agent therapy with trastuzumab as adjuvant treatment for HER2 positive early breast cancer. The safety profile was consistent with the established safety profile of the study drugs, with no new safety signals observed.

These results were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

“While it is disappointing that ALTTO did not meet its primary endpoint, we now have a tremendous amount of information that will help to further our knowledge of the biology of this disease and inform future studies in HER2 positive breast cancer in the adjuvant setting. Further analysis of these data will continue over the coming months,” said Dr. Rafael Amado, senior vice president Oncology R&D at GSK.  “We are most grateful to the more than 8,000 patients across the world who participated in ALTTO—their generous contribution to the scientific community will facilitate a greater understanding of this aggressive disease.”

The primary analysis of the study tested for superiority (p=0.025) between the combination arm and trastuzumab alone with respect to DFS; the trastuzumab followed by lapatinib arm was tested for non-inferiority (p=0.025). The results showed that at four years, 88 per cent of women lived without their disease returning (4-year DFS) in the lapatinib plus trastuzumab arm and 86 per cent in the trastuzumab arm . The 4-year DFS rate for the trastuzumab followed by lapatinib arm was 87 per cent compared to 86 per cent in the trastuzumab arm

Adverse events (AEs) more frequently reported in the lapatinib plus trastuzumab arm compared to the trastuzumab arm were diarrhoea (75per cent vs. 20 per cent ), rash (55 per cent vs. 20 per cent ) and hepatobiliary (23 per cent vs. 16 per cent). Diarrhoea, grade 3 or higher, was increased in all lapatinib containing treatment arms (5-15 per cent ), compared to trastuzumab alone (1per cent ). The incidence of febrile neutropenia was <1 per cent across treatment arms and primary cardiac endpoints were <1per cent  in all arms. Overall, fatal AEs were consistent between treatment groups (<1per cent ), with no clear pattern to the reported events. AEs leading to discontinuation were higher in the lapatinib containing arms (23 per cent  in the combination arm) compared with the trastuzumab arm (8 per cent ).

ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation trial; NCT00490139) is a randomised, multi-centre, open-label, Phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2 positive primary breast cancer. Randomised patients received anti-HER2 therapy (lapatinib, trastuzumab) after completing all chemotherapy, concurrent with a taxane following anthracycline, or concurrent with a non-anthracycline, platinum-containing regimen.

ALTTO randomised 8,381 patients at nearly 1,000 research sites in 44 countries. Patient enrolment began in June 2007 and was completed in July 2011.  The lapatinib arm was discontinued in 2011, after an independent review committee determined that the lapatinib alone arm was unlikely to meet the pre-specified criteria to demonstrate non-inferiority to trastuzumab alone with respect to disease-free survival.

Lapatinib an orally active, reversible, small molecule TKI that potently inhibits both ErbB1 and ErbB2 tyrosine kinase activity is marketed as Tykerb in the US. and as Tyverb in Europe and other countries across the world. Lapatinib is not approved or licensed anywhere in the world for the treatment of HER2 positive early breast cancer.