Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study

This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Subjects were randomized to receive lapatinib, trastuzumab or lapatinib plus trastuzumab for a total of 6 weeks. After this biological window, subjects continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). Paclitaxel could be initiated at Week 4 if there is evidence of progressive disease (PD) at that time. Within 6 weeks after surgery, subjects received 3 cycles of adjuvant 5-flourouracil, epirubicin and cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy).

After completing 52 weeks of (neo-)/adjuvant anti-HER2 therapy, subjects were scheduled to attend post-treatment follow-up every 3 months during the first year (months 12, 15, 18, 21, and 24), every 6months in Years 3 to 5 inclusive, and annually thereafter up to Year 10. Each subject was to be followed for 10 Years. All subjects were to be followed for EFS and OS up to 10 years from last subject randomized.

• Lapatinib (Drug): Small molecule receptor tyrosine kinase inhibitor
• Trastuzumab (Biological): Therapeutic Monoclonal Antibody
• Paclitaxel (Drug): antimicrotubule agent

Primary outcomes

• Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery [Weeks 20 to 22]: Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.

Secondary outcomes

• Number of Participants With Overall Response at Week 6 [Week 6]: The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
• Overall Response at the Time of Surgery [Time of surgery (Weeks 20 to 22)]: The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
• Number of Participants With Negative Lymph Nodes at the Time of Surgery [Time of surgery (Weeks 20 to 22)]: Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.
• Number of Participants With Actual Indicated Surgery [At surgery (Weeks 20 to 22)]: Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.
• Mean Change From Baseline in Tumor Size at Week 6 and at Surgery [Week 6 and surgery (Weeks 20 to 22)]: Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.
• Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab [Week 6]: Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.
• Event-free Survival (EFS) - Median Clinical Follow-up [From randomization up to approximately year 10]: Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
• Event-free Survival (EFS) - Events and Censoring [From randomization up to approximately year 10]: Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
• Overall Survival (OS) - Median Survival Follow-up [From randomization up to approximately year 10]: Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
• Overall Survival (OS) - Deaths and Censoring [From randomization up to approximately year 10]: Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population) [up to year 10]: The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population) [up to year 10]: The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population) [up to year 10]: The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population) [up to year 10]: The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.
• To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints [Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.]
• Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT) [Week 2 and Week 6]: Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)
• Percentage of Participants With the Indicated Biomarker Expression - PIK3CA. [Baseline]: Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.
• Percentage of Participants With the Indicated Biomarker Expression - PTEN. [Baseline]: Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.
• Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR [Baseline]: Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR
• Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream [Measurement performed at one or more of the time points: baseline, week 2 or week 18]: Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* Female gender;
* Age ≥18 years;
* Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
* Histologically confirmed invasive breast cancer:
* Primary tumour greater than 2 cm diameter, measured by clinical examination and mammography or echography,
* Any N,
* No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed);
* Over expression and/or amplification of HER2 in the invasive component of the primary tumour \[Wolff et al 2006\] and confirmed by a certified laboratory prior to randomisation
* Known hormone receptor status.
* Haematopoietic status:
* Absolute neutrophil count ≥ 1,5 x 10\^9/L,
* Platelet count ≥ 100 x 10\^9/L,
* Hemoglobin at least 9 g/dl,
* Hepatic status:
* 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) is allowed,
* Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN,
* Alkaline phosphatase ≤ 2.5 times ULN,
* Renal status:
* Creatinine ≤ 2.0 mg/dL,
* Cardiovascular:
* Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,
* Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential)
* Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)
* Signed informed consent form (ICF)
* Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol

Exclusion Criteria:

* Received any prior treatment for primary invasive breast cancer;
* Previous (less than 10 years) or current history of malignant neoplasms, except for curatively treated:
* Basal and squamous cell carcinoma of the skin;
* Carcinoma in situ of the cervix.
* Patients with a prior malignancy diagnosed more than 10 years prior to randomisation may enter the study. Patients must have been curatively treated with surgery alone. Radiation therapy or systemic therapy (chemotherapy or endocrine) are NOT permitted. Prior diagnoses of breast cancer or melanoma are excluded.
* Diagnosis of inflammatory breast cancer;
* Bilateral cancer;
* This criterion has been deleted from the protocol Version 1. Patients with multi-focal cancer are no longer excluded.
* Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen;
* Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;
* Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
* Active or uncontrolled infection;
* Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
* Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients;
* Pregnant or lactating women;
* Concomitant use of CYP3A4 inhibitors or inducers

Participant flow

Outcome results

• Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery (Primary), Number, participants: Lapatinib 1500 mg 38; Trastuzumab 2 mg/kg 44; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 78 (p 0.3416)
• Number of Participants With Overall Response at Week 6 (Secondary), Number, participants: Lapatinib 1500 mg 81; Trastuzumab 2 mg/kg 45; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 102
• Overall Response at the Time of Surgery (Secondary), Number, participants: Lapatinib 1500 mg 114; Trastuzumab 2 mg/kg 105; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 122
• Number of Participants With Negative Lymph Nodes at the Time of Surgery (Secondary), Number, participants: Lapatinib 1500 mg 72; Trastuzumab 2 mg/kg 82; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 100
• Number of Participants With Actual Indicated Surgery (Secondary), Number, participants: Lapatinib 1500 mg 66; Trastuzumab 2 mg/kg 58; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 63
• Mean Change From Baseline in Tumor Size at Week 6 and at Surgery (Secondary), Mean, millimeters: Lapatinib 1500 mg -20.45 +/- 18.43; Trastuzumab 2 mg/kg -13.42 +/- 16.44; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg -25.77 +/- 19.91
• Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab (Secondary), Number, participants: Lapatinib 1500 mg 8; Trastuzumab 2 mg/kg 12; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 6
• Event-free Survival (EFS) - Median Clinical Follow-up (Secondary), Median, years: Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 9.69 (9.55 to 9.73); Lapatinib 1500 mg 9.60 (8.21 to 9.69); Trastuzumab 2 mg/kg 9.66 (9.50 to 9.72)
• Event-free Survival (EFS) - Events and Censoring (Secondary), Number, Number of Participants: Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 43; Lapatinib 1500 mg 47; Trastuzumab 2 mg/kg 47 (p 0.548)
• Overall Survival (OS) - Median Survival Follow-up (Secondary), Median, years: Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 9.70 (9.60 to 9.76); Lapatinib 1500 mg 9.62 (8.86 to 9.67); Trastuzumab 2 mg/kg 9.64 (9.35 to 9.71)
• Overall Survival (OS) - Deaths and Censoring (Secondary), Number, Number of Participants: Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 26; Lapatinib 1500 mg 31; Trastuzumab 2 mg/kg 32 (p 0.379)
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population) (Secondary), Median, years: Pathological Complete Response (pCR) 9.05 (8.86 to 9.14); No Pathological Complete Response (pCR) 9.11 (9.05 to 9.14); Overall 9.09 (9.03 to 9.13) (p 0.00079)
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population) (Secondary), Number, Number of participants: Pathological Complete Response (pCR) 29; No Pathological Complete Response (pCR) 98; Overall 127
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population) (Secondary), Median, years: Pathological Complete Response (pCR) 9.10 (8.97 to 9.18); No Pathological Complete Response (pCR) 9.09 (9.03 to 9.12); Overall 9.09 (9.04 to 9.13) (p 0.00041)
• Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population) (Secondary), Number, Number of Participants: Pathological Complete Response (pCR) 15; No Pathological Complete Response (pCR) 70; Overall 85
• To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints (Secondary), Count of participants, Participants: Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 2 (0.16 to 4.76); Lapatinib 1500 mg 0 (0.00 to 2.41); Trastuzumab 2 mg/kg 1 (0.02 to 3.71)
• Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT) (Secondary), Number, Percentage of participants: Lapatinib 1500 mg 66.7; Trastuzumab 2 mg/kg 56.5; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 95.0
• Percentage of Participants With the Indicated Biomarker Expression - PIK3CA. (Secondary), Number, Percentage of participants: Lapatinib 1500 mg 23; Trastuzumab 2 mg/kg 19; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 25
• Percentage of Participants With the Indicated Biomarker Expression - PTEN. (Secondary), Number, Percentage of participants: Lapatinib 1500 mg 74; Trastuzumab 2 mg/kg 70; Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 75
• Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR (Secondary), Geometric mean, Ratio: Lapatinib 1500 mg 1.0 (0.50 to 1.87); Trastuzumab 2 mg/kg 1.6 (1.0 to 2.71); Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg 2.1 (1.2 to 3.7)
• 2 more outcome measures not shown.

Adverse events

Time frame: Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.

Serious adverse events by term

19 more terms not shown.

Other adverse events by term

118 more terms not shown.

21 more sites not listed.

• Baselga J, Piccart M, Gelber R, di CosimoS, Viale G, Koehler M, Rojo F. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study [BIG 1-06 /solti/EGF106903]: a phase III translational study for HER2-overexpressing early breast cancer. [Lancet]. 2012;S140-6736(11):
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• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals