Supplemental Table 1. CNS response criteria.

CNS complete response (CR) will be defined if all of the following are satisfied:

·  Complete resolution of all evaluable (≥1cm diameter) and non-evaluable (non-measurable) brain metastases

·  No new lesions (new lesion defined as ≥6 mm)

CNS partial response (PR) will be defined if all of the following are satisfied:

·  ≥50% reduction in the volumetric sum of all evaluable (≥1 cm in diameter) brain metastases compared to baseline

·  No progression of non-evaluable (non-measurable) lesions

·  No new lesions (new lesion defined as ≥6 mm in diameter)

CNS stable disease (SD) will be defined if all of the following are satisfied:

·  <50% reduction in the volumetric sum of all evaluable (≥1 cm in diameter) brain metastases (compared to baseline) and not fulfilling the criteria for progressive disease.

·  No progression of non-evaluable (non-measurable) lesions

·  No new lesions (new lesion defined as ≥6 mm in diameter)

Note: CNS lesions that were initially evaluable (≥1 cm in diameter) at baseline and have decreased in size on trial therapy to <1 cm in diameter will continue to be assessed volumetrically for response.

CNS progression will be defined if any of the following are satisfied:

·  ≥40% increase in the volumetric sum of all evaluable lesions as compared to the smallest volume since investigational therapy was initiated, or

·  Progression of non-evaluable (non-measurable) lesions*, or

·  New lesions (new lesion defined as ≥6 mm in diameter).

*NOTE: Progression of non-evaluable (non-measurable) CNS lesions is defined as follows:

·  a lesion initially at baseline ≤5 mm in diameter that increases to ≥10 mm in diameter, or

·  a lesion initially at baseline 6-9 mm in diameter that increases by at least 5 mm in diameter.

These criteria were chosen to minimize classifying subjects as having progressive disease due to MRI sampling error, given an MRI slice thickness of 3 mm.

Supplemental Table 2. Description of adverse events that resulted in treatment discontinuation (including their management and outcome).

Patient / Adverse Event / Management / Outcome
1 / Grade 3 jejunal perforation / Laparotomy / Recovered
2 / Grade 4 pneumonia / Hospitalization, bronchodilatator (Berovent) with Oxygen Mask Venturi, Salbutamol Sulfate + Ipratropium bromide monohydrate (Berovent), Piperacillin Sodium + Tazobactam sodium (Tazocin) intravenous and Levoflacin hemihydrate (Tavanic). / Recovered
3 / Grade 3 pulmonary/pleural infection (empyema) / Hospitalization and administration of Moxifloxacin (Octegra), Ipratropium + Salbutamol (Berovent) inhaler, Budesonide (Pulmicort) inhaler, Dalacin 600 mg and Ciprofloxacin (Ciproxin) 500 mg. Pleural fluid removal. Chest tube drainage (bullau). / Not recovered
4 / Grade 3 rash / Xozal and Medrol. / Recovered

Supplemental Table 3. Objective response rates and median TTP and OS in months, for the total cohort (N=81) and patients with pre and post MRIs (N=43), broken down by cancer type.

Total cohort / Patients with pre and post brain MRI scans*
All patients / N=81 / N=43
Objective Response N (%)
PR / 27 (62.8%)
SD / 15 (34.9%)
PD / 1 (2.3%)
Median TTP (95% CI) / 3.4 (1.8-5.0) / 3.4 (1.8-7.6)
Median OS (95% CI) / 4.8 (3.7-8.1) / 10.1 (4.9-17.2)
Breast cancer patients / N=21 / N=14
Objective Response N (%)
PR / 10 (71.4%)
SD / 3 (21.4%)
PD / 1 (7.1%)
Median TTP (95% CI) / 5.0 (1.4-9.2) / 7.2 (1.7-11.2)
Median OS (95% CI) / 11.8 (4.9-23.4) / 17.7 (4.9-25.4)
NSCLC patients / N=60 / N=29
Objective Response N (%)
PR / 17 (58.6%)
SD / 12 (41.4%)
PD / 0 (0%)
Median TTP (95% CI) / 2.8 (1.7-4.1) / 2.6 (1.6-4.1)
Median OS (95% CI) / 4.2 (3.2-5.1) / 5.6 (3.9-14.7)
*only these patients were used for the assessment of objective response rates.

Supplemental Table 4. Objective response and median TTP and OS (months) in breast cancer patients by HER2 status and NSCLC patients by EGFR protein expression status.

Breast cancer patients (N=21)
HER2-positive (N=12) / HER2-negative (N=9)
Objective Response N (%)
PR / 7 (77.8%) / 3 (60.0%)
SD / 2 (22.2%) / 1 (20.0%)
PD / - / 1 (20.0%)
Median TTP (95% CI) / 9.1 (1.7-22.3) / 1.3 (0.2-4.6)
Median OS (95% CI) / 17 (8.1-25.3) / 4.9 (1.1-28.1)
NSCLC patients (N=38)
EGFR-positive (N=27) / EGFR-negative (N=11)
Objective Response N (%)
PR / 7 (58.3%) / 5 (71.4%)
SD / 5 (41.7%) / 2 (28.6%)
PD / - / -
Median TTP (95% CI) / 4.0 (1.7-9.4) / 2.1 (1.0-4.1)
Median OS (95% CI) / 4.5 (2.2-14.7) / 3.9 (2.3-17.9)

Supplemental Table 5. Most common treament-related grade 3 and 4 adverse eventsa in the present study (HE42/09) and in a previously reported lapatinib monotherapy study (Study 2).

Adverse event / HE42/09 / Study 2
n / % / n / %
Total patientsb / 23 / 28 / 14 / 18
Diarrhea / 6 / 7 / 7 / 9
Rash / 4 / 5 / 3 / 4
GGT / 3 / 4 / 0 / 0
Infection / 3 / 4 / 0 / 0
Blood toxicity / 2 / 2 / 0
Fatigue / 2 / 2 / 1 / 1
Vomiting / 2 / 2 / 0 / 0

aIn total 28 treatment-related grade 3 and 4 adverse events were recorded.

bNumber of patients with one or more treatment-related adverse events.

Study 2: Blackwell KL, et al. (2009). Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Annals of Oncology, 20(6):1026-1031.