Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.

CALYPSO (NCT02435212), a randomized, open-label, multicenter, phase 2 study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pre-treated patients aged 2 to 0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and dispersible tablets formulations, and was consistent with the general safety profile of deferasirox.

Tolerability and toxicity of trastuzumab or trastuzumab + lapatinib in older patients: a sub-analysis of the ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D).

PURPOSE: Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization. RESULTS: A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65-80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients. CONCLUSION: Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.

BACKGROUND: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. METHODS: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. RESULTS: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]). CONCLUSIONS: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial.

The Complement 1 trial investigated the efficacy and safety of ofatumumab + chlorambucil with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia (CLL). On long-term follow-up in the chemoimmunotherapy arm vs. the chemotherapy arm there was an estimated 12% (not significant) and 39% risk reduction in overall survival and progression-free survival, respectively. A high rate (61%) of treatment with next-line therapies in both the treatment arms may dilute any potential OS difference and confound the interpretation of the OS results. Addition of ofatumumab to chlorambucil demonstrated clinical benefit and tolerability as a frontline treatment option in patients unfit for fludarabine-containing therapy, with no new safety concerns.

Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial.

PURPOSE: Limited evidence exists on the impact of hormone receptor (HR) status to counsel HER2-positive early breast cancer patients receiving adjuvant anti-HER2 therapy. METHODS: ALTTO (BIG 2-06) was an international, intergroup, open-label, randomized phase III trial in HER2-positive early breast cancer patients randomized to receive 1 year of trastuzumab and/or lapatinib. HER2, estrogen and progesterone receptors were centrally tested for all patients. We investigated the impact of HR status on prognosis, risk of disease-free survival (DFS) events over time, patterns of first DFS events, and factors associated with risk of DFS events overall, in years 0-5 and 6-8. RESULTS: Out of 6273 patients included in this analysis, 3603 (57.4%) had HR-positive tumors. Median follow-up was 6.93 years. Five-year and 8-year DFS were 86% and 80% in patients with HR-positive disease, and 83% and 79% in those with HR-negative tumors, respectively. Mean annual hazards of recurrence in years 0-5 were 3% in patients with HR-positive disease and 4% in those with HR-negative tumors, while in years 6-8 they were 3% and 2%, respectively. Distribution of first DFS event in years 6-8 (P = 0.005) and type of first distant recurrence (P < 0.001) were significantly different between the two groups. Risk factors for DFS events overall, in years 0-5, and 6-8 were different in patients with HR-positive and HR-negative tumors. CONCLUSIONS: HER2-positive early breast cancer is characterized by the presence of two diseases with distinct natural history based on HR status requiring the development of different follow-up strategies and future de-escalation and escalation clinical trials.

Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials.

Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial.

BACKGROUND: In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease ('trastuzumab-free interval', TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role. METHODS: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models. RESULTS: Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233). CONCLUSIONS: TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.