Data from Advances in Precision Cancer Care - Curated by EPG Health - Last updated 02 November 2018

Saturday’s ESMO 2018 report comes from Presidential Symposium 1, moderated by Andrés Cervantes (Valencia, ES) and Josep Tabernero (Barcelona, ES), discussing the scientific results and clinical implications of new data from the phase 3 IMpassion130, PALOMA-3 and SOLAR-1 trials. 

Scroll down for key insights from each presentation.


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LBA1_PR - IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC)

Dr Schmid presented the results of the IMpassion130 trial, a randomised, double-blind, placebo-controlled, phase III study investigating the addition of atezolizumab to nab-paclitaxel in patients with treatment-naive, locally advanced or metastatic triple-negative breast cancer. 

The optimal treatment for triple-negative breast cancer represents an area of unmet need. The prognosis for patients with this condition is significantly worse than patients with other subtypes of breast cancer. In the first-line setting, patients with triple negative breast cancer are generally treated with anthracycline-based chemotherapy or single agent taxanes with a median overall survival of 18 months. Preliminary data from smaller studies showed atezolizumab was active in triple negative breast cancer, especially in patients with PD-L1 positive tumours (≥1% in tumour-infiltrating immune cells).

In the IMpression130 study, patients were randomised in a 1:1 ratio to nab-paclitaxel plus atezolizumab or nab-paclitaxel plus placebo. Previous adjuvant chemotherapy, including taxanes was allowed as long as the treatment-failure interval was equal to or longer than 12 months. Co-primary endpoints were progression-free survival and overall survival in the ITT and PD-L1 positive populations. 902 patients were randomised (451 in each treatment group). Patients’ baseline characteristics were well balanced. The majority of patients had visceral disease, 50% had received previous taxane-based adjuvant chemotherapy and 41% of patients had PD-L1 positive tumours. 

Adding atezolizumab to nab-paclitaxel was associated with a statistically significant improvement in progression-free survival in the ITT population (median PFS 7.2 months in the investigational arm vs 5.5 months in the placebo arm, stratified HR 0.80, p=0.0025) and in the PD-L1 positive population (median PFS 7.5 months in the investigational arm vs 5.0 months in the placebo arm, stratified HR 0.62, p<0.0001). 

Preliminary overall survival data at a median follow-up of 12.9 months showed a trend towards a statistically significant improvement in overall survival for the investigational arm (median OS 21.3 months in the investigational arm vs 17.6 months in the placebo arm, stratified HR 0.84, p=0.0840) and in the PD-L1 positive population (median OS 25.0 months in the investigational arm vs 15.5 months in the placebo arm, stratified HR 0.62, p not tested due to the hierarchical statistical design). 

The benefit of atezolizumab on PFS was consistent across patient subgroups, except patients with PD-L1 negative tumours. There was a higher response rate (56% vs 46% in the ITT population and 59% vs 43% in the PD-L1 positive population) and longer duration of response (7.4 months vs 5.6 months in the ITT population and 8.5 months vs 5.5 months in the PD-L1 positive population). 

Analysis of drug exposure showed the addition of atezolizumab did not compromise the dose intensity of nab-paclitaxel. Regarding safety, a higher rate of grade ≥3 AEs was observed in the investigational arm (50% vs 43%). In particular, an increase in the risk of peripheral neuropathy was reported in patients receiving atezolizumab, likely due to the longer duration of nab-paclitaxel treatment in this treatment group. The rate of grade ≥3 immune-related adverse events was only slightly increased with the use of atezolizumab (8% vs 4%). 

Dr Schmid concluded that adding atezolizumab to first-line nab-paclitaxel resulted in a statistically significant PFS benefit in patients with triple negative breast cancer. This was also clinically meaningful in those with PD-L1 positive tumours. Therefore, he suggested atezolizumab plus nab-paclitaxel should be considered the new standard of care for this poor prognosis patient group.


LBA2_PR - Overall survival (OS) with palbociclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2_) advanced breast cancer (ABC): Analyses from PALOMA-3

Dr Cristofanilli presented mature overall survival data from the PALOMA-3 trial, a study of palbociclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. 

The use of palbociclib in advanced breast cancer is supported by strong clinical data. Nevertheless, it is not known whether the previously demonstrated benefit in progression-free survival translates into a significant benefit in overall survival. This updated analysis aims to address this.

In the PALOMA-3 trial, 521 patients with HR+/HER2- tumours who had progressed on prior endocrine therapy were randomised in a 2:1 ratio to treatment with fulvestrant plus palbociclib or fulvestrant plus placebo. Of note, the primary endpoint of the study was progression-free survival while the study was not adequately powered to demonstrate a statistically significant difference in overall survival. 

Patients’ baseline characteristics were well balanced between treatment arms. Although the majority of patients were postmenopausal (79%) the study recruited a relatively high proportion of pre- and peri-menopausal patients (21%), especially when compared with previous studies in the same setting. Of note, 60% had visceral metastases. 

An updated analysis of the primary endpoint confirmed a statistically significant improvement in median progression-free survival with the addition of palbociclib (11.2 months in the investigational arm vs 4.6 months in the control arm, HR 0.497, p<0.000001). After a median follow-up of 44.8 months, overall survival in the ITT population showed an improvement in PFS that translated into a statistically significant improvement in OS. 

Median overall survival was 34.9 months in the investigational arm and 28.0 months in the control arm (stratified HR 0.814, p=0.0429). Treatment effect was consistent across clinical and molecular subgroups. Nevertheless, previous response to endocrine therapy appeared to drive the overall survival benefit associated with palbociclib. 

While the overall survival advantage was maintained in 410 patients who were sensitive to prior endocrine therapy (39.7 months in the investigational arm vs 29.7 months in the control arm, HR 0.721, p=0.0081), no statistically significant difference was observed between investigational and control treatment in the smaller group of patients who were not sensitive to prior endocrine therapy (20.2 months in the investigational arm versus 26.2 months in the control arm, HR 1.137, p=0.2969). 

Regarding subsequent therapies, no difference in the number and type of post-study treatments were observed between groups. Of note, although cross-over was not allowed, 27 patients in the control group received post-study CDK4/6 inhibitors. 

Dr Cristofanilli concluded that adding palbociclib to fulvestrant resulted in a clinically meaningful improvement in OS (+6.9 months), confirming fulvestrant plus palbociclib should be considered a standard of care for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.  


LBA3_PR - Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial

Dr André presented the results of the SOLAR-1 trial, a phase III study of alpelisib plus fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC).  

PI3KCA is involved in breast cancer progression and resistance to endocrine therapy. Approximately 40% of breast cancer patients have tumours with activating mutations of PI3KCA. Alpelisib specifically inhibits the PI3K alpha isoform and has demonstrated anti-tumour activity in preclinical models. Also, a previous phase Ib study in patients with heavily pre-treated ER+ breast cancer suggested the combination of alpelisib plus fulvestrant was particularly effective in PIK3CA-mutant patients. 

The SOLAR-1 trial was a biomarker-stratified, 2-cohort trial with eligibility limited to men or post-menopausal women who had progressed or recurred after previous AI therapy and had tumour tissue available for the mutational analysis of PI3KCA. Eligible patients with PI3KCA-mutant tumours (n=341) or PI3KCA wild-type tumours (n=231) were randomised in a 1:1 ratio to receive fulvestrant plus alpelisib or fulvestrant plus placebo. The primary endpoint of the study was progression-free survival in the PI3KCA mutant cohort. Patient characteristics were well balanced between treatment groups. Only 5–6% of patients had received prior therapy with CDK4/6 inhibitors. Visceral metastases were present in the majority of patients. 

The study met its primary endpoint: median PFS was 11.0 months in the alpelisib arm vs 5.7 months in the placebo arm (HR 0.65, p=0.00065). Similar results were achieved when the analysis of PFS was based on central radiological assessment (11.1 months vs 3.7 months, HR 0.48). In contrast, no difference in median PFS, with or without alpelisib, was observed in the cohort of patients with PI3KCA wild-type tumours: median PFS was 7.4 months in the alpelisib arm vs 5.6 months in the placebo arm (HR 0.85). 

In the PI3KCA-mutant cohort, treatment effect was consistent across patient subgroups and not influenced by the specific type of PI3KCA mutation. Overall response rate in patients with measurable disease was also higher in the investigational arm (35.7% vs 16.2%, p=0.0002).

Adding alpelisib to fulvestrant was associated with an increased risk of grade ≥3 AEs (76% vs 35.5%) and a higher rate of treatment discontinuation due to AEs (25% versus 4%). Most common grade ≥3 AEs, which occurred more frequently in the investigational arm, were hyperglycaemia (36.6%) and rash (9.9%).  
 
Dr André concluded alpelisib is the first PI3KCA inhibitor to show a statistically significant and clinically meaningful benefit in patients with advanced breast cancer and should be considered for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) disease who have progressed on prior endocrine therapy. 

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