Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial.

BACKGROUND: Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. MATERIALS AND METHODS: Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant-palbociclib (FP) or letrozole-palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. RESULTS: A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). CONCLUSION: The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. CLINICALTRIALS.GOV IDENTIFIER: NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study.

Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 4 weeks for four cycles, followed by 80 mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65 years, 64 % suffered from hypertension, and 10 % had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32 % (95 % CI 19.5-46.7 %) and pCR in breast and axilla was 24 % (95 % CI 12.1-35.8 %). At diagnosis only, 26 % of patients were candidates for breast conservative surgery, which increased to 58.7 % after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer.

BACKGROUND: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. METHODS: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. RESULTS: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). CONCLUSIONS: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer.

PURPOSE: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. EXPERIMENTAL DESIGN: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. RESULTS: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. CONCLUSIONS: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study.

PURPOSE: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. PATIENTS AND METHODS: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. RESULTS: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. CONCLUSIONS: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.

Long-Term Cardiac Safety and Survival Outcomes of Neoadjuvant Pegylated Liposomal Doxorubicin in Elderly Patients or Prone to Cardiotoxicity and Triple Negative Breast Cancer. Final Results of the Multicentre Phase II CAPRICE Study.

BACKGROUND: The CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS). METHODS: In this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m2) plus cyclophosphamide (600 mg/m2) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed. RESULTS: Between Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%). CONCLUSION: At 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov reference NCT00563953.

Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: a phase Ib/II, open-label, multicentre, randomised study.

BACKGROUND: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models. METHODS: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine. RESULTS: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model. CONCLUSION: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine. TRIAL REGISTRATION NUMBER: NCT01934361.

Long-term response to first-line bevacizumab-based therapy in patients with metastatic breast cancer: results of the observational "LORENA" study.

BACKGROUND: Randomized controlled trials of the first-line combination of bevacizumab and chemotherapy in patients with metastatic breast cancer (MBC) have shown improvements in tumor response and progression-free survival (PFS). OBJECTIVE: The aim of this ambispective, observational study (LORENA) was to describe the clinical characteristics of long-term responders to bevacizumab-based therapy. PATIENTS AND METHODS: This study consisted of a retrospective and a prospective phase. During the retrospective phase, patients with HER2-negative MBC who were treated with bevacizumab-based first-line therapy were included. During the prospective phase, patients with PFS of ≥12 months were treated according to routine clinical practice procedures. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. RESULTS: In total, 148 women were included (median age: 50 years; range: 29-81 years). The mean duration of exposure to bevacizumab was 18 months. The majority of patients experienced objective response (complete: 23%; partial: 57%). Median PFS was 22.7 months and median OS was 58.2 months. In multivariate analyses, patients receiving maintenance hormonal therapy (MHT) had longer PFS (P=0.002; hazard ratio [HR] =1.8) and OS (P=0.009; HR=2.0), while patients not previously treated with taxanes had longer OS (P<0.0001; HR =3.3). No unexpected adverse events were observed. CONCLUSION: The results of this study suggest, that among long-term responders, first-line bevacizumab-based therapy is more effective in patients who had not been previously treated with taxanes, and that MHT provides additional therapeutic benefits by extending PFS and OS.

Geometrical Measures Obtained from Pretreatment Postcontrast T1 Weighted MRIs Predict Survival Benefits from Bevacizumab in Glioblastoma Patients.

BACKGROUND: Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. METHODS: 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE 'rim' geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. RESULTS: Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. CONCLUSION: Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results.

Bevacizumab for the treatment of glioblastoma.

Glioblastoma (GBM) or grade IV glioma is the most common primary brain tumor in adults. Standard treatment median overall survival (OS) is only 14-15 months and less than 10% of patients will survive 5 years after diagnosis. There is no standard treatment in recurrent GBM and OS ranges from 3 to 9 months. GBM is 1 of the most vascularized human tumors and GBM cells produce vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, has demonstrated activity in vitro and in phase II trials in relapse, as well as in 1 phase III trial as first line therapy. Bevacizumab also improves quality of life for patients suffering GBM. This paper reviews the mechanism of action of bevacizumab, its metabolism and pharmacokinetic profile. It summarizes the clinical studies in recurrent and newly diagnosed GBM, its potential side effects and complications and its place in therapy.