REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas.

BACKGROUND: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs. PATIENTS AND METHODS: Adult patients with IDHm WHO grade 3-4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria. RESULTS: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15-44.9%). Median PFS and OS were 1.84 (CI95% 1.81-5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies. CONCLUSIONS: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

Evaluating everolimus for the treatment of breast cancer.

INTRODUCTION: Everolimus is an oral drug that inhibits mTOR with immunosuppressive and antiproliferative characteristics. It is commonly used in association with exemestane in hormone receptor (HR)-positive advanced breast cancer (ABC). AREAS COVERED: The current review summarizes the publications relating to everolimus from clinical research in breast cancer. Everolimus showed treatment efficacy and an acceptable safety tolerance with the prevention of side effects in Phase II/III studies. BOLERO-2 study showed a progression-free survival improvement in patients with HR - positive ABC previously treated with aromatase inhibitors (AI) and leading to its acceptance in this indication. The absence of a post-CDK4/6 inhibitor (CDK4/6i.) study and the arrival of new drugs may raise questions about its current place in the therapeutic strategy. EXPERT OPINION: Everolimus is relevant in the management of HR - positive ABC. Because of its efficacy, acceptable tolerability and the absence of drugs that have shown a greater benefit, it remains a second-line treatment option in HR-positive, HER2 negative (score 0) patients without BRCA mutation or visceral crisis and can be discussed with fulvestrant in second line after CDK4-6i. It is likely that within 5 years this treatment will be replaced in second-line HR-positive breast cancer by new emerging treatments: drug-conjugated antibodies, tyrosine kinase inhibitors or immunotherapy in combination with chemotherapy.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Standard 6-week chemoradiation for elderly patients with newly diagnosed glioblastoma.

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI 95%: 10-13 months). Median PFS was 9.5 months (CI 95%: 9-10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for "real-life" elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-ß and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

BACKGROUND: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-ßRII receptor (a TGF-ß "trap") fused to a human IgG1 antibody blocking PD-L1. METHODS: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety. RESULTS: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with IDH-mutant GBM (n = 6) and 13.8% (3.9-31.7%) for patients with IDH-wild-type GBM (n = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [n = 6]). CONCLUSIONS: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.

The fully synthetic glycopeptide MAG-Tn3 therapeutic vaccine induces tumor-specific cytotoxic antibodies in breast cancer patients.

Cancer is one of the main causes of mortality worldwide and a major public health concern. Among various strategies, therapeutic vaccines have been developed to stimulate anti-tumoral immune responses. However, in spite of extensive studies, this approach suffers from a lack of efficacy. Recently, we designed the MAG-Tn3 vaccine, aiming to induce antibody responses against Tn, a tumor-associated carbohydrate antigen. The Tn antigen is of interest because it is expressed by several adenocarcinomas, but not normal cells. The fully synthetic glycopeptide vaccine MAG-Tn3 is composed of four arms built on three adjacent Tn moieties associated with the tetanus toxin-derived peptide TT830-844 CD4+ T-cell epitope. This promiscuous CD4+ T-cell epitope can bind to a wide range of HLA-DRB molecules and is thus expected to activate CD4+ T-cell responses in a large part of the human population. The MAG-Tn3 vaccine was formulated with the GSK-proprietary immunostimulant AS15, composed of CpG7909, MPL, and QS21, which has been shown to stimulate both innate and humoral responses, in addition to being well tolerated. Here, seven patients with localized breast cancer with a high-risk of relapse were immunized with the MAG-Tn3 vaccine formulated with AS15. The first results of phase I clinical trial demonstrated that all vaccinated patients developed high levels of Tn-specific antibodies. Moreover, these antibodies specifically recognized Tn-expressing human tumor cells and killed them through a complement-dependent cytotoxicity mechanism. Overall, this study establishes, for the first time, the capacity of a fully synthetic glycopeptide cancer vaccine to induce specific immune responses in humans.

Pertuzumab for the treatment of breast cancer.

Introduction: Pertuzumab, a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), inhibits the heterodimerization of HER2 with other HER receptors. It has been approved both by the Food and Drug Administration and the European Medicine Agency in the metastatic, neoadjuvant and adjuvant setting.Areas covered: This review analyses and discusses preclinical and clinical studies of pertuzumab in breast cancer. In this article, we review the status of pertuzumab, the completed and ongoing trials, and its safety.Expert opinion: Pertuzumab is a key drug for the treatment of HER2-positive metastatic or early breast cancer. However, it is imperative to identify patients that will need dual-targeting and mechanisms of resistance. Moreover, the value of pertuzumab beyond progression needs to be evaluated.

Benefits versus risk profile of buparlisib for the treatment of breast cancer.

Introduction: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination. Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib. Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α-selective PI3K inhibitors for ongoing and future trials.

Pharmacokinetic drug evaluation of abemaciclib for advanced breast cancer.

INTRODUCTION: The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.

[Early phase trials at the "Institut de cancérologie de l'Ouest": Clinical outcome and validation of prognostic scores]. / Essais de phase précoce à l'Institut de cancérologie de l'Ouest : réponse au traitement et validation de scores pronostiques.

INTRODUCTION: Early phase therapeutic trials in oncology are being offered to an increasing number of patients. The objective of this study is to retrospectively evaluate the treatment efficacy and survival of patients included in early phase trials at the "Institut de Cancérologie de l'Ouest" (ICO), as well as the interest of the Royal Marsden Hospital (RMH) and PRONOPALL scores in this population. PATIENTS AND METHODS: All patients with cancer screened or included for an early phase trial at ICO between January 2012 and December 2015 have been identified. RESULTS: Out of 1312-screened patients, 710 were included in 115 trials (34 phase 1 trials). The absence of molecular anomaly was the main cause of inclusion failure (49.5%). The disease control rate was 90.9%, the median overall survival was 14.7 months (95% CI 12.7 to 16.4) and the median progression-free survival was 5.7 months (95% CI 5.5 to 6.6). The median overall survival was better for patients with good prognosis based on Royal Marsden Hospital score (16.6 months versus 6 months, P=0.0011) and PRONOPALL score (15.6 months versus 4.6 months, P<0.001). DISCUSSION: Our results are better than in the literature, mainly because of the high proportion of first-line treatments and the consideration of phase II trials. Patients with lung cancer particularly benefited from these treatments, in part because of the role of immunotherapy. The Royal Marsden Hospital score can guide the decision to include in early phase trials, whereas the PRONOPALL score is not enough efficient.

Emerging PARP inhibitors for treating breast cancer.

INTRODUCTION: Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance.

An Update on the Clinical Use of CDK4/6 Inhibitors in Breast Cancer.

Deregulated cell division, resulting in aberrant cell proliferation, is one of the key hallmarks of cancer. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression in cancer, and the clinical development of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has changed clinical practice in the setting of endocrine-receptor positive breast cancer. Results of pivotal phase II and III trials investigating these CDK4/6 inhibitors in patients with endocrine receptor-positive, advanced breast cancer have demonstrated a significant improvement in progression-free survival, with a safe toxicity profile. No validated biomarkers of sensitivity or resistance exist at the moment. Future development of CDK4/6 inhibitors in breast cancer should focus on the identification of predictive biomarkers, the development of drug combinations to overcome resistance, and the application of CDK4/6 inhibitors to other breast cancer subtypes.

Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. RESULTS: 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). CONCLUSION: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

Efficacy of buparlisib in treating breast cancer.

INTRODUCTION: Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types. Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety. Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.

Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy.

Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined.

Olaparib for the treatment of breast cancer.

INTRODUCTION: Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.

Vinflunine for the treatment of breast cancer.

INTRODUCTION: Breast cancer is the most frequently diagnosed cancer and the highest cause of cancer mortality in females worldwide. The development of drugs improving overall survival in late-stage metastatic breast cancer remains a challenge. Vinflunine is the most recently developed drug in the vinca alkaloid class. Its arrival has been eagerly awaited for treatment of solid tumors, and in particular, for metastatic breast cancer. AREAS COVERED: The pharmacological features of vinflunine are described. Its clinical development as monotherapy or in combination in metastatic breast cancer is detailed. A literature search on the topic was conducted through PubMed, clinical trials and the proceedings of the main cancer congresses. EXPERT OPINION: The overall results from phase III studies, and in particular those that combined vinflunine with capecitabine, have been less favorable. The combination's effectiveness was at best moderate compared with other drugs which also target metastatic breast cancer, and complicated by significant hematological and gastrointestinal adverse effects. Its use in advanced metastatic breast cancer cannot currently be recommended.

What is the best choice of partner chemotherapy with trastuzumab for metastatic breast cancer?

The HER2 gene and its role in pathogenicity in human breast cancer were detected in the 1980s. Trastuzumab is a monoclonal antibody directed against the HER2 membrane receptor. The aim of this article is to describe chemotherapy-trastuzumab combinations that have been evaluated in patients with HER2-positive metastatic breast cancer, and to define the possible standards and options.

Eribulin mesylate for the treatment of late-stage breast cancer.

INTRODUCTION: Chemotherapy agents, particularly anthracycline and taxane, have demonstrated their significance in metastatic breast cancer. However, improving overall survival in late-stage breast cancer remains a challenge. Eribulin mesylate, a new chemotherapy agent, has a proven significance in this setting. Eribulin mesylate is a synthetic analog of a macrolide isolated from a marine sponge. It inhibits microtubule polymerization, inducing mitosis arrest and apoptosis, and aggregates soluble tubulin in nonproductive form. In Phase II studies, this drug has shown a partial and stable response. The Phase III EMBRACE study showed that eribulin mesylate improved overall survival, compared with the physician's choice of treatment, in women who had received two to five prior chemotherapy regimens, including anthracycline and taxane for advanced breast cancer (median overall survival: 13.1 versus 10.6 months HR 0.81, p = 0.041). This compound is well tolerated. The most common adverse event is neutropenia. AREAS COVERED: This paper provides an introduction to the drug, eribulin mesylate, along with an overview of the current drug market for late-stage breast cancer; it also reviews its pharmacodynamics, pharmacokinetics and clinical efficacy. EXPERT OPINION: Currently, eribulin mesylate is only the third single-agent chemotherapy that has improved overall survival (after anthracycline and taxane) in advanced breast cancer. These results, particularly in heavily pretreated breast cancer, suggest that this drug could become a new standard in the treatment of metastatic breast cancer, and should, therefore, be further developed in its earlier stages.