Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Oral selective estrogen receptor degraders (SERDs): The new emperors in breast cancer clinical practice?

Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as tamoxifen or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, de novo or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the ESR1 gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against ESR1 mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

BACKGROUND: KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker. OBJECTIVE: The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. PATIENTS AND METHODS: We retrospectively identified 119 patients, most of whom (58%) were KRAS wild type. For each patient we evaluated overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). An exploratory analysis was performed among KRAS mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes. RESULTS: After a median follow-up of 10.3 months, the median OS was 14.9 months (95% confidence interval [CI] 7.6-22.7) in wild-type KRAS patients versus 14.7 months (95% CI 8.0-19.5) in mutated KRAS patients (p = 0.529). No differences were detected between the two groups in terms of PFS and DCR. Patients with a KRAS G12C mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations. CONCLUSION: Our data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non-squamous NSCLC patients treated with immunotherapy alone or combined with chemotherapy.

Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis.

OBJECTIVES: We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. METHODS: We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. RESULTS: Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. CONCLUSION: Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy.

Pretreatment lung immune prognostic index as a biomarker in advanced non-small-cell lung cancer patients receiving first line pembrolizumab.

Background: To investigate the role of pretreatment lung immune prognostic index (LIPI) as biomarker in PD-L1 ≥50% non-small-cell lung cancer patients receiving pembrolizumab. Patients & methods: We retrospectively identified 117 patients, divided into three prognostic groups according to LIPI score. For each patient, we evaluated 1-year overall survival (OS) and progression-free survival rate. C-statistic and survival receiver operating characteristic curves were used to study discrimination of LIPI. Results: After a median follow-up of 11.7 months, 1-year OS rate was 60.1%, 35.3% and 28.6%, while 1-year progression-free survival rate was 39.1%, 20.6% and 14.3% in good, intermediate and poor LIPI groups, respectively (p < 0.001). The c-statistic and area under the curve of LIPI were 0.63 and 0.662 for OS and 1-year OS, respectively. Conclusions: Higher LIPI score is related to worse survival in advanced non-small-cell lung cancer patients treated with first-line pembrolizumab. However, based on c-statistic and area under the curve, LIPI does not represent a good prognostic survival model.

Lay abstract In recent years, immunotherapy has become a milestone in the treatment of non-small-cell lung cancer, but clinicians need clinical and/or laboratory factors able to predict the benefit of immunotherapy. Therefore, we investigated the role of pretreatment lung immune prognostic index (LIPI) as biomarker in advanced non-small-cell lung cancer patients with high PD-L1 expression levels and receiving pembrolizumab as first line. We retrospectively identified 117 patients divided into three prognostic groups (good, intermediate and poor) according to LIPI score. We found that patients belonging to good prognostic group (LIPI score 0) lived longer and responded better than those of intermediate and poor prognostic groups (LIPI score 1 or 2), confirming the correlation between LIPI score and survival and response outcomes.

Meta-analysis of immune-related adverse events in phase 3 clinical trials assessing immune checkpoint inhibitors for lung cancer.

INTRODUCTION: The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23rd, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade ≥3) irAEs, drug discontinuation due to irAEs or toxic death. RESULTS: Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs. CONCLUSIONS: Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.

Management of brain metastases from lung cancer in the era of immunotherapy: a review of the literature.

The brain is one of the most frequent sites of metastases in lung cancer patients, whose prognosis is related to the histological, biomolecular and clinical features of the disease. Over the years, the survival has improved significantly with the introduction of immune checkpoint inhibitors (ICIs), but there are limited data concerning their efficacy in patients with brain metastases. The aim of this review is to describe the biological mechanisms supporting the use of immunotherapy for brain metastases and the outcomes experienced by lung cancer patients with brain involvement enrolled in Phase III registration trials of ICIs. We also review retrospective data on ICIs alone or combined with brain radiotherapy, and indicate future directions for preclinical and clinical research.

Role of circulating tumor DNA in the detection of sensitizing and resistance to epidermal growth factor receptor mutations in metastatic lung adenocarcinoma.

PURPOSE: The EGFR (Epidermal Growth Factor Receptor) mutations may predict sensitivity and resistance to EGFR-TKIs (Tyrosine Kinases Inhibitors) in metastatic lung adenocarcinoma. The detection of these mutations is usually performed on tumor tissue samples. However, when a biopsy is not feasible or the amount of tissue is limited, circulating tumor DNA (ctDNA) may represent an alternative source for genotyping the tumor. METHODS: In the first phase of the study, the liquid biopsy was performed in newly diagnosed metastatic lung adenocarcinoma patients with and without EGFR mutations to evaluate the concordance between EGFR mutational analysis on ctDNA by real time PCR and on tissue. In the second phase it was performed in EGFR positive patients progressing after first or second generation TKIs in order to detect the T790M mutation. RESULTS: In the first phase, a 100% concordance between EGFR on ctDNA and tissue was revealed, leading to validation of the test. In the second phase, 44.8% of patients showed T790M positive result at liquid biopsy. Considering the re-biopsies performed in 31% of the cases, the overall positivity rate of T790M was 58.6%. Sensitivity and specificity were 76% and 75%, respectively. The median time to development of T790M mutation from the start of first line EGFR TKI was 244 days. CONCLUSIONS: Our experience confirms that liquid biopsy is a valid method to detect sensitizing and resistant EGFR mutations in patients with metastatic lung adenocarcinoma. Nevertheless, in the presence of negative ctDNA analysis, a rebiopsy should be performed whenever possible to confirm this result.

Weekly paclitaxel after first-line failure in patients with advanced non-small-cell lung cancer: everyday clinical practice in a single centre.

To assess the activity of weekly paclitaxel (wPCT) in pretreated patients with advanced non-small-cell lung cancer (aNSCLC). In 2005, we included wPCT 80 mg/m for 6 consecutive weeks, followed by a 2-week interval in our department's everyday clinical practice guidelines for the second-line (or subsequent) treatment of patients with nonsquamous histologies who have previously received pemetrexed-based treatments and patients with squamous histology. In the absence of clinical evidence of disease progression, patients repeat the pretreatment staging procedures after 16 weeks (two cycles) and, in the absence of disease progression or severe toxicity, continue treatment for a maximum of four courses. Between May 2005 and December 2013, we treated 60 patients (47 in second-line and 13 in third/fourth line), who received a median of two courses (range: 1-4). The most frequent toxicity was grade 1-2 neutropaenia (five patients); only four patients experienced grade 3-4 toxicity. When used as a second-line treatment, wPCT led to a disease control rate of 36.2%, with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months; when used in the third/fourth line, the disease control rate was 41.7%, the median progression-free survival was 5.0 months and the median overall survival was 10.3 months. Our data confirm that wPCT is active and well tolerated in an unselected patient population with aNSCLC and can be considered a valuable alternative to docetaxel in a second-line treatment.

Modified 3-week schedule of gemcitabine plus cisplatin for non-small cell lung cancer treatment.

PURPOSE: Gemcitabine-cisplatin combination is one of the most used schedules for non small cell lung cancer (NSCLC). Aiming to enhance dose intensity and reduce toxicity, the original 4-week schedule was modified or transformed into a 3-week schedule. The purpose of this study was to report the efficacy and tolerability of a modified 3-week regimen of gemcitabine-cisplatin. METHODS: Our patients were treated with gemcitabine (1000 mg7sol;m2) on days 1, 8 and cisplatin on day 8 (75-100 mg/m2). The toxicity was recorded according to the NCIC criteria. RESULTS: From October 2000 to December 2009 a consecutive series of 196 patients with a median age of 62 years and III-IV stage NSCLC received gemcitabine-cisplatin as induction therapy (76 patients) or palliative treatment (120 patients). The median dose intensity was 89%. In relation to day 8 of chemotherapy, 16.2% of the treatments were delayed due to hematologic toxicities. Grade 3-4 anaemia, neutropenia and thrombocytopenia was reported in 3.5, 43.8 and 4.6%, respectively. Response rate (RR) and median overall survival (OS) were 74% and 11 months in patients with locally advanced disease, and 46.7% and 9 months in metastatic patients, respectively. CONCLUSIONS: In comparison with standard or modified schedules of literature, our modified 3-week regimen of gemcitabine- cisplatin demonstrated to be equally active, similar for dose intensity and well tolerated, with better hematologic toxicity profile in terms of anaemia and thrombocytopenia.

An evaluation of the pharmacokinetics and clinical use of vinorelbine for NSCLC treatment.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers, and one of the leading causes of cancer-related mortality. As most newly diagnosed patients present distant metastases, chemotherapy is the treatment of choice. Chemotherapy also plays a central role in postoperative and radical treatment in addition to radiotherapy. AREAS COVERED: This paper reviews the role of vinorelbine , both alone and in combination with platinum-derivates, in the treatment of NSCLC. The authors review its efficacy at different stages of disease and under different conditions. Specifically, the authors evaluate its pharmacokinetic and toxicity profile and provide insight into its future as an NSCLC therapeutic. EXPERT OPINION: In the first-line treatment of advanced NSCLC, the use of vinorelbine-based regimens may be less efficacious in controlling disease than other combinations. However, since their activity is not related to histology, vinorelbine still has potential as a first-line treatment for NSCLC patients in whom histology has failed to distinguish non-squamous from squamous histotypes. The use of an oral formulation may furthermore improve tolerability and patient compliance. Vinorelbine should be the drug of choice in the adjuvant setting as the vinorelbine/cisplatin doublet is the only regimen so far that has led to a survival gain in two Phase III trials. In patients aged > 70 years, vinorelbine (together with gemcitabine) should furthermore be the reference drug for first- and second-line therapy when single-agent chemotherapy is the treatment of choice. However, new efforts still need to be made to develop oral schedules for NSCLC.