Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

INTRODUCTION: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. METHODS: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. RESULTS: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. CONCLUSIONS: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup.

BACKGROUND: Immunotherapy has improved the survival of patients with stage IV melanoma. In responders, clinical benefits may be long-lasting and persist even after treatment discontinuation. The optimal duration of anti-PD1 (anti-Programmed cell death-1) therapy in metastatic melanoma patients remains to be elucidated. Moreover, limited data are available on clinical outcomes of patients that discontinued anti-PD1 immunotherapy in a real-life setting. The aim of this study was to evaluate the progression-free survival (PFS) in patients with metastatic melanoma who interrupted anti-PD-1 treatment in the in the absence of disease progression. METHODS: We retrospectively reviewed patients with advanced/metastatic melanoma treated with anti-PD1 immunotherapy at 23 Italian Melanoma Intergroup (IMI) centres. The study investigated the risk of relapse in patients who stopped anti-PD1 therapy due to CR (Complete response), treatment-related toxicity, or by their own choice after a long period of treatment. Clinical and biological factors associated with or without recurrence were evaluated. RESULTS: The study population included 237 patients. The median age of patients was 68.9 years (standard deviation: 13; range 33-95). The median time on treatment was 33 months (standard deviation: 18, 7; range 1-98). Among the 237 patients, 128 (54%) interrupted the anti-PD1 for CR, 74 patients (31.2%) for adverse events (37 patients in CR, 27 patients in partial response (PR), ten patients in stable disease (SD), and 35 patients (14.8%) by their own choice (12 patients in CR, 17 patients in PR, and 6 patients in SD). After a mean follow-up of 21 months (range 1-81), PFS after anti-PD1 discontinuation was 85.7%. Thirty-four patients (14.3%) developed disease progression after a median of 12 months (range 1-35): ten patients (29.4%) after discontinuation in CR, 17 patients (50%) after discontinuation for treatment-related toxicity (seven in CR, five in PR, five in SD), and seven (20.6%) after discontinuation due to the patient's decision (two in CR, four in PR, one in SD). Only 7.8% of patients who interrupted in CR (10/128), along with 23% of patients who interrupted for limiting toxicity (17/74) and 20% of patients who interrupted by their own choice (7/35), developed recurrence. Regarding patients who discontinued therapy because of CR, we observed a negative association between recurrence and site of primary melanoma, especially mucosal sites (p = <0.05, HR (Hazard ratio) 15.57 IC (confidence interval) 95% 2.64-91.73). Moreover, M1b patients who achieved a CR showed a lower number of relapses (p = <0.05, HR 3.84 IC 95% 1.40-8.48). CONCLUSIONS: This study shows in a real-life setting that, with anti-PD-1 therapy, long-lasting responses, can be maintained after anti-PD1 interruption. In 70.6% of cases, recurrences were observed among patients who did not obtain a CR at treatment discontinuation.

Oral Problems in Oncology Patients Undergoing Chemotherapy for Solid Tumors: A Prospective Observational Study.

PURPOSE: Oral problems in a group of oncological patients undergoing chemotherapy (CT) for solid tumors have been examined. Incidence and severity of patients' self-reported oral problems have been evaluated along their interaction with age, gender, tumor diagnosis and stage, presence of mestastasis, CT agent type, and number of CT cycle. We also analyzed the presence of paraesthesia and anaesthesia and their predisposing factors associated with clinical and treatment-related variables. METHODS: Patients were asked to fill in a questionnaire to evaluate the onset and the intensity of oral and perioral pain, oral mucositis, salivary gland hypofunction, dysgeusia, dysphagia, dysphonia, and sensitivity neuropathy (paraesthesia or dysaesthesia) since the last CT infusion. We also investigated which types of medications have possibly been used and who recommended it, as well as patients' degree of awareness about the possibility of oral problems arising during CT. RESULTS: We recruited 194 patients and obtained 491 questionnaires. We found that a metastatic disease was a risk factor for OM (OR 2.02, p = 0.026) and salivary gland hypofunction (OR 1.66, p = 0.042) and that platinum agents, compared to mitotic inhibitors, increased the risk of developing salivary gland hypofunction (OR 2.16, p = 0.013), dysphagia (OR 3.26, p = 0.001), and anaesthesia (OR 5.16, p = 0.041). Young age was a slight protective factor for most symptoms. The 80% of enrolled patients were informed by the oncologist about possible oral problems arising during CT. CONCLUSIONS: Our study highlighted the importance of collecting observational data from the patients' perspective on oral problems arising during the routine oncology practice, across a range of solid tumors and CT regimens. The relevance of these findings focused on the key role of the multidisciplinary team in advising the patients on the possible occurrence of oral problems, also by recommending their management.

CDK4/6 Inhibitors as Upfront Treatment in a Patient with Breast Cancer Presenting with a Clinical Critic Situation: A Case Report and Review of the Literature.

CDK4/6 inhibitors have revolutionized the treatment algorithm of luminal metastatic breast cancer, becoming the recommended first-line therapy in association with endocrine therapy. However, due to its theoretically greater and more rapid tumor shrinkage, the upfront use of chemotherapy is considered in some clinical situations like visceral crisis. At the state of the art level, a paucity of data is available about the use of CDK4/6 inhibitors in patients presenting with visceral crisis or with life-threatening conditions since this population was historically excluded from clinical trials. In addition, data regarding direct comparison between combinations of chemotherapy and CDK4/6 inhibitors in terms of efficacy, rapidity of responses and long-term outcomes are lacking. We report the case of a 68-year-old woman with luminal metastatic breast cancer presenting at diagnosis with a critical and potentially life-threatening condition. The patient was treated with first-line Abemaciclib plus letrozole and achieved a rapid partial response with sudden clinical stabilization. Although the patient did not technically present with a visceral crisis, this case presentation also endorsed the upfront use of CDK4/6 inhibitor combinations in critical clinical situations in the absence of severe organ dysfunction and after multidisciplinary discussion.

Immunotherapy in NSCLC Patients with Brain Metastases.

Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs.

Multidisciplinary Team Meeting Proposal and Final Therapeutic Choice in Early Breast Cancer: Is There an Agreement?

Background: A multidisciplinary team meeting (MDM) approach in breast cancer (BC) management is a standard of care. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early BC. The purpose of this study was to define whether there was an agreement between the planned program (i.e., MDMs-based decision) and that actually applied. In addition, the study explored factors associated with discordance. Methods: We conducted a retrospective study of a consecutive series of 291 patients with new diagnosis of early BC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. The association between clinico-biological factors and discordance between what was decided during the MDMs and what was consequently applied by the oncologist was explored through uni- and multivariate logistic regression analyses. Results: The median age was 62 years (range 27-88 years). Among invasive early BC patients, the most frequent phenotype was luminal A (38%), followed by luminal B (33%), HER2-positive (12%), and triple-negative (5%). In situ carcinoma (DCIS) represented 12% of cases. The median time from MDM discussion to first oncologic examination was 2 weeks. The rate of discordance between MDM-based decision and final choice, during a face-to-face consultation with the oncologist, was 15.8% (46/291). The most frequent reason for changing the MDM-based program was clinical decision (87%). Follow-up was preferred to the chemotherapy (CT) proposed within the MDMs in 15% of cases, and to the endocrine therapy (ET) in 39% of cases (among these, 44.5% had a diagnosis of DCIS). Therapeutic change from sequential CT-ET to ET alone was chosen in 16/46 pts (35%): among these patients, seven had a luminal B disease and six had an HER2-positive disease. On univariate analysis, factors associated with discordance were values of Ki-67 14%-30% (OR 3.91; 95% CI 1.19-12.9), age >70 years (OR 2.44, 95% CI 1.28-4.63), housewife/retired status (OR 2.35, 95% CI 1.14-4.85), polypharmacy (OR 1.95; 95% CI 1.02-3.72), postmenopausal status (OR 4.15; 95% CI 1.58-10.9), and high Charlson Comorbidity Index (OR 1.31; 95% CI 1.09-1.57). The association with marital status, educational level, alcohol and smoke habits, presence of a caregiver, parity, grading, histotype and phenotype, and stage was not statistically significant. On multivariate analysis, only Ki-67 value maintained its statistical significance. Conclusion: The results of our study could be useful for enhancing the role of MDMs in the clinical decision-making process in early BC.

Multidisciplinary Approach to Patients With Metastatic Spinal Cord Compression: A Diagnostic Therapeutic Algorithm to Improve the Neurological Outcome.

Introduction: The morbidity associated with metastatic spinal disease is significant because of spinal cord and/or nerve root compression. The purpose of this paper is to define a diagnostic-therapeutic path for patients with vertebral metastases and from this path to build an algorithm to reduce the devastating consequences of spinal cord compression. Materials and Methods: The algorithm is born from the experience of a primary care center. A spine surgeon, an emergency room (ER) physician, a neuroradiologist, a radiation oncologist, and an oncologist form the multidisciplinary team. The ER physician or the oncologist intercept the patient with symptoms and signs of a metastatic spinal cord compression. Once the suspicion is confirmed, the following steps of the flow-chart must be triggered. The spine surgeon takes charge of the patient and, on the base of the anamnestic data and neurological examination, defines the appropriate timing for magnetic resonance imaging (MRI) in collaboration with the neuroradiologist. From the MRI outcome, the spine surgeon and the radiation oncologist consult each other to define further therapeutic alternatives. If indicated, surgical treatment should precede radiation therapy. The oncologist gets involved after surgery for systemic therapy. Results: In 2021, the Spine and Spinal Cord Surgery department evaluated 257 patients with vertebral metastasis. Fifty-three patients presented with actual or incipient spinal cord compression. Among these, 27 were admitted due to rapid progression of symptoms, neurological deficits and/or spine instability signs. The level was thoracic in 21 cases, lumbar in 4 cases, cervical in 1 case, sacral in 1 case. Fifteen were operated on, 10 of these programmed and 5 in emergency. Discussion: Patients with a history of malignancy can present to the ER or to the oncology department with symptoms that must be correctly framed in the context of a metastatic involvement. Even when there is no previous cancer history, the patient's pain characteristics and clinical signs must be interpreted to yield the correct diagnosis of vertebral metastasis with incipient or current spinal cord compression. The awareness of the alert symptoms and the application of an integrated paradigm consent to frame the patients with spinal cord compression, obtaining the benefits of a homogeneous step-by-step diagnostic and therapeutic path. Early surgical or radiation therapy treatment gives the best hope for preventing the worsening, or even improving, the deficits. Conclusions: Metastatic spinal cord compression can cause neurological deficits compromising quality of life. Treatment strategies should be planned comprehensively. A multidisciplinary approach and the application of the proposed algorithm is of paramount importance to optimize the outcomes of these patients.

First-Line Osimertinib in Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Outcome and Safety in the Real World: FLOWER Study.

BACKGROUND: Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. METHODS: We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. RESULTS: At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3-4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). CONCLUSION: Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported.

CDK4/6 Inhibitors in Melanoma: A Comprehensive Review.

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study.

BACKGROUND: Treatment sequencing with first-line immunotherapy, followed by second-line chemotherapy, is still a viable option for NSCLC patients with PD-L1 expression ≥50%. METHODS: We evaluated post-progression treatment pathways in a large real-world cohort of metastatic NSCLC patients with PD-L1 expression ≥ 50% treated with first-line pembrolizumab monotherapy. RESULTS: Overall, 974 patients were included. With a median follow-up of 22.7 months (95%CI: 21.6-38.2), the median overall survival (OS) of the entire population was 15.8 months (95%CI: 13.5-17.5; 548 events). At the data cutoff, among the 678 patients who experienced disease progression, 379 (55.9%) had not received any further treatment, and 359 patients (52.9%) had died. Patients who did not receive post-progression therapies were older (p = 0.0011), with a worse ECOG-PS (p < 0.0001) and were on corticosteroids prior to pembrolizumab (p = 0.0024). At disease progression, 198 patients (29.2%) received a switched approach and 101 (14.9%) received pembrolizumab ByPD either alone (64 [9.4%]) or in combination with local ablative treatments (37 [5.5%]) (LATs). After a random-case control matching according to ECOG-PS, CNS metastases, bone metastases, and (previous) best response to pembrolizumab, patients receiving pembrolizumab ByPD plus LATs were confirmed to have a significantly longer post-progression OS compared to patients receiving pembrolizumab ByPD alone 13.9 months versus 7.8 months (p = 0.0179) 241 patients (35.5%) among the 678 who had experienced PD, received a second-line systemic treatment (regardless of previous treatment beyond PD). As compared to first-line treatment commencement, patients' features at the moment of second-line initiation showed a significantly higher proportion of patients aged under 70 years (p = 0.0244), with a poorer ECOG-PS (p < 0.0001) and having CNS (p = 0.0001), bone (p = 0.0266) and liver metastases (p = 0.0148). CONCLUSIONS: In the real-world scenario NSCLC patients with PD-L1 expression ≥50% treated with first-line single-agent pembrolizumab achieve worse outcomes as compared to the Keynote-024 trial. Poor post-progression outcomes are major determinants of the global results that should be considered when counselling patients for first-line treatment choices.

Feasibility and Predictive Performance of a Triage System for Patients with Cancer During the COVID-19 Pandemic.

BACKGROUND: Triage procedures have been implemented to limit hospital access and minimize infection risk among patients with cancer during the coronavirus disease (COVID-19) outbreak. In the absence of prospective evidence, we aimed to evaluate the predictive performance of a triage system in the oncological setting. MATERIALS AND METHODS: This retrospective cohort study analyzes hospital admissions to the oncology and hematology department of Udine, Italy, during the COVID-19 pandemic (March 30 to April 30, 2020). A total of 3,923 triage procedures were performed, and data of 1,363 individual patients were reviewed. RESULTS: A self-report triage questionnaire identified 6% of triage-positive procedures, with a sensitivity of 66.7% (95% confidence interval [CI], 43.0%-85.4%), a specificity of 94.3% (95% CI, 93.5%-95.0%), and a positive predictive value of 5.9% (95% CI, 4.3%-8.0%) for the identification of patients who were not admitted to the hospital after medical review. Patients with thoracic cancer (odds ratio [OR], 1.69; 95% CI, 1.13-2.53, p = .01), younger age (OR, 1.52; 95% CI, 1.15-2.01, p < .01), and body temperature at admission ≥37°C (OR, 9.52; 95% CI, 5.44-16.6, p < .0001) had increased risk of positive triage. Direct hospital access was warranted to 93.5% of cases, a further 6% was accepted after medical evaluation, whereas 0.5% was refused at admission. CONCLUSION: A self-report questionnaire has a low positive predictive value to triage patients with cancer and suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms. Differential diagnosis with tumor- or treatment-related symptoms is always required to avoid unnecessary treatment delays. Body temperature measurement improves the triage process's overall sensitivity, and widespread SARS-CoV-2 testing should be implemented to identify asymptomatic carriers. IMPLICATIONS FOR PRACTICE: This is the first study to provide data on the predictive performance of a triage system in the oncological setting during the coronavirus disease outbreak. A questionnaire-based triage has a low positive predictive value to triage patients with cancer and suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms, and a differential diagnosis with tumor- or treatment-related symptoms is mandatory to avoid unnecessary treatment delays. Consequently, adequate recourses should be reallocated for a triage implementation in the oncological setting. Of note, body temperature measurement improves the overall sensitivity of the triage process, and widespread testing for SARS-CoV-2 infection should be implemented to identify asymptomatic carriers.

Adjuvant chemotherapy after severe myelotoxicity during chemoradiation phase in malignant gliomas. Is it feasibile? Results from AINO study (Italian Association for Neuro-Oncology).

BACKGROUND: Malignant gliomas (MG) are aggressive brain tumours in adults. The standard of care is concurrent radiation plus temozolomide (TMZ) [chemo-radiotherapy (CRT)] followed by TMZ maintenance up to 6 months. TMZ is considered to have a low toxicity profile, but several studies reported occurrence of severe myelosuppression, especially during the concomitant phase. Toxicity may be prolonged, thus treatment should be discontinued. PURPOSE: To evaluate the risk of recurrente myelotoxicity during adjuvant chemotherapy (CT) in patients who recovered from severe myelotoxicity during CRT. METHODS: We retrospectively collected data on patients with MG who developed and recovered from severe myelotoxicity during CRT from eight Italian neuro-oncology centers. RESULTS: We included 87 patients. Histology was Glioblastoma (GBM) in 78 patients (89.7%); 60% of patients were female. After myelotoxicity recovery, 54 (62%) received treatment. The majority of them (82%, n = 44) received adjuvant TMZ and 18% (n = 10) others treatments. Out of 44 patients who received adjuvant TMZ, 34% experienced the re-occurrence of grade 3-4 myelotoxicity which required permanent CT discontinuation in 6 (13%) cases. Patients who received TMZ or other treatments had longer overall (OS) (adjusted HR 0.46, p = 0.008) and progression free survival (PFS) (adjusted HR 0.57, p = 0.034) than those who remained untreated. CONCLUSION: Our study suggests that after severe myelotoxicity the majority of patients received treatment, particularly with TMZ. Only a fraction of patients experienced toxicity recurrence, suggesting that TMZ is well tolerated and had an impact on PFS and OS.

Plasma-Based Longitudinal Evaluation of ESR1 Epigenetic Status in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer.

BACKGROUND: Endocrine therapy (ET) is the mainstay of treatment for hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, adaptive mechanisms emerge in about 25-30% of cases through alterations in the estrogen receptor ligand-binding domain, with a consequent ligand-independent estrogen receptor activity. Epigenetic-mediated events are less known and potentially involved in alternative mechanisms of resistance. The aim of this study was to test the feasibility of estrogen receptor 1 (ESR1) epigenetic characterization through liquid biopsy and to show its potential longitudinal application for an early ET sensitivity assessment. METHODS: A cohort of 49 women with hormone receptor-positive HER2-negative MBC was prospectively enrolled and characterized through circulating tumor DNA using methylation-specific droplet digital PCR (MS-ddPCR) before treatment start (BL) and after 3 months concomitantly with computed tomography (CT) scan restaging (EV1). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). The most established cell-free tumor DNA (ctDNA) factors associated with ET resistance [ESR1 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations] were assessed through next-generation sequencing. Associations were tested through Mann-Whitney U test, matched pairs variations through Wilcoxon signed rank test, and survival was analyzed by log-rank test. RESULTS: The ET backbone was mainly based on aromatase inhibitors (AIs) (70.83%) in association with CDK4/6 inhibitors (93.75%). Significantly lower promA levels at baseline were observed in patients with liver metastases (P = 0.0212) and in patients with ESR1 mutations (P = 0.0091). No significant impact on PFS was observed for promA (P = 0.3777) and promB (P = 0.7455) dichotomized at the median while a ≥2-fold increase in promB or in either promA or promB at EV1 resulted in a significantly worse prognosis (respectively P = 0.0189, P = 0.0294). A significant increase at EV1 was observed for promB among patients with PIK3CA mutation (P = 0.0173). A trend was observed for promB in ESR1 wild-type patients and for promA in the ESR1 mutant subgroup. CONCLUSION: The study proofed the concept of an epigenetic characterization strategy based on ctDNA and is capable of being integrated in the current clinical workflow to give useful insights on treatment sensitivity.

Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation.

BACKGROUND: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression. METHODS: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group. RESULTS: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts. CONCLUSIONS: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50.

BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.