Long-term responders to nivolumab in previously treated advanced renal cell carcinoma: a sub-analysis of meet-URO15 study.

BACKGROUND: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. MATERIALS AND METHODS: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. RESULTS: A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. CONCLUSION: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.

Dabrafenib-trametinib in BRAF V600-mutated non-small-cell lung cancer: a single center real world experience.

Aim: We retrospectively evaluated the effect of dabrafenib/trametinib combination in patients with BRAF-mutated non-small-cell lung cancer (NSCLC) treated in a single center from 2017 to 2022. Patients: The response and safety data of 42 patients (27 treated in first-line and 15 as second/subsequent lines) were analyzed. Results: The objective response was 73.8%, with no differences between patients undergoing first- or second-line. A longer, statistically significant median progression-free survival (PFS) was observed in patients receiving the combination in first-line vs those in the second/subsequent lines (19.9 months [95% CI: 19.7-20] vs 13.1 months [95% CI: 8.6-17.6], respectively; p = 0.012). The median overall survival (OS) was 29.9 months (95% CI: 14.1-45.7) for patients treated with the combination in first-line and 22.4 months (95% CI: 14.6-30.2) for those treated in subsequent lines. The combination was well tolerated. Conclusion: We confirm the efficacy of dabrafenib/trametinib in BRAF-V600-mutated NSCLC.

[Box: see text].

Early-Stage Non-Small Cell Lung Cancer: Prevalence of Actionable Alterations in a Monocentric Consecutive Cohort.

Early-stage (ES) non-small cell lung cancer (NSCLC) is diagnosed in about 30% of cases. The preferred treatment is surgery, but a significant proportion of patients experience recurrence. Neoadjuvant and adjuvant chemotherapy has a limited clinical benefit. EGFR tyrosine kinase inhibitors and immunotherapy have recently opened new therapeutic scenarios. However, only a few data are available about the ES-NSCLC molecular landscape and the impact of oncogene addiction on therapy definition. Here, we determined the prevalence of the main lung cancer driver alterations in a monocentric consecutive cohort. Molecular analysis was performed on 1122 cases, including 368 ES and 754 advanced NSCLC. The prevalence of actionable alterations was similar between early and advanced stages. ES-NSCLC was significantly enriched for MET exon-14 skipping alterations and presented a lower prevalence of BRAF p.(V600E) mutation. PD-L1 expression levels, evaluated according to actionable alterations, were higher in advanced than early tumors harboring EGFR, KRAS, MET alterations and gene fusions. Taken together, these results confirm the value of biomarker testing in ES-NSCLC. Although approved targeted therapies for ES-NSCLC are still limited, the identification of actionable alterations could improve patients' selection for immunotherapy, favoring the enrollment in clinical trials and allowing a faster treatment start at disease recurrence.

Clinical utility of Next Generation Sequencing of plasma cell-free DNA for the molecular profiling of patients with NSCLC at diagnosis and disease progression.

BACKGROUND: The present study evaluates the utility of NGS analysis of circulating free DNA (cfDNA), which incorporates small amounts of tumor DNA (ctDNA), at diagnosis or at disease progression (PD) in NSCLC patients. METHODS: Comprehensive genomic profiling on cfDNA by NGS were performed in NSCLC patients at diagnosis (if tissue was unavailable/insufficient) or at PD to investigate potential druggable molecular aberrations. Blood samples were collected as routinary diagnostic procedures, DNA was extracted, and the NextSeq 550 Illumina platform was used to run the Roche Avenio ctDNA Expanded Kit for molecular analyses. Gene variants were classified accordingly to the ESCAT score. RESULTS: A total of 106 patients were included in this study; 44 % of cases were requested because of tissue unavailability at the diagnosis and 56 % were requested at the PD. At least one driver alteration was observed in 62 % of cases at diagnosis. Driver druggable variants classified as ESCAT level I were detected in 34 % of patients, including ALK-EML4, ROS1-CD74, EGFR, BRAF, KRAS p.G12C, PI3KCA. In the PD group, most patients were EGFR-positive, progressing to a first line-therapy. Sixty-three percent of patients had at least one driver alteration detected in blood and 17 % of patients had a known biological mechanism of resistance allowing further therapeutic decisions. CONCLUSIONS: The present study confirms the potential of liquid biopsy to detect tumour molecular heterogeneity in NSCLC patients at the diagnosis and at PD, demonstrating that a significant number of druggable mutations and mechanisms of resistance can be detected by NGS analysis on ctDNA.

STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines.

INTRODUCTION: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC). METHODS: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints. RESULTS: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs. CONCLUSIONS: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment.

First-line cetuximab + platinum-based therapy for recurrent/metastatic head and neck squamous cell carcinoma: A real-world observational study-ENCORE.

BACKGROUND: ENCORE, an observational, prospective, open-label study, investigated real-world treatment practices and outcomes with cetuximab plus platinum-based therapy (PBT) in first-line (1L) recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). AIMS: This multinational study aimed to investigate the long-term use of cetuximab plus PBT for 1L R/M SCCHN in a clinical setting. In particular, this study aimed to explore clinical considerations such as the decision to prescribe cetuximab plus PBT in R/M SCCHN, the mode and duration of treatment, and patient outcomes. METHODS AND RESULTS: Previously untreated patients with R/M SCCHN whose planned treatment was cetuximab plus PBT were enrolled from 6 countries. Among 221 evaluable patients, planned treatments included cetuximab plus carboplatin (31.2%), cisplatin plus 5-fluorouracil (31.7%), or carboplatin plus 5-fluorouracil (23.1%); 3.2% included a taxane, and 45.2% did not include 5-fluorouracil. Cetuximab treatment was planned for a fixed duration (≤24 weeks) in 15 patients (6.8%) and until disease progression in 206 (93.2%). Median progression-free survival and overall survival were 6.5 and 10.8 months, respectively. Grade ≥3 adverse events occurred in 39.8% of patients. Serious adverse events occurred in 25.8% of patients; 5.4% were cetuximab-related. CONCLUSION: In patients with R/M SCCHN, first-line cetuximab plus PBT was feasible and modifiable in a real-world setting with similar toxicity and efficacy as in the pivotal phase III EXTREME trial. CLINICAL TRIAL REGISTRATION NUMBER: EMR 062202-566.

MASCC guideline: cannabis for cancer-related pain and risk of harms and adverse events.

BACKGROUND: Approximately 18% of patients with cancer use cannabis at one time as palliation or treatment for their cancer. We performed a systematic review of randomized cannabis cancer trials to establish a guideline for its use in pain and to summarize the risk of harm and adverse events when used for any indication in cancer patients. METHODS: A systematic review of randomized trials with or without meta-analysis was carried out from MEDLINE, CCTR, Embase, and PsychINFO. The search involved randomized trials of cannabis in cancer patients. The search ended on November 12, 2021. The Jadad grading system was used for grading quality. Inclusion criteria for articles were randomized trials or systematic reviews of randomized trials of cannabinoids versus either placebo or active comparator explicitly in adult patients with cancer. RESULTS: Thirty-four systematic reviews and randomized trials met the eligibility criteria for cancer pain. Seven were randomized trials involving patients with cancer pain. Two trials had positive primary endpoints, which could not be reproduced in similarly designed trials. High-quality systematic reviews with meta-analyses found little evidence that cannabinoids are an effective adjuvant or analgesic to cancer pain. Seven systematic reviews and randomized trials related to harms and adverse events were included. There was inconsistent evidence about the types and levels of harm patients may experience when using cannabinoids. CONCLUSION: The MASCC panel recommends against the use of cannabinoids as an adjuvant analgesic for cancer pain and suggests that the potential risk of harm and adverse events be carefully considered for all cancer patients, particularly with treatment with a checkpoint inhibitor.

Multinational Association of Supportive Care in Cancer (MASCC) guidelines: cannabis for psychological symptoms including insomnia, anxiety, and depression.

PURPOSE: During the treatment of cancer, 18% of patients use cannabis for symptom management. Anxiety, depression, and sleep disturbances are common symptoms in cancer. A systematic review of the evidence for cannabis use for psychological symptoms in cancer patients was undertaken to develop a guideline. METHODS: A literature search of randomized trials and systematic reviews was undertaken up to November 12, 2021. Studies were independently assessed for evidence by two authors and then evaluated by all authors for approval. The literature search involved MEDLINE, CCTR, EMBASE, and PsychINFO databases. Inclusion criteria included randomized control trials and systematic reviews on cannabis versus placebo or active comparator in patients with cancer and psychological symptom management (anxiety, depression, and insomnia). RESULTS: The search yielded 829 articles; 145 from Medline, 419 from Embase, 62 from PsychINFO, and 203 from CCTR. Two systematic reviews and 15 randomized trials (4 on sleep, 5 on mood, 6 on both) met eligibility criteria. However, no studies specifically assessed the efficacy of cannabis on psychological symptoms as primary outcomes in cancer patients. The studies varied widely in terms of interventions, control, duration, and outcome measures. Six of 15 RCTs suggested benefits (five for sleep, one for mood). CONCLUSION: There is no high-quality evidence to recommend the use of cannabis as an intervention for psychological symptoms in patients with cancer until more high-quality research demonstrates benefit.

Surgical treatment of recurrent retroperitoneal sarcoma in its different patterns: A 15-years' two-centers experience.

INTRODUCTION: There is limited data available regarding the role of surgery in the treatment of retroperitoneal sarcoma (RPS) recurrences. We herein report the short- and mid-term outcomes of patients who underwent surgical treatment of RPS recurrences at two Italian centers over a 15-years' experience. MATERIALS AND METHODS: From January 2005 to January 2020, 33 patients underwent surgical treatment of isolated locally recurrent RPS (LR group), locally recurrent RPS associated with the presence of distant recurrence (LR + DM group), and distant-only recurrent RPS (DM group). Only procedures performed to obtain a macroscopically radical treatment with curative intent were included. Data regarding pre-, intra-, post-operative course, and follow-up, collected in an Institutional database, were retrospectively analyzed, and compared. RESULTS: LR-group was composed of 15 patients, LR + DM group of 9 patients, and DM group of 9 patients. During the follow-up, 78.5% of the LR group, 77.8% of the DM group and 100% of the LR + DM group (p = 0.244) experienced a second recurrence. 7/11 (63.6%) patients in the LR group, 2/7 (28.5%) patients in the DM-group, and 0/9 (0.0%) patients in the LR + DM group underwent to almost one further local treatments of their recurrences (p = 0.010). No differences in the mean disease-free survival (p = 0.127), overall survival (OS) (p = 0.165) was reported among the three groups. Repeated surgery was an independent factor affecting survival in multivariate analysis (p = 0.01). CONCLUSIONS: A surgical treatment of RPS recurrences should always be taken into consideration, also in metastatic patients and/or in those who have already undergone surgery for previous RPS recurrence, because this approach may offer survival benefits.

First-line treatment of metastatic castration-resistant prostate cancer: the real-world Italian cohort of the Prostate Cancer Registry.

BACKGROUND: With the availability of multiple treatment options for metastatic castration-resistant prostate cancer (mCRPC), new real-world data on disease management and drugs' performance are needed. METHODS: We described characteristics, management and clinical outcomes of patients receiving first-line mCRPC treatment within the Italian cohort of the real-world, prospective, international Prostate Cancer Registry. Patients were enrolled consecutively (2013-2016) in 32 Italian sites and followed for 3 years. RESULTS: 238 patients were included: 157 received first-line abiraterone acetate plus prednisone ("abiraterone" thereafter) and 70 first-line docetaxel; 11 patients receiving other treatments were not considered. Compared with docetaxel-treated patients, those receiving abiraterone were significantly older (age ⩾75: 63.7% vs 38.6%), less frequently had a Gleason score >8 (48.2% vs 67.6%, p<0.005) at initial diagnosis, and more frequently an ECOG score ⩾1 (52.7% vs 36.2%, p<0.05) and comorbidities (76.4% vs 57.1%, p<0.05) at baseline; they reported a lower analgesic use (15.3% vs 30%, p<0.005). In the abiraterone group (median follow-up 22.1 months), median time to progression (TTP) and progression-free survival (PFS) were, respectively, 14.4 months (95% confidence interval, CI, 10.6-18.0) and 13.0 months (95% CI, 9.1-16.8); median overall survival (OS) was not reached, and 3-year OS was 59.1%. In the docetaxel treatment group (median follow-up 25.3 months), median TTP, PFS and OS were, respectively, 8.2 months (95% CI, 6.1-10.3), 8.2 months (95% CI, 5.8-10.3) and 33.2 months (95% CI, 19.2-not estimable). CONCLUSION: This investigation provided valuable information on the overall mCRPC treatment pattern and the effectiveness of first-line abiraterone and docetaxel in a population representative of everyday practice.

Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/consensus guidance on the use of cannabinoids for gastrointestinal symptoms in patients with cancer.

BACKGROUND: Gastrointestinal symptoms are common in patients with cancer, whether related to treatment or a direct effect of the disease itself. Patients may choose to access cannabinoids outside of their formal medical prescriptions to palliate such symptoms. However, clinical guidelines are lacking in relation to the use of such medicines for gastrointestinal symptoms in patients with cancer. METHODS: A systematic review of the evidence for the use of cannabinoids for symptom control in patients with cancer was undertaken. Search strategies were developed for Medline, Embase, PsychINFO, and the Cochrane Central Register of Controlled Trials, including all publications from 1975 up to 12 November 2021. Studies were included if they were randomized controlled trials of cannabinoids compared with placebo or active comparator in adult patients with cancer, regardless of type, stage, or treatment status. Articles for inclusion were agreed by all authors, and data extracted and summarized by two authors. Each study was scored according to the Jadad scale. This review was specifically for the purpose of developing guidelines for the use of cannabis for gastrointestinal symptoms, including chemotherapy-induced nausea and vomiting (CINV), chronic nausea, anorexia-cachexia syndrome, and taste disturbance. RESULTS: Thirty-six randomized controlled trials were identified that met the inclusion criteria for this review of gastrointestinal symptoms: 31 relating to CINV, one to radiotherapy-induced nausea and vomiting, and the remaining four to anorexia-cachexia and altered chemosensory disturbance. The populations for the randomized controlled trials were heterogeneous, and many studies were of poor quality, lacking clarity regarding method of randomization, blinding, and allocation concealment. For CINV, eleven RCTs showed improvement with cannabis compared to placebo, but out of 21 trials where cannabis was compared to other antiemetics for CINV, only 11 favoured cannabis. CONCLUSION: Tetrahydrocannabinol (THC) and nabilone were more effective in preventing CINV when compared to placebo but are not more effective than other antiemetics. For refractory CINV, one study of THC:CBD demonstrated reduced nausea as an add-on treatment to guideline-consistent antiemetic therapy without olanzapine. The MASCC Guideline Committee found insufficient evidence to recommend cannabinoids for the management of CINV, nausea from advanced cancer, cancer-associated anorexia-cachexia, and taste disturbance. High-quality studies are needed to inform practice.

Pralsetinib in RET fusion-positive non-small-cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP).

OBJECTIVES: The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the real-world efficacy of pralsetinib in this population is unknown. MATERIALS AND METHODS: A retrospective efficacy and safety analysis was performed on data from patients with RET-fusion positive NSCLC enrolled in the pralsetinib Italian expanded access program between July 2019 and October 2021. RESULTS: Overall, 62 patients with RET-fusion positive NSCLC received pralsetinib at 20 Italian centers. Next-generation sequencing was used to detect RET alterations in 44 patients (73 %). The most frequent gene fusion partner was KIF5B (75 % of 45 evaluable). Median age was 62 years (range, 36-90), most patients were female (57 %) and never smokers (53 %). Brain metastases were known in 18 patients (29.5 %) at the time of pralsetinib treatment. 13 patients were treatment naïve (unfit for chemotherapy), 48 were pretreated (median number of previous lines: 1, range, 1-4). The objective response rate (ORR) was 66 % [95 % confidence interval (CI), 53-81] in the evaluable population (n = 59). The disease control rate (DCR) was 79 %. After a median follow-up of 10.1 months, the median progression free survival was 8.9 months (95 %CI, 4.7-NA). In patients with measurable brain metastases (n = 6) intracranial ORR was 83 %, intracranial DCR was 100 %. Overall, 83.6 % of patients experienced any-grade treatment-related adverse events (TRAEs), 39 % grade 3 or greater (G ≥ 3). The most common G ≥ 3 TRAEs were neutropenia (9.8 %), dry mouth/oral mucositis (8.2 %), and thrombocytopenia (6.6 %). Seven patients (12 %) discontinued pralsetinib due to TRAEs, twenty-six had at least one dose level modification due to TRAEs. Two treatment-related deaths were observed (1 sepsis, 1 typhlitis). CONCLUSIONS: In the real-world setting, pralsetinib confirmed durable systemic activity and intracranial response in RET-fusion positive NSCLC. Toxicity profile was consistent with previous reports.

Effectiveness of a phone-based nurse monitoring assessment and intervention for chemotherapy-related toxicity: A randomized multicenter trial.

Purpose: Anticancer treatment-related toxicities can impact morbidity and mortality, hamper the administration of treatment, worsen the quality of life and increase the burden on the healthcare system. Therefore, their prompt identification is crucial. NICSO (Italian Network for Supportive Care in Cancer) conducted a nationwide randomized trial to evaluate the role of a planned, weekly phone-based nurse monitoring intervention to prevent and treat chemotherapy, targeted therapy- and immunotherapy-related toxicities. Here, we report the results from the chemotherapy arm. Methods: This was a nationwide, randomized, open-label trial conducted among 29 Italian centers (NCT04726020) involving adult patients with breast, colon, or lung cancer and a life expectancy ≥6 months receiving adjuvant chemotherapy. Patients received either a weekly nurse monitoring phone call and an educational leaflet reporting practical advice about prevention and treatment of toxicities (experimental group) or the educational leaflet only (control group). Results: The addition of a nurse monitoring intervention may help reduce time spent with severe toxicities (grade ≥3), particularly those less frequently reported in clinical practice, such as fatigue. When considering grade 1-2 AEs, times with mild/moderate diarrhea, mucositis, fatigue and pain were shorter in the experimental arm. Time spent without AEs was significantly longer in the experimental arms for all the toxicities. The requirement for special medical attention was comparable between groups. Conclusion: This study suggests the need for implementing a better system of toxicity assessment and management for patients treated with adjuvant chemotherapy to promote effective preventive and/or therapeutic intervention against these events.

Safety and Tolerability of COVID-19 Vaccines in Patients with Cancer: A Single Center Retrospective Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused a worldwide challenging and threatening pandemic. Multinational, placebo-controlled, observer-blinded trials were conducted since the beginning of pandemic because safe and effective vaccines were needed urgently. In most trials of COVID-19 vaccines patients affected by malignancies or on treatment with immunosuppressive drugs were excluded. PATIENTS AND METHODS: A retrospective monocentric study was conducted at Medical Oncological Unit of Santa Chiara Hospital (Pisa, Italy) in this subset of population to investigate safety and tolerability of COVID-19 vaccines; 377 patients with solid tumor on treatment were enrolled. Vaccine-related adverse events were recorded using a face-to-face questionnaire including a toxicity grading scale. Most of the patients (94%) received mRNA vaccine as indicated by Italian health ministry guidelines. Mean age was 66 years (range 27-87), 62% of the patients were older than 65 years and 68% had at least one additional comorbidity. The majority (86%) of patients were in a metastatic setting and 29% received immunotherapy-based treatment. For statistical analysis, multivariate binary logistic regression models were performed and linear regression models were applied. RESULTS: Adverse events were mild and transient and ended in a few days without any sequelae. No severe or uncommon adverse events were recorded. In multivariate analysis, we found that the female sex was associated with a greater risk of more severe and longer lasting adverse events, and a higher risk of adverse events was found for patients treated with immunotherapy. CONCLUSIONS: Our results demonstrate that COVID-19 vaccines were safe and well-tolerated in this population of patients being treated for solid tumors.

Cytokinetic-driven myeloprotection after cytotoxic chemotherapy: from an old idea to a new clinical approach.

Chemotherapy is the backbone of the treatment of several solid tumours and lymphomas. Myelotoxicity is often a dose-limiting toxicity and myeloprotection has always been investigated. In fact, over the years, several approaches have been studied in order to reduce the incidence of haematological toxicities and allow patients to receive effective, full-dose, chemotherapy. After the use of stimulating factors, such as granulocyte colony-stimulating factors and erythropoiesis-stimulating agents, in the very last years, a new approach has emerged. Trilaciclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, has been studied and it has been demonstrated in several clinical trials to reduce the incidence of myelotoxicity in small-cell lung cancer patients treated with chemotherapy or chemo-immunotherapy. Its potential role has not been fully studied yet, but it represents a highly effective tool to reduce myelotoxicity, widen the applicability of full-dose chemotherapy, even in frailer patients, and finally to increase the efficacy of chemotherapy in those tumours where relative dose intensity is a standard to achieve to get the best clinical results.

Effect of systemic therapies or best supportive care after disease progression to both nivolumab and cabozantinib in metastatic renal cell carcinoma: The Meet-Uro 19BEYOND study.

BACKGROUND: Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC. METHODS: In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated. RESULTS: After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2). CONCLUSION: After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.

Clinical outcome of renal cancer patients who early interrupted immunotherapy due to serious immune-related adverse events. Meet-Uro 13 trial on behalf of the MeetUro investigators.

BACKGROUND: Severe immune-related Adverse Events (irAEs) develop in 10-27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748-757, 2018); Galsky (Lancet 395:1547-1557, 2020); Haanen (Ann Oncol 28:119-142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs. METHODS: We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3-G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3-4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago). RESULTS: 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6-2.1), mPFS was 7.4 months (95% CI 3.16-11.6) and mOS was 15.5 months (5.1-25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5-5.6), mPFS was 4.6 months (95% CI 3.5-5.6) and mOS was 19.6 months (95% CI 15.1-24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0-5.9) and mOS was 19.6 months (95% CI 15.1-24.0). CONCLUSIONS: ICIs seem to maintain efficacy even after early interruption due to severe irAE.

Impact of Previous Nephrectomy on Clinical Outcome of Metastatic Renal Carcinoma Treated With Immune-Oncology: A Real-World Study on Behalf of Meet-URO Group (MeetUro-7b).

BACKGROUND: Immune-Oncology (IO) improves Overall Survival (OS) in metastatic Renal Cell Carcinoma (mRCC). The prognostic impact of previous Cytoreductive Nephrectomy (CN) and radical nephrectomy (RN), with curative intent, in patients treated with IO is not well defined. The aim of our paper is to evaluate the impact of previous nephrectomy on outcome of mRCC patients treated with IO. METHODS: 287 eligible patients were retrospectively collected from 16 Italian referral centers adhering to the MeetUro association. Patients treated with IO as second and third line were included, whereas patients treated with IO as first line were excluded. Kaplan-Meier method and log-rank test were performed to compare Progression Free Survival (PFS) and OS between groups. In our analysis, both CN and RN were included. The association between nephrectomy and other variables was analyzed in univariate and multivariate setting using the Cox proportional hazard model. RESULTS: 246/287 (85.7%) patients had nephrectomy before IO treatment. Median PFS in patients who underwent nephrectomy (246/287) was 4.8 months (95%CI 3.9-5.7) vs 3.7 months (95%CI 1.9-5.5) in patients who did not it (HR log rank 0.78; 95%CI 0.53 to 1.15; p = 0.186). Median OS in patients who had previous nephrectomy (246/287) was 20.9 months (95%CI 17.6-24.1) vs 13 months (95%CI 7.7-18.2) in patients who did not it (HR log rank 0.504; 95%CI 0.337 to 0.755; p = 0.001). In the multivariate model, nephrectomy showed a significant association with OS (HR log rank 0.638; 95%CI 0.416 to 0.980), whereas gland metastases were still associated with better outcome in terms of both OS (HR log rank 0.487; 95%CI 0.279 to 0.852) and PFS (HR log rank 0.646; 95%CI 0.435 to 0.958). CONCLUSIONS: IO treatment, in patients who had previously undergone nephrectomy, was associated with a better outcome in terms of OS. Further prospective trials would assess this issue in order to guide clinicians in real word practice.

Inflammatory indices and clinical factors in metastatic renal cell carcinoma patients treated with nivolumab: the development of a novel prognostic score (Meet-URO 15 study).

BACKGROUND: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. METHODS: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. RESULTS: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. CONCLUSION: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.