Background:
First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target ...kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear.
Methods:
This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety.
Results:
31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension.
Conclusions:
The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable.
Trial registration number:
NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681
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•Real-world data confirm activity and safety of vinflunine within its approved use.•Immunotherapy is a new standard for relapsed advanced urothelial cancer.•Immunotherapy offers ...long-term responses to only 25% of patients.•Vinflunine represents a useful option in patients not responding to immunotherapy.
Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL.
We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded.
Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies.
Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC.
Prostate carcinoma (PC), the second most diagnosed cancer globally, saw approximately 1,414,000 new cases in 2020, with 17% being de novo metastatic. In these cases, the 5-year relative survival rate ...is 32%. Metastatic hormone-sensitive prostate cancer (mHSPC) includes those with metastatic disease at initial diagnosis or after initial therapy without long-term androgen deprivation therapy (ADT), eventually progressing to castration-resistant prostate cancer (CRPC). The established therapeutic principle of ADT has persisted for 80 years, with luteinizing hormone-releasing hormone (LHRH) agonists like leuprorelin being commonly used. LHRH antagonists, such as degarelix, have also emerged. Recent advances in mHSPC treatment involve combination strategies with drugs proven effective in CRPC, considering prognostic factors like disease volume and presentation. This review outlines pivotal trials leading to drug approvals in mHSPC and proposes a treatment decision algorithm for the same, based on statement from the Tuscan Interdisciplinary Uro-Oncological Group. A multidisciplinary approach is crucial to tailor treatment intensity and weigh risks and benefits effectively.
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Background: For many years, vascular endothelial growth factor (VEGF)-targeted therapy (tp) has been a milestone for metastatic renal cell carcinoma (mRCC). Recently, first line tp ...based on anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICIs) plus tyrosine-kinase-inhibitors (IO-TKI) and anti-PD-1 plus anti-CTLA-4 combos (IO-IO) significantly improved survival of mRCC patients (pts). Prospective data are lacking to determine the efficacy of anti-VEGF tp after IO-IO or IO-TKI. Cabozantinib (Cabo) showed to prolong survival in mRCC pts pre-treated with TKIs and to target kinases involved in immune-escape. So, it may represent an ideal agent to be used sequentially after ICIs. Methods: This is an open label, single arm, multicenter, phase II study evaluating efficacy and safety of Cabo in mRCC pts who received an anti-PD-1/PD-L1-based adjuvant (adj) or first line tp. Cabo 60 mg/daily was administered until progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression free survival (PFS) by Brookmeyer-Crowley test, secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Exploratory endopoints were to investigate tissue PD-L1 expression, to assess the modulating activity of Cabo on local and systemic tumor immunity and to explore bone formation and reabsorption markers. Results: From July 2018, 49 pts were enrolled and 48 were included in the analysis. Median age was 62.5 years (range: 30-78), 63% of pts were male. At baseline, 26% of pts had a good Heng risk score, 47% intermediate and 28% a poor risk, while in 2% of pts the class of risk was undetermined. 74% of pts received an IO-IO combo as first line tp, 17% IO-TKI, 9% pts an adj IO monotherapy. Pts received a median of 10 cycles of Cabo (range 5-17 cycles). 25 pts (53%) are still on tp, 1 patient discontinued Cabo for AEs, 13 pts for radiological PD, 6 pts discontinued for clinical PD or death, while 2 pts for reasons other than AEs or PD. Among evaluable cases, 17 pts (43%) achieved a partial response and 15 pts (37%) stable disease. Complete responses were not observed. At a median (m) follow-up of 8.0 months (mo) (4.4-13.5 mo), 71% of pts were alive and mPFS was 9.3 mo (95% CI 7.1-29.0 mo). Grade (G) 3-4 adverse events (AEs) occurred in 34% of pts, including more frequently serum bilirubin increase, hypertension, calcium and sodium serum levels alterations and oral mucositis. G1-2 were observed in 61% of pts, including in most of cases diarrhoea, nausea, oral mucositis, disgeusia, hand-foot syndrome, fatigue and hypothyroidism. Due to AEs, transitory withholding of Cabo was observed in 53.5% of pts and for 23 pts (48%) dose reductions were needed. Conclusions: So far, Cabo tp after IO-IO or IO-TKI showed promising results and was well tolerated. Longer follow-up is needed for final OS and exploratory endpoints results. Clinical trial information: NCT03463681.
Purpose of Review
Therapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune ...checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.
Recent Findings
The first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with pancreatic or lung metastases, or previously undergoing organ transplantation and elderly subjects.
Summary
Some selected categories of patients may still benefit from monotherapy with TKI, and smart sequential therapies can also be considered instead of a combination strategy. Tyrosine kinase inhibitors can also act as immune modulator agents, boosting the immune response to facilitate and potentiate the therapeutic effectiveness of subsequent immunotherapy.
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Background: Nivolumab is approved in the second or further line of treatment for patients with metastatic renal cell carcinoma (mRCC); cabozantinib is approved in a similar setting ...of patients. Unfortunately, no evidence is currently available regarding the best treatment option after disease progression to both nivolumab and cabozantinib. The aim of this study is to compare the treatment choices after progression to nivolumab and cabozantinib including patients followed in best supportive care (BSC) or active therapy. Methods: In this retrospective observational study, we selected 42 patients from 8 Italian cancer centers. Enrolled patients had progressed to both nivolumab and cabozantinib and subsequently referred to active treatment or BSC. Primary endpoint of the study was the OS of patients on active treatment versus BSC. Secondary endpoints were ORR, PFS and OS of patients on active treatment who received sorafenib versus everolimus. Results: The median age was 65 years, 76.2% were male. The majority of patients had undergone nephrectomy (78.6%), had clear cell histology (83%) and were at intermediate-poor risk at the diagnosis (85.7%). The most frequent site of metastatic disease in the general population and in patients referred to BSC was the lung (73.8% and 88.9%, respectively). For patients referred to active treatment, the most frequent site of metastasis was bone (70.8%). Sunitinib (71.4%), nivolumab (64.3%), and cabozantinib (54.7%) were the most commonly used drugs in the I, II and III lines of treatment, respectively. After progression to both nivolumab and cabozantinib 42.9% of patients were referred to BSC, while 57.1% received active treatment (28.6% everolimus, 16.7% sorafenib, 4.8% sunitinib, 4.8% IL2-HD, 2.4% lenvatinib + everolimus). Median OS was 13 (95% CI: 4-NR) and 3 months (95% CI: 2-4) in patients on active treatment versus BSC ( p=0.001). Patients treated with sorafenib had better disease control when compared with those treated with everolimus (SD 71.4% versus 16.7%, PD 14.3% versus 58.3%; p=0.03), but no significant advantage in terms of PFS (5 versus 3 months, 95% CI: 2-6 versus 2-5; p= 0.5) and OS (NR versus 13 months, 95% CI: 3-NR versus 2-NR; p=0.2) was observed. Conclusions: After treatment with both nivolumab and cabozantinib, when possible, the choice of an active treatment seems to produce an OS advantage when compared with BSC. However, although sorafenib seems to demonstrate better results, we cannot indicate which is the drug of choice, as no significant advantage was shown in terms of OS or PFS from the comparison between sorafenib and everolimus. The limitations of this study are given by the size of the sample examined and its retrospective nature. Further studies are needed to confirm whether active treatment choice is associated with improved OS.
Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the ...response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb (MALVA in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25).
Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported.
At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (<median) compared to 5.1 months for patients with baseline NER greater than the median (≥median) (P = .0005). Median OS was significantly longer for patients with baseline NER <median compared with patients with baseline NER ≥median (not reached vs. 11.7 months, respectively; P = .0016). Significantly better PFS and OS were confirmed for NER after 3 cycles of avelumab <median compared with NER ≥median at the same timepoint.
NER <median may be predictive of PFS in aUC patients treated with avelumab, and prognostic for OS regardless of treatment. Prospective studies are warranted to validate NER as a readily available and reproducible laboratory-biomarker for efficacy outcomes of avelumab in aUC.
Our retrospective analysis from MALVA Meet-URO 25 study reports progression-free survival (PFS) and overall survival (OS) by neutrophil-to-eosinophil ratio (NER) during avelumab treatment for advanced urothelial cancer (aUC). NER <median may be predictive of PFS, and prognostic for OS regardless of treatment. Prospective studies are warranted to validate NER as reproducible laboratory-biomarker for efficacy outcomes of avelumab in aUC.
Cutaneous immune-related adverse events occur in more than one-third of patients treated with immune checkpoint inhibitors; they are often the first clinical manifestation although they may occur ...months after initiation of therapy.We noticed that our patients usually have these cutaneous adverse events on photodamaged skin. In fact, out of 19 patients being treated for metastatic melanoma, patients (42%) with significant cutaneous actinic damage presented cutaneous immuno-related adverse events earlier and in a more serious form. Thus, our metastatic melanoma patients with photodamaged skin who were initiating immunotherapy were given a high oral dose of nicotinamide (500 mg twice daily)for the entire duration of therapy. In treated patients, the appearance of the first signs of cutaneous immuno-related adverse events was 180 days after starting therapy rather than 65 days for untreated patients.
Background
There is an increase in the attention to factors influencing the quality of life of cancer patients. The aim of the present study was to evaluate temperament and character traits related ...to health-related quality of life (HRQoL) in patients with cancer.
Methods
Two hundred and three inpatients from three Italian oncology departments filled in the Temperament Character Inventory (TCI-140) based on Cloninger's personality model, the SF-36 questionnaire assessing HRQoL, and the Hospital Anxiety and Depression Scale (HADS). Eighty percent of patients were undergoing chemotherapy.
Results
Lower levels of harm avoidance and higher levels of self-directedness were significantly correlated with a better HRQoL. Regression analysis controlling for psychopathology (anxiety and depression symptoms) showed that the influence of temperament and character traits on quality of life seemed to add little to the influence of psychopathology.
Conclusions
The present study demonstrates the existence of some relations between HRQoL and temperament and character traits assessed using the TCI-140 questionnaire. However, among the psychological factors, psychopathology seems to retain more influence on HRQoL of cancer patients.
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