Treatment beyond progression with immunotherapy may be appropriate in selected patients based on the potential for late responses. The aim of this systematic review was to explore the impact of ...treatment beyond progression in patients receiving an anti-PD-1/PD-L1 based regimen for an advanced solid tumor.
A systematic literature search was performed to identify prospective clinical trials reporting data on overall response rate by immune-related criteria and/or the number of patients treated beyond conventional criteria-defined PD and/or the number of patients achieving a clinical benefit after an initial PD with regimens including an anti-PD-1/PD-L1 agent which received the FDA approval for the treatment of an advanced solid tumor.
254 (4.6%) responses after an initial RECIST-defined progressive disease were observed among 5588 patients, based on 35 trials included in our analysis reporting this information. The overall rate of patients receiving treatment beyond progressive disease was 30.2%, based on data on 5334 patients enrolled in 36 trials, and the rate of patients who achieved an unconventional response among those treated beyond progressive disease was 19.7% (based on 25 trials for a total of 853 patients).
The results of our systematic review support the clinical relevance of unconventional responses to anti-PD-1/PD-L1-based regimens; however, most publications provided only partial information regarding immune-related clinical activity, or did not provide any information at all, highlighting the need of a more comprehensive report of such data in trials investigating immunotherapy for the treatment of patients with advanced tumors.
Cutaneous squamous cell carcinoma (CSCC) accounts for approximately 20% of all keratinocytic tumors. In most cases, the diagnosis and treatments are made on small, low-risk lesions. However, in about ...5% of cases, CSCC may present as either locally advanced or metastatic (i.e. with locoregional lymph nodes metastases or distant localizations). Prior to the introduction of immunotherapy in clinical practice, the standard treatment of advanced CSCC was not clearly defined, and up to 60% of patients received no systemic therapy. Thanks to a strong pre-clinical rationale, clinical trials led to the FDA (Food and Drug Administration) and EMA (European Medicines Agency) registration of cemiplimab, a PD-1 inhibitor that achieved encouraging results in terms of objective response, overall survival, and quality of life. Subsequently, the anti-PD-1 pembrolizumab received the approval for the treatment of advanced CSCC by the FDA only. In this review, we will focus on the definition of advanced CSCC and on the current and future therapeutic options, with a particular regard for immunotherapy.
Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than ...melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.
Adjuvant treatment of operated melanoma has deeply changed in the last few years with the introduction of immune-checkpoint inhibitors and BRAF/MEK inhibitors. Sarcoidosis is a systemic inflammatory ...disease causing non-caseous granulomatous reactions. Sarcoid-like granulomatous reactions have been reported in patients with advanced melanoma, mostly related to immunotherapy with immune-checkpoint inhibitors. We report a case of a 38-year-old woman with stage III operated melanoma treated with adjuvant BRAF plus MEK inhibitors, who developed sarcoidosis-like syndrome with systemic involvement, resolved after discontinuation of treatment. The occurrence of immune-related toxicity with the use of MAPK inhibitors supports the hypothesis that this class of drugs may also have an immunological effect, and that the long-term efficacy of adjuvant MAPK inhibitors may be due to their immunological function.
The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and ...better define the role of candidate genes. We characterized 273
and
negative probands through a custom-designed targeted gene panel that included
and
Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (
and
), including two novel variants in
and 4 in
. We also found four deleterious and five likely deleterious variants in
(3.3%). Thus, including potentially deleterious variants in
increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative
deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
Background
There is a concern that influenza vaccination may increase the incidence of immune‐related adverse events in patients receiving immune checkpoint inhibitors (ICIs). The aim of this ...systematic review was to summarize the available data on the safety and efficacy of influenza vaccination in cancer patients receiving ICIs.
Methods
Studies reporting safety and efficacy outcomes of influenza vaccination in cancer patients receiving ICIs were included. Only descriptive statistics were conducted to obtain a pooled rate of immune‐related adverse events in vaccinated patients.
Results
Ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs were identified, for a total of 1124 and 986 vaccinated patients, respectively. Most patients had melanoma or lung cancer and received a single agent anti‐PD‐1, but also other tumour types and immunotherapy combinations were represented. No severe vaccination‐related toxicities were reported. The pooled incidence of any grade immune checkpoint inhibitor–related adverse events was 28.9%. In the 6 studies specifying the incidence of grade 3‐4 toxicities, the pooled incidence was 7.5%. No grade 5 toxicities were reported. No pooled descriptive analysis was conducted in studies reporting efficacy outcomes due to the heterogeneity of endpoints and data reporting. Nevertheless, among the eight studies included, seven reported positive efficacy outcomes of influenza vaccination.
Conclusion
The results of this systematic review support the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. These results are particularly relevant in the context of the SARS‐CoV‐2 pandemic.
Immune checkpoint inhibitors (ICIs) have revolutionised clinical practice in oncology in the last years, leading to a survival benefit in several tumour types. To investigate whether these benefits ...are associated with improved quality of life, we conducted a systematic review and meta-analysis comparing patient-reported outcomes (PROs) between ICIs and standard chemotherapy (CT) in patients with advanced solid tumours.
Clinical trials comparing the efficacy of ICIs (either programmed death receptor-1 and programmed death-ligand 1 inhibitors or cytotoxic T-lymphocyte antigen 4 inhibitors, as single agent or in combination) versus CT were included. Trials evaluating treatment with ICIs plus CT versus CT alone were also included, whereas studies in which the control arm included other anticancer agents (such as targeted therapy and other ICIs) or placebo alone were excluded. The aim of our meta-analysis was to compare PROs in subjects treated with ICIs or ICIs plus CT (intervention) with those reported by patients receiving CT (control). The co-primary endpoints were time from baseline to first deterioration in PROs, defined as the time from baseline to the first clinically significant deterioration in PROs, and the changes in PROs from baseline to follow-up between ICI and CT treatment groups (PROSPERO registration number CRD42021247440).
A total of 8341 patients from 17 randomised trials of ICI versus CT were included in the analysis. Treatment with ICI delayed clinical deterioration over standard CT in Global Health Status/QoL EORTC QLQ-C30 (hazard ratio HR 0.81; 95% confidence interval CI, 0.74–0.89), and in both EQ-5D utility index (HR 0.65; 95% CI, 0.52–0.82) and EQ-5D visual analogue scale (VAS; HR 0.70; 95% CI, 0.61–0.80). The difference in mean change between the ICI-treated group and the CT-treated group was 5.82 (95% CI, 4.11–7.53) in favour of ICI. Similarly, in the EQ-5D, the mean change differences favoured treatment with ICIs in both Utility Index and VAS, with differences of 0.05 (95% CI, 0.03–0.07) and 5.41 (95% CI, 3.39–7.43), respectively.
ICIs are associated with higher levels of quality of life and longer time to clinical deterioration on several PROs scales compared with CT in different types of solid tumours.
•First meta-analysis on health-related quality of life directly comparing ICIs and chemotherapy.•A total of 8341 patients included from 17 trials of seven different tumour histology.•ICIs linked to benefit in patient reported outcomes compared with standard chemotherapy.
Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ...ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma.
Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events.
A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 95% CI 0.75–1.31 and RR = 0.99 95% CI 0.78–1.27, respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 95% CI 0.37–0.84) and ORR (RR = 3.07 95% CI 1.61–5.85). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 95% CI 0.30–1.67) versus ipilimumab/nivolumab.
Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.
•First NMA on advanced melanoma with ipilimumab/nivolumab as comparator.•9070 patients included from 18 first-line clinical trials of metastatic melanoma.•Similar activity for ipilimumab/nivolumab and relatlimab/nivolumab.•PD-(L)1/BRAF/MEKi triplets showed better outcomes in terms of progression-free survival and overall response rate.•Ipilimumab/nivolumab was the least favourable treatment in terms of safety.
Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking.
We performed a retrospective multicenter study to ...characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into ‘early’ (≤12 months) and ‘late’ (>12 months).
From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval CI: 2.8–4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8–17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio HR = 0.63 95% CI: 0.30–1.29, p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 95% CI: 0.37–1.56, p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 95% CI: 0.34–1.86, p = 0.598) and late-irAEs (HR = 0.92 95% CI: 0.49–1.74, p = 0.811) did not show statistically significant differences.
Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.
•Clinical trial adverse events methods do not consider the duration of treatment.•Study confirms spectrum of immune-related adverse events (irAEs) described in clinical trials and real-life studies.•Among late-irAEs, cutaneous, endocrine and gastrointestinal were the most common.•Early-irAEs were not related with progression-free survival and overall survival, late-irAEs were associated with them.•Time-adjusted progression risk was not reduced in accordance with early- and late-irAEs.
The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for ...immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker.
•CTLA-4 overexpression on melanoma cells is associated with response to ipilimumab.•CTLA-4 expression on melanoma cells is higher than that on infiltrating lymphocytes (TIL).•CTLA-4 expression on melanoma cells might have some influence on TIL subset distribution.
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