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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.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.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).After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients.

Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients65 years. However, data on patients75 years are lacking as co-morbidities and logistics often exclude them from clinical trials.We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors.174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p .001) and lower performance status (p .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary.Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma.

Cemiplimab is a highly potent, hinge-stabilized human IgG4 monoclonal antibody (mAb) targeting programmed cell death 1 (PD-1) receptor approved for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (SCC) who are not candidates for curative surgery or curative radiation. Recently, the phase 3 trial EMPOWER-Cervical 1 has investigated cemiplimab in patients with recurrent/metastatic cervical cancer. At interim analysis, overall survival (OS), progression free survival (PFS) and objective response rate (ORR) in overall and SCC populations favored cemiplimab over single agent chemotherapy. Cervical SCCs are the first for incidence among Human Papilloma Virus (HPV) related neoplasms and are highly correlated (about 95%) with the viral infection. Similarly, penile and vulvar SCC may develop on chronic HPV infections or on dermatological chronic conditions (ie, lichen). The molecular and viral similarities between external genital SCC and SCC originating from the cervical epithelium could be the rationale for using cemiplimab to treat locally advanced or metastatic penile and vulvar SCC as well. Some retrospective data have shown that cemiplimab may provide objective response and clinical benefit to some patients with penile or vulvar SCC and is overall safe to utilize in this population. Given the complexity of the immune activation and the considerable variability in tumor biology across patients and tumor types, the identification of biomarkers to warrant patient selection needs to be further explored. Ongoing clinical trials will hopefully shed light on the treatment paradigm of these rare tumors too, with special regard to the ideal combination and sequencing of immunotherapeutic strategies.

Background: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. Methods: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. Results: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36–0.97], p = 0.037). Conclusions: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.

Harnessing the power of the immune system in fighting cancer with immunotherapeutic agents is increasingly recognized as an integral component of cancer care for multiple neoplasm, and first of all for cutaneous melanoma. Immunotherapy can provide cancer patients with durable tumor control and long-term survival; however, maximizing the number of patients who can benefit from this approach undoubtedly requires additional efforts. Along this line, immunotherapy combinations and the association of immunotherapeutic agents with targeted therapy, oncolytic viral therapy, tumor microenvironment modulators, and epigenetic drugs represent areas of active investigation that could eventually lead to enhanced efficacy. Thus, identifying optimal therapeutic combinations and sequences will facilitate the integration of novel and more effective immunotherapy-based combinations into the clinical practice.

Background The major challenge for treating non-squamous (non-Sq) non-small cell lung cancer (NSCLC) patients without actionable biomarkers is the actual selection of proper treatment, weighing expected clinical outcomes and safety profile. Methods Consecutive non-Sq NSCLC patients were treated with platinum-pemetrexed (PP) doublets in clinical practice. Subgroup analyses were conducted in patients treated with standard (s)PP and modified (m)PP doublets (because of age, performance status, and/or comorbidities) and in patients treated with cisplatin-based and carboplatin-based PP doublets. Activity, efficacy, safety, and toxicities were evaluated. Results From November 2009 to April 2017, 111 patients were treated: 87 (78.4%) with sPP and 24 (21.6%) with mPP; 76 (68.5%) with cisplatin-based and 35 (31.5%) with carboplatin-based regimens. The objective response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were 49.0%, 7, and 13 months in the entire patient population, respectively. We found no significant differences in ORR, median PFS, and median OS between sPP and mPP. Cisplatin-based PP showed higher ORR (53.7%) versus carboplatin-based PP (38.7%) and longer PFS (7 vs. 6 months; P = 0.028) and OS (18 vs. 11 months; P = 0.006). We confirm that carboplatin has a better toxicity profile than cisplatin. The received dose-intensities were ~80% of standard full doses. Conclusions Accurate management allowed us to treat the majority of advanced non-Sq NSCLC patients with PP combination therapy without significant differences in ORR, median PFS, and median OS. Even considering the selection bias, our data seems to confirm the greater effectiveness of cisplatin-based over carboplatin-based regimens.

Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

Several small molecules, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib, have been demonstrated to significantly improve clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), but erlotinib activity in EGFR wild-type squamous carcinoma is still highly debated. Here, we describe a prolonged and unexpected clinical response to erlotinib in a male former heavy cigarette smoker with wild-type EGFR squamous-cell cancer.

Background: Therapeutic targeting of the PD-1/PDL-1 axis significantly increases the survival of melanoma (MM) and non-small cell lung cancer (NSCLC) patients. Despite this unprecedented efficacy, a sizeable proportion of MM and NSCLC patients fails to benefit from therapy due to primary or secondary resistance to treatment. In this scenario, deepening the knowledge on mechanism(s) underlying treatment failure allows to design novel, mechanism-based, therapeutic approaches to overcome resistance to anti-PD-1/PDL-1 therapy. Along this line, we have extensively characterized the immunomodulatory properties of DNA hypomethylating agents (DHA) in different human malignances. Exposure of neoplastic cells to DHA efficiently improved antigen-restricted and -unrestricted T cell recognition of cancer cells in vitro through the upregulation/induction of the expression of epigenetically regulated tumor associated antigens, HLA class I and/or accessory/co-stimulatory molecules by neoplastic cells. Supporting these ex vivo data, combining the systemic administration of DHA (ie, decitabine or guadecitabine) with antibodies to different immune checkpoints significantly reduced tumor growth of murine syngeneic grafts, compared to single-agent therapy. Supporting these pre-clinical findings, our phase Ib NIBIT-M4 study has been the first clinical trial demonstrating that systemic administration of guadecitabine followed by CTLA-4 blockade with ipilimumab is safe and tolerable in MM patients, shows a promising anti-tumor, and induces a significant modulation of immune related pathways in tumor samples (Di Giacomo AM, Clin Cancer Res 2019). Prompted by these results and to further explore the efficacy of DHA combined with immune-checkpoints blockade we have designed and activated the NIBIT-ML1 trial. This study aims at investigating the efficacy of guadecitabine combined with ipilimumab and nivolumab in reverting the resistance to PD-1/PDL-1 therapy of MM and NSCLC patients. Methods: The NIBIT-ML1 is a randomized, phase II study designed according to the two stages optimal design by Simon, in unresectable Stage III or Stage IV MM (Cohort A) or NSCLC (Cohort B) patients who failed therapy with anti-PD-1/PDL-1 as last treatment. Primary objective of the study is immune (i)-ORR according to iRECIST criteria. Secondary objectives include safety, DCR, PFS, median OS, and survival rate at 1 and 2-years. Extensive cellular and molecular immune correlates will also be explored. Following a safety run-in phase in 6 subjects per Cohort, eligible patients will be randomized to receive: guadecitabine plus ipilimumab and nivolumab (ARM A) or ipilimumab and nivolumab (ARM B). Sample size will range from 6 to 92 patients per Cohort. The first patient first visit is foreseen by March 2020 (NCT04250246) Citation Format: Anna Maria Di Giacomo, Luana Calabrò, Riccardo Danielli, Monica Valente, Elisabetta Gambale, Sandra Coral, Giovanni Amato, Harold Keer, Diana Giannarelli, Mohammad Azab, Andrea Anichini, Alessia Covre, Michele Maio. A randomized, multi-center, phase II study of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab in melanoma and NSCLC patients resistant to anti-PD-1/-PD-L1: The NIBIT-ML1 Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT270.

Rationale: Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumour in adults, with a very dismal prognosis and limited effective therapies. Immunotherapy may play a role in treating GBM, though the initial clinical results are still poor, and novel combined treatment(s) could possibly improve its efficacy. Manipulating the epigenome has been considered a therapeutic opportunity in GBM, since epigenetic modifications regulate glioma proliferation, metastasis, invasion, and prognosis. In addition, epigenetic alterations may negatively regulate the cross-talk between GBM and immune cells in GBM microenvironment (TME), thus limiting the efficacy of immunotherapy. We previously demonstrated the immunomodulatory potential of epigenetic drugs in cancer cells, and translated this notion in the clinic to improve efficacy of immunotherapy of melanoma patients (Di Giacomo AM, CCR 2019). Accordingly, this study aimed to evaluate the immunomodulatory potential of epigenetic drugs in GBM, and to provide the scientific rationale for new combinatorial therapeutic approaches in GBM patients. Methods: Patient-derived GBM (pGBM) cell lines (n=10) were established from surgically-removed GBM lesions and treated with the DNA hypomethylating agent guadecitabine (1 µM); commercially available human GBM (cGBM) cell lines (n=3) were treated with guadecitabine (1 µM) and/or with the EZH2-inhibitor GSK126 (10 µM). Expression of HLA class I and ICAM-1 by GBM cells was investigated by flow-cytometry; cancer testis antigens (CTA, i.e., NY-ESO, MAGE-A1 and MAGE-A3) and the epithelial-mesenchymal transition (EMT)-regulating cadherins (i.e., CDH1 and CDH2) expression was analyzed by quantitative Real-Time PCR. Results: A positive modulation of immune profile was observed in all investigated guadecitabine-treated GBM cells. Specifically, in untreated vs guadecitabine-treated cells, MFI mean values ± SD of HLA class I were 402±326 vs 442±303 in pGBM cells, and 277±127 vs 381±138 in cGBM cells; MFI mean values ± SD of ICAM-1 were 53±72 vs 92±116 in pGBM cells, and 5±6 vs 26±17 in cGBM cells. Though a slight increment was induced by GSK126 for HLA class I (312±169) and ICAM-1 (9±11) expression in cGBM, an additive effect was detected with GSK126+guadecitabine (405±261 for HLA class I and 35±22 for ICAM-1) in cGBM cells. Guadecitabine induced NY-ESO-1, MAGE-A1, and MAGE-A3 expression in 9/10, 6/10, and 5/8 pGBM cells, respectively and in all cGBM cells. Levels of CTA expression were increased in cGBM by GSK126+guadecitabine vs guadecitabine with mean Fold Change (FC) of 1.5, 1.6 and 1.6 for NY-ESO-1, MAGE-A1 and MAGE-A3 expression. Finally, CDH1 expression was induced in 1/3 and in 2/3 cGBM cells by guadecitabine and guadecitabine+GSK126, respectively; CDH2-positive expression was upregulated by guadecitabine (mean FC=2.45) but not by guadecitabine+GSK126. Conclusions: Immunomodulatory properties of epigenetic drugs in GBM should be exploited to improve the efficacy of GBM immunotherapy. Citation Format: Maria Fortunata Lofiego, Francesca Piazzini, Carolina Fazio, Ornella Cutaia, Carla Chiarucci, Sara Cannito, Elisabetta Gambale, Monica Valente, Anna Maria Di Giacomo, Sandra Coral, Clelia Miracco, Giuseppe Oliveri, Michele Maio, Alessia Covre. Immunomodulatory activity of epigenetic drugs: Laying the ground for new combined immunotherapeutic strategies for glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4488.

Aim: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population. Methods: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016–2017. Results: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23–4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77–31.14; p

Background Adherence to adjuvant endocrine therapy (HT) is suboptimal among breast cancer patients. A high rate of nonadherence might explain differences in survival between clinical trial and clinical practice. Tailored interventions aimed at improving adherence can only be implemented if subgroups of patients at higher risk of poor adherence are identified. Because no data are available for Italy, we undertook a large survey on adherence among women taking adjuvant HT for breast cancer. Patients and Methods Patients were recruited from 10 cancer clinics in central Italy. All patients taking HT for at least 1 year were invited, during one of their follow-up visit, to fill a confidential questionnaire. The association of sociodemographic and clinical characteristics of participants with adherence was assessed using logistic regression. The RECPAM method was used to evaluate interactions among variables and to identify subgroups of patients at different risk of nonadherence. Results A total of 939 patients joined the study and 18.6% of them were classified as nonadherers. Among possible predictors, only age, working status, and switching from tamoxifen to an aromatase inhibitor were predictive of nonadherence in multivariate analysis. RECPAM analysis led to the identification of 4 classes of patients with a different likelihood of nonadherence to therapy, the lowest being observed in retired women with a low level of education, the highest in the group of unmarried, employed women, or housewives. Conclusion The identification of these subgroups of “real life” patients with a high prevalence of nonadherers might be functional in designing intervention studies aimed at improving adherence.

The reported frequency of ipilimumab-induced hypophysitis (IIH), a cytotoxic T-lymphocyte antigen 4 antibody, ranges from 0 to 17%, in contrast to the rarity of idiopathic autoimmune hypophysitis that has an estimated incidence of one in nine million people per year. Here we present the case of a patient with ipilimumab- induced hypophysitis (IIH). After his third course of ipilimumab, the patient began to present worsening asthenia and severe headache. A brain MRI scan showed the mild swelling of the anterior pituitary gland and thickening of the stalk. Haematological reports were consistent with hypophysitis diagnosis: in fact, ACTH and cortisol levels were very low. Then ipilimumab was interrupted and therapy with a large dose of glucocorticoids (dexamethasone) was promptly started. A rapid symptoms improvement was obtained by this therapeutic approach. The dose of dexamethasone was gradually decreased over 4 weeks and hydrocortisone replacement was started. Development of IIH is associated with the risk of acute adrenal insufficiency or adrenal crisis, so early recognition and therapeutic intervention are extremely relevant. Furthermore, in the absence of data demonstrating clinical benefit from high-dose glucocorticoid therapy, we wondered if, in absence of symptoms such as visual disturbances or other life-threatening simultaneous irAEs in other organs, there is the indication to start with hydrocortisone replacement therapy alone from the beginning. We also wondered if it was reasonable to administer ipilimumab during prolonged high-dose glucocorticoid therapy. Thus, guidelines for surveillance and management of IH are highly required.

// Giuseppe Bronte 1, * , Tindara Franchina 2, * , Massimiliano Alu 3, * , Giovanni Sortino 1 , Claudia Celesia 1 , Francesco Passiglia 1 , Giuseppina Savio 3 , Agata Laudani 3 , Alessandro Russo 2 , Antonio Picone 2 , Sergio Rizzo 1 , Michele De Tursi 4 , Elisabetta Gambale 4 , Viviana Bazan 1 , Clara Natoli 4 , Livio Blasi 3 , Vincenzo Adamo 2 , Antonio Russo 1 1 Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy 2 Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy 3 Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy 4 Department of Medical, Oral and Biotechnological Sciences, University “G. D'Annunzio”, Chieti, Italy * These authors contributed equally to this work Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: non-small-cell lung cancer, EGFR, tyrosine kinase inhibitor, chemotherapy Received: January 21, 2016 Accepted: February 28, 2016 Published: March 16, 2016 ABSTRACT Background: Second-line treatment for advanced non-small-cell lung cancer (NSCLC) patients includes monotherapy with a third-generation cytotoxic drug (CT) or a tyrosine kinase inhibitor (TKI). These options are the actual standard for EGFR wild-type (WT) status, as patients with EGFR mutations achieve greater benefit by the use of TKI in first-line treatment. Some clinical trials and meta-analyses investigated the comparison between CT and TKI in second-line, but data are conflicting. Methods: We designed a retrospective trial to gather information about TKI sensitivity in comparison with CT. We selected from clinical records patients treated with at least 1 line of CT and at least 1 line of TKI. We collected data about age, sex, performance status, comorbidity, smoking status, histotype, metastatic sites, EGFR status, treatment schedule, better response and time-to-progression (TTP) for each line of treatment and overall survival (OS). Results: 93 patients met selection criteria. Mean age 66,7 (range: 46–84). M/F ratio is 3:1. 39 EGFR-WT and 54 EGFR-UK. All patients received erlotinib or gefitinib as second-line treatment or erlotinib as third-line treatment. No TTP differences were observed for both second-line (HR:0,91; p = 0,6333) and third-line (HR:1.1; p = 0,6951) treatment (TKI vs CT). A trend of a benefit in OS in favor of 3rd-line TKI (HR:0,68; p = 0,11). Conclusions: This study explores the role of TKIs in EGFR non-mutated NSCLC patients. OS analysis highlights a trend to a benefit in patients who received TKI in third-line, even if this result is statistically non-significant. Further analysis are needed to find an explanation for this observation.

10038Background: advanced age is associated with comorbidities and impairment of the immune system: these aspects may influence efficacy and tolerability of immune checkpoint inhibitors. Limited da...

We describe the case of a 59-year-old woman who underwent a radical left nephrectomy for renal cell cancer in 1993. After 7 years, the disease relapsed as thyroid and pulmonary metastases and she has been initially treated with chemotherapy. At further progression we administered an antiangiogenic drug, Sunitinib for 9 months then we switched to Pazopanib. The patient is still receiving a half-dose of Pazopanib (46 months) and she is showing a longlasting response with an optimal safety profile. In this patient, Pazopanib demonstrated a significant improvement in PFS and tumor response also with half a dose. Nephrectomy, metastasectomy, medical therapy and targeted treatments have been shown able to prolong survival and improve quality of life. This is an example of chronicized disease in a patient who can be defined as a long-term survivor.

e21009Background: Ipilimumab is an inhibitor of CTLA4 receptor of T lymphocytes that has been approved by FDA both as first and second line treatment for patients with metastatic melanoma. Despite ...