Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. METHODS: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. RESULTS: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. CONCLUSION: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.

Prevalence and Clinical Impact of SARS-CoV-2 Silent Carriers Among Actively Treated Patients with Cancer During the COVID-19 Pandemic.

INTRODUCTION: In Europe, the SARS-CoV-2 pandemic had its first epicenter in Italy. Despite a significant mortality rate, the severity of most cases of COVID-19 infection ranges from asymptomatic to mildly symptomatic, and silent infection affects a still-unknown proportion of the general population. No information is available on the prevalence and clinical impact of SARS-CoV-2 silent infection among patients with cancer receiving anticancer treatment during the pandemic. MATERIALS AND METHODS: From April 1, 2020, to the end of the same month, 560 consecutive patients with cancer, asymptomatic for COVID-19 and on anticancer treatment at Papa Giovanni XXIII Hospital in Bergamo, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including the rapid serological immunoassay for anti-SARS-CoV-2 immunoglobulin (Ig) G/IgM and the nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test in case of seropositivity to identify SARS-CoV-2 silent carriers. RESULTS: In 560 patients, 172 (31%) resulted positive for anti-SARS-CoV-2 IgM/IgG antibodies, regardless of different type of cancer, stage, and treatment. The Ig-seropositive patients were then tested with RT-PCR nasopharyngeal swabs, and 38% proved to be SARS-CoV-2 silent carriers. At an early follow-up, in the 97 SARS-CoV-2-seropositive/RT-PCR-negative patients who continued their anticancer therapies, only one developed symptomatic COVID-19 illness. CONCLUSION: Among patients with cancer, the two-step diagnostics is feasible and effective for SARS-CoV-2 silent carriers detection and might support optimal cancer treatment strategies at both the individual and the population level. The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in cases of RT-PCR-negative patients. IMPLICATIONS FOR PRACTICE: This is the first study evaluating the prevalence and clinical impact of SARS-CoV-2 silent infection in actively treated patients with cancer, during the epidemic peak in one of the worst areas of the COVID-19 pandemic. Lacking national and international recommendations for the detection of asymptomatic SARS-CoV-2 infection, a pragmatic and effective two-step diagnostics was implemented to ascertain SARS-CoV-2 silent carriers. In this series, consisting of consecutive and unselected patients with cancer, the prevalence of both SARS-CoV-2-seropositive patients and silent carriers is substantial (31% and 10%, respectively). The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in case of RT-PCR-negative patients.

Chemotherapy in non-small cell lung cancer patients after prior immunotherapy: The multicenter retrospective CLARITY study.

OBJECTIVES: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients. MATERIALS AND METHODS: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed. RESULTS: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71). CONCLUSIONS: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC.

Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report.

BACKGROUND: Meningeal carcinomatosis is rare in patients with kidney cancer and treatment options are limited. Few patients treated with systemic approaches have been reported. We describe a case of complete remission of leptomeningeal metastasis in a patient with renal cell carcinoma treated with nivolumab. To our knowledge, this is the first report of nivolumab safety and efficacy in this particular site of metastasis. CASE PRESENTATION: Our patient was a 60-year-old Caucasian man with bone and lung metastases from renal cell carcinoma. He developed leptomeningeal metastasis and progression of bone and lung lesions after only 2 months of his first-line treatment. He was then treated with nivolumab in second-line setting and experienced a rapid improvement of cancer-related symptoms, complete remission of leptomeningeal and lung lesions, and increased bone mineral density in bone metastasis. The patient did not experience any drug-related toxicity. CONCLUSIONS: Meningeal carcinomatosis metastasis from renal cancer is a rare condition. Diagnosis is often challenging: the onset of nonspecific presenting symptoms could be initially attributed to bone involvement, side effects of oncologic therapy, or paraneoplastic syndromes. Our case suggests that nivolumab could be an effective and safe treatment option in patients with pretreated renal cancer with leptomeningeal metastasis.

Prognostic impact of regression in patients with primary cutaneous melanoma >1 mm in thickness.

BACKGROUND: The impact of histologic regression on sentinel lymph node biopsy (SLNB) status and on clinical outcome is uncertain. OBJECTIVE: To investigate whether and to what extent regression <75% is able to predict SLNB status and clinical outcome of patients with melanoma >1-mm thick. METHODS: The study included patients with diagnoses given at 4 centers of the Italian Melanoma Intergroup. Univariate and multivariate Cox proportional hazard models stratified by center were used to analyze the effect of regression on disease-free interval and melanoma-specific survival. RESULTS: Out of 1182 patients given primary cutaneous melanoma diagnoses during 1998-2015 with a Breslow thickness >1 mm, 954 (304 with and 650 without regression) were included in the analysis. The proportion of patients with a positive SLNB was lower in patients with regression than without (24.4% vs 31.6%, chi-squared test P = .0368). At multivariate analysis, no association was detected between regression and disease-free interval (hazard ratio 1.11, 95% confidence interval 0.85-1.46; P = .4509) or melanoma-specific survival (hazard ratio 1.05, 95% confidence interval 0.77-1.44; P = .7600). LIMITATION: Retrospective analysis. CONCLUSION: In our series, regression was not an independent prognostic factor in primary cutaneous melanoma patients with Breslow thickness >1 mm whereas it was associated with a lower incidence of SLNB positivity.