Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports.

Avelumab treatment in Italian patients with metastatic Merkel cell carcinoma: experience from an expanded access program.

BACKGROUND: The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP. METHODS: Eligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician's discretion. RESULTS: Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5-41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]). CONCLUSIONS: Results from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.

Consensus Recommendations for the Diagnosis, Biomarker Testing, and Clinical Management of Advanced or Metastatic Non-small Cell Lung Cancer With Mesenchymal-Epithelial Transition Exon 14 Skipping Mutations in the Middle East, Africa, and Russia.

Mesenchymal-epithelial transition exon 14 (METex14) skipping mutations occur in about 3%-4% of patients with non-small cell lung cancer (NSCLC). This is an aggressive subtype associated with poor prognosis. METex14 skipping is a potentially targetable mutation. Targeted therapy is a promising treatment modality for patients with advanced/metastatic METex14-mutant NSCLC. Performing systematic molecular testing to detect the driver mutation is essential for initiating targeted therapy. However, there is a lack of guidelines on molecular testing for assessing the eligibility of patients for targeted therapy. Therefore, a multidisciplinary panel consisting of experts from the Middle East, Africa, and Russia convened via a virtual advisory board meeting to provide their insights on various molecular testing techniques for the diagnosis of METex14 skipping mutation, management of patients with targeted therapies, and developing consensus recommendations for improving the processes. The expert panel emphasized performing molecular testing and liquid biopsy before treatment initiation and tissue re-biopsy for patients with failed molecular testing. Liquid biopsy was recommended as complementary to tissue biopsy for disease monitoring and prognosis. Selective MET inhibitors were recommended as the first and subsequent lines of therapy. These consensus recommendations will facilitate the management of METex14 skipping NSCLC in routine practice and warrant optimum outcomes for these patients.

Rechallenge with anti-EGFR therapy to extend the continuum of care in patients with metastatic colorectal cancer.

In patients with RAS wild-type metastatic colorectal cancer (mCRC), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody plus chemotherapy is a standard option for treatment in the first-line setting. Patients who progress while on treatment with anti-EGFR-based therapy can be resistant to further anti-EGFR treatment, but evidence suggests that the anti-EGFR-resistant clones decay, thereby opening the potential for rechallenge or reintroduction in later lines of treatment. Results from recent clinical studies have shown that some patients with mCRC who are rechallenged with anti-EGFR monoclonal antibodies exhibit durable responses. While other therapies have demonstrated improved overall survival in chemorefractory mCRC over the past decade, rechallenge with anti-EGFR monoclonal antibodies in later lines of treatment represents a new option that deserves further investigation in clinical trials. In this review, we summarize the molecular rationale for rechallenge or reintroduction in patients with mCRC who have progressed on earlier-line anti-EGFR treatment and examine the current evidence for using liquid biopsy as a method for selecting rechallenge as a therapeutic option. We also provide an overview of published trials and trials in progress in this field, and outline the potential role of rechallenge in the current clinical setting.

Italian survey on cetuximab-based therapy of elderly patients with metastatic colorectal cancer.

PURPOSE: There is no consensus on the use of cetuximab in elderly patients with metastatic colorectal cancer. To this end, a survey was carried in 17 Italian oncology centers. METHODS: The centers answered a 29-item questionnaire structured as follows: (i) demographic characteristics; (ii) medical history; (iii) assessment of RAS/BRAF mutations and DPD/UGT polymorphism before treatment; (iv) treatment schemes and side effects; (v) geriatric assessment and customization of treatment. RESULTS: One-third of patients are over 80 years old. The RAS/BRAF mutational status is not primarily evaluated by 17.6% of the centers, while DPD and UGT polymorphism is not evaluated by 82.4% and 76.5% of the centers. The most common therapeutic scheme is cetuximab/FOLFIRI and diarrhea is the main cause of suspension/reduction of treatment. The 70% of centers use systemic tetracyclines for skin toxicity. The 23.5% of the centers do not carry out any geriatric evaluation before the start of the therapy and those who perform it prefer the G8 (70.6%) and VES-13 (29.4%) scales. CONCLUSIONS: Greater efforts should be made to improve the evaluation of the patient both about mutational and genetic procedures with geriatric evaluation. As for cetuximab in elderly patients, randomized studies are needed to provide guidance to physicians.

Complete response to capecitabine in a frail, elderly patient with metastatic colorectal cancer: A case report.

The clinical management of frail, elderly patients affected by colorectal cancer (CRC) remains a subject of debate. The present study reports the case of an elderly man with metastatic CRC (mCRC) who was successfully treated with capecitabine. The patient survived for 29 months, thus highlighting its potential activity in terms of obtaining a complete response and high efficacy. A 77-year-old man presented with adenocarcinoma of the rectum with multiple and synchronous liver metastases, in addition to several comorbidities. The patient received single-agent capecitabine chemotherapy (825 mg/mq twice a day) on days 1-14 of a 21-day cycle. Following 12 cycles of well-tolerated therapy, a computed tomography scan revealed a complete response with no evidence of liver metastases. An overall survival of 29 months was documented, and the patient eventually succumbed to a diabetes-related complication. In compromised patients with mCRC, reduced-dose capecitabine is an excellent therapeutic option due to its positive safety profile, activity and efficacy.

Magnetic resonance imaging as an early indicator of clinical outcome in patients with metastatic colorectal carcinoma treated with cetuximab or panitumumab.

UNLABELLED: We show that detection, by week-2 magnetic resonance imaging, of tumor shrinkage >10% in response to therapy with cetuximab or panitumumab for metastatic colorectal carcinoma represents an early indicator of clinical outcome because it is predictive of the prolongation of progression-free survival and overall survival. PURPOSE: The early identification of patients with metastatic colorectal carcinoma who are likely to benefit from treatment with panitumumab or cetuximab remains of paramount importance. We evaluated whether the early tumor shrinkage assessed by magnetic resonance imaging (MRI) is predictive of long-term outcome to these epidermal growth factor receptor-targeted therapies. PATIENTS AND METHODS: Thirty-nine patients with chemorefractory metastatic colorectal carcinoma were treated with cetuximab or panitumumab. The patients were evaluated by unenhanced MRI at baseline, week 2, and week 8 after the beginning of the treatment and by contrast-enhanced computed tomography within 3 months. Early response was defined as a tumor shrinkage ≥ 10% at week-2 MRI, whereas response by contrast-enhanced computed tomography was defined according to standard Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: At week-2 MRI, 15 (38.5%) of 39 patients had an early response. Eleven (73.3%) of these 15 early responders then presented a partial response by contrast-enhanced computed tomography, whereas none of the 24 early nonresponders obtained a partial response (P < .0005, Fisher exact test). Median progression-free survival (PFS) was 29.7 and 8 weeks in patients with or without early response, respectively (hazard ratio [HR] 0.156 [95% CI, 0.069-0.355]; P < .0001)]. The median overall survival (OS) was 80 weeks in patients with early response and 23.3 weeks in those without early response, respectively (HR 0.154 [95% CI, 0.057-0.420]; P < .00005]). CONCLUSIONS: Early detection of tumor response by week-2 MRI without contrast medium is associated with a prediction of clinical outcome in patients with metastatic colorectal carcinoma treated with cetuximab or panitumumab.

Single agent panitumumab in KRAS wild-type metastatic colorectal cancer patients following cetuximab-based regimens: Clinical outcome and biomarkers of efficacy.

BACKGROUND: Few data are available outlining outcomes of panitumumab in advanced colorectal cancer patients benefiting from prior cetuximab-based regimens. PATIENTS AND METHODS: Thirty patients with KRAS wild type metastatic colorectal cancer with clinical benefit from prior cetuximab-based regimens between May 2004 and October 2011 were reviewed at nine Italian Institutions. Inclusion key criteria included interruption of cetuximab for reasons other than progressive disease. Patients were classified according to prior regimens (0 or ≥1), prior response or stabilization, surgery of metastases, and Köhne prognostic score. At the time of subsequent progression, patients were treated with single agent panitumumab until progressive disease, unacceptable toxicity, or consent withdrawal. RESULTS: Panitumumab obtained 67% disease control rate and 30% objective response rate, with median PFS of 4.2 and median OS of 9.6 mo. Patients with BRAF/NRAS/PI3KCA and KRAS (by mutant enriched technique) wild-type tumors had the best chance of response to panitumumab. CONCLUSIONS: Single agent panitumumab provided significant clinical benefit in heavily pretreated patients without acquired resistance to prior cetuximab-based regimens.

Cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomicin and prednisone plus rituximab in untreated young patients with low-risk (age-adjusted international prognostic index 0-1) diffuse large B-cell lymphoma.

Young patients (aged 18-60 years) with good-prognosis diffuse large B-cell lymphoma (DLBCL) [0 and 1 risk factor according to age-adjusted international prognostic index (aa-IPI)] are distinguished from patients with poor-prognosis. Six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in combination with rituximab achieved best results in young patients with low-risk DLBCL. We retrospectively analyzed the data of 82 patients (18-60 years) with untreated aa-IPI 0-1 DLBCL, from six Italian institutions, who underwent, between January 2002 and January 2007, rituximab-cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomicin and prednisone (R-MACOP-B) therapy followed, in patients with bulky presentation, by 30-36 Gy involved-field radiation therapy (34 patients). An overall response rate was noted in 77 out of 82 (94%) patients (75 patients had a complete response (91%), 2 patients had a partial response). With a median follow-up of 46 months, 7-year progression-free and overall survival were estimated to be 91% and 94%, respectively. R-MACOP-B regimen followed by involved-field radiation on bulky presentation is safe and very effective in the treatment of young patients with low-risk DLBCL.

Pretransplantation positron emission tomography scan is the main predictor of autologous stem cell transplantation outcome in aggressive B-cell non-Hodgkin lymphoma.

BACKGROUND: Limited data exist about the role of second-line chemotherapy response assessed by positron emission tomography (PET) as a prognostic factor in patients with aggressive non-Hodgkin Lymphoma (NHL) who undergo autologous stem cell transplantation (ASCT). The objective of this analysis was to investigate the main determinants of prognosis in patients with aggressive B-cell NHL who undergo ASCT, focusing on the impact of pretransplantation PET, secondary age-adjusted International Prognostic Index (sAA-IPI) score, histology, and previous response to first-line chemotherapy. METHODS: Seventy-five patients with diffuse, large B-cell lymphoma or grade 3 follicular lymphoma who were treated at the author' institution with second-line chemotherapy (combined ifosfamide, etoposide, and epirubicin [IEV]) followed by ASCT between September 2002 and September 2006 were included. All patients were evaluated by PET after 1 to 3 courses of IEV chemotherapy before ASCT, and all patients received a conditioning regimen of combined carmustine, etoposide, cytosine arabinoside, and melphalan. The prognostic impact of pretransplantation PET, sAA-IPI score, histology, and previous response to first-line chemotherapy was evaluated by univariate and multivariate analyses. RESULTS: Seventy-two of 75 patients underwent ASCT. In a univariate analysis for progression-free survival (PFS) and overall survival (OS), a significant association was observed with pretransplantation PET (PFS, P< .00001; OS, P< .01) and previous first-line response (PFS, P= .02; OS, P= .04). In the multivariate framework, pretransplantation PET was identified as the only independent prognostic factor (PFS, P< .001; OS, P= .01). CONCLUSIONS: The current data indicated that pretransplantation PET is the main prognostic predictor in patients with aggressive B-cell NHL who are scheduled for ASCT.