•Optimize the access of new innovative drugs to the Italian market.•Methodological tool for new drug’s priority status assessment partially based on that used by the AIFA.•An SPA has been carried out based on three dimensions: UMN, AB and QE. BackgroundWith the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones.Materials and methodsAfter a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA).ResultsBy applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate.ConclusionsThe use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments’ value in these contexts. Its generalizability in other national contexts needs further evaluation. With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments’ value in these contexts. Its generalizability in other national contexts needs further evaluation.
Endosonography is increasingly used for the diagnosis of centrally located, bronchoscopically invisible intrapulmonary lesions, but data regarding its utility for molecular profiling are lacking. We aimed to assess the suitability of endosonography samples obtained from intrapulmonary lesions for cancer genotyping and programmed-death ligand 1 (PD-L1) testing.A prospectively collected database regarding 99 consecutive patients undergoing endosonography for the diagnosis of an intrapulmonary lesion was retrospectively reviewed. Genotyping ± PD-L1 testing was carried out in the 53 patients with advanced lung cancer and was classified as complete if all clinically indicated tests could be performed, incomplete if at least one test could not be carried out, and unsuccessful if the sample was unsuitable for molecular analysis.All clinically indicated biomarkers could be tested in 44 (83%) patients, whereas the molecular profiling was classified as incomplete in 6 (11.3%), and unsuccessful in 3 (5.7%). Thirty-seven genetic alterations (KRAS mutation, 17; EGFR mutation, 17; ALK rearrangement, 3) and 2 cases of PD-L1 expression >50% were found in 31 (58%) patients. EGFR was successfully analysed in 94.1% of cases, KRAS in 93.9%, ALK in 89%, ROS1 in 90% and PD-L1 in 63.1%.Endosonography-derived samples from intrapulmonary lesions were suitable for a thorough molecular profiling in most patients. The few cases of incomplete accomplishment of the testing algorithm were related to the failure of PD-L1 analysis due to the exhaustion of the sample or the lack of sufficient tumour cells in the paraffin-embedded material.
ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it.The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo.2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment.The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.
Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19–56% and 9–51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.
Abstract Between August 1983 and December 1986, 116 previously untreated patients with squamous cell carcinoma of the head and neck were randomized to receive induction chemotherapy followed by radiotherapy given in conventional fractions (55 patients, arm A) or an alternating chemotherapy and radiotherapy (3 courses of 20 Gy, 10 daily fractions each; 61 patients, arm B). The same chemotherapy was used in both arms: 6 mg/m 2 vinblastine sulfate, hour 0; 30 mg bleomycin, hour 6; 200 mg methotrexate, hours 24 to 26; 45 mg leucovorin, hour 48. Forty‐five patients had stage III disease and 71 had stage IV disease. All patients were evaluated for survival, 112 for toxicity, and 105 for analyses of response and time from the start of treatment until progression of disease. At the end of the combined treatment, we observed an overall response rate of 52% in arm A and an overall response rate of 64.9% in arm B. The incidence of mucositis was more relevant in arm B compared to arm A ( P >.00004). The difference in complete response, progression‐free survival, and survival was statistically significant, with an advantage for arm B ( P >.03, P >.02, and P >.03, respectively). The analysis at a median follow‐up of 36 months (range = 19 to 59) demonstrates a higher effectiveness for the alternating program.
