Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design approaches were explored. This metrics-based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.
e14062 Background: In certain clinical settings ICI have demonstrated unprecedented patterns of efficacy, resulting since 2011 in regulatory approvals worldwide in a variety of cancer indications. As immuno-oncology (IO) drugs constitute today an intense area of oncology drug development, we sought to analyze and compare the regulatory approval decisions for ICI, issued until end of 2018 by the US FDA and the European Medicines Agency (EMA). Methods: We reviewed the biological license applications (BLA) of the 7 (EU: 6) ICI, for which marketing approval decisions for were granted so far. Together with parallel and extension of indication applications, 43 (FDA) respectively 23 (EMA) approval procedures were finalized between March 2011 and December 2018. We analyzed agency decision outcomes and timeline patterns; approval decisions issued for novel non-IO cancer drugs served as benchmarks. The primary variable for analysis was median approval time (MAT). Results: MAT for initial BLA applications for ICI in the USA were with 189 days [Interquartile range (IQR) 154-209] shorter than MAT for BLA and NDA approvals for non-IO drugs: for the 51 novel oncology drugs approved 2011-2018 by the FDA, MAT was 227 days [IQR 159-303]. With 181 days [IQR 155-184], FDA’s MAT for ICI line extensions did not differ from MAT for initial ICI approvals. For the EU, MAT for initial ICI marketing applications were with 373 days (IQR 326-413) also shorter than MAT for the 51 non-IO drugs approved 2011-18 (422 days [IQR 368-450]); for ICI line extensions, MAT was 254 days [IQR 187-293). Conclusions: For ICI as for novel non-IO cancer drugs, initial regulatory approvals are usually issued in the USA first. Regulatory approval times for initial approvals are shorter in the USA, compared to Europe, the same applies for ICI extensions of indication. FDA’s extensive granting of breakthrough therapy designations (BTD) helped to bring US MAT for initial ICI BLA down to 6 months – i.e. to the same time, FDA requires for its priority review of extensions of indication. For some ICI extensions of indication, the granting of BTD supported approval decisions within 3 months, supporting patients’ rapid access to novel therapies.
Background
Chemotherapy, radiation and autologous bone marrow transplant are conventional standard therapies in Non-Hodgkin's lymphoma (NHL). Nowadays the introduction of monoclonal antibodies has enhanced the specificity of treatment, reducing the toxicity and presenting synergism with conventional chemotherapy.
Purpose
To compare rituximab efficacy and safety in combination with CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine and prednisone) in the treatment of NHL in our hospital, with that published in the literature.
Materials and methods
Retrospective observational study of 116 patients diagnosed with NHL who received chemotherapy with R-CHOP (rituximab-CHOP) between January 2005 and December 2010. The authors reviewed the medical history (100%) and the data were analysed using SPSS predictive analytics software. Were recorded: demographic data (age, sex); efficacy (complete response (CR), partial response (PR), overall response rate (ORR), progression and relapse, overall survival (OS) and event free survival (EFS)); toxicity (haematological and non-haematological).
Results
53.5% of patients were male and mean age at diagnosis was 59 years. The authors obtained an ORR of 80.2% (71.3% CR and 8.9% PR). 14.8% of patients did not respond, and 5% had an unknown response. The progression and relapse rates were 18.8% and 17.8% respectively. Projected median OS for responding patients was over 30 months and EFS after one year was 70.3%. Neutropenia, anaemia and thrombocytopenia rates were reported as 15.8%, 12.4% and 2.3% respectively. Infusion-related reactions were reported in 1.95% of patients, 72.2% during the first session. The detected rate of infection was relatively low, and 3.5% of all infections were microbiologically documented.
Conclusions
The results obtained were comparable to those of published studies in the literature for the treatment arm with R-CHOP in randomised patients (GELA NHL-95.5 study group, U.S. Intergroup Study, Mabthera International Trial MINT study). Neutropenia rates were higher than those found in the study of McLaughlin et al, while the other cell lines the results were similar.
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