The European Medicines Agency review of sacituzumab govitecan for the treatment of triple-negative breast cancer.

Sacituzumab govitecan (SG) is an antineoplastic agent which combines a humanized monoclonal antibody binding to trophoblast cell surface antigen-2 (Trop-2)-expressing cancer cells, linked with cytotoxic moiety SN-38 (govitecan) with topoisomerase I inhibitor action. On 22 November 2021, a marketing authorization valid through the European Union (EU) was issued under the European Medicines Agency (EMA)'s accelerated assessment program for SG as monotherapy for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, including at least one of them for advanced disease. The assessment was based on results from an open-label, randomized, phase III trial to evaluate the safety, tolerability, pharmacokinetics and efficacy of SG versus treatment of physician's choice (TPC) in patients with mTNBC who received at least two prior treatments including at least one of them for advanced disease. The efficacy results in the overall population, based on mature data, showed a statistically significant improvement of SG over TPC in progression-free survival (PFS) and overall survival (OS). The median PFS was 4.8 months versus 1.7 months [hazard ratio (HR) = 0.43, n = 529; 95% CI 0.35-0.54; P < 0.0001] and the median OS was 11.8 months versus 6.9 months (HR = 0.51, n = 529; 95% CI 0.41-0.62; P < 0.0001). The most common (>30%) side effects of SG were diarrhea, neutropenia, nausea, fatigue, alopecia, anemia, constipation and vomiting. The aim of this manuscript is to summarize the scientific review of the application leading to regulatory approval in the EU.

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.

On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit-risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

Genetic influence on natural cytotoxicity and interferon production in multiple sclerosis studies in monozygotic discordant twins.

A dysfunction in natural killer (NK) cell activity has been assumed to play a substantial role in the pathogenesis of multiple sclerosis (MS). To investigate whether such a defect is genetically determined and thus in combination with a certain HLA status may represent an additional risk factor for contracting MS, spontaneous and interferon (IFN) induced NK cells activity against the K562 target cell were analyzed in nine pairs of monozygotic twins discordant for MS. In addition, IFN production was tested in nonadherent lymphocytes stimulated with PHA, influenza virus or leukemia cells. When compared to healthy controls, NK function appeared to be normal in healthy twins, whereas some MS patient displayed decreased activity. No difference in IFN induced NK cell activity and IFN production could be detected between normal controls, healthy twins, and MS patients. These data argue against a genetically determined dysfunction within the NK-IFN system in patients with MS.

Multiple sclerosis: immunogenetic analyses of sib-pair double case families. II. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6, and GLO polymorphisms.

The complement component polymorphisms of C2, C4, BF, C3, C6, and the enzyme polymorphism GLO were studied in 13 sib-pair double case families with multiple sclerosis. A significant association was seen between MS patients and the C4 haplotype A4,B2 as compared with their healthy siblings. This finding seems to parallel reports on C2 hypocomplementemia in MS patients since C4 A4,B2 in normal individuals was also seen to be in linkage disequilibrium with the C2 deficiency allele (C2QO) by other investigators.

Transmission of multiple sclerosis by blood transfusion?

A survey of 14,000 multiple sclerosis patients revealed 289 blood donors; 65 of them had already shown clinical manifestations at the time of blood donation. In view of current immunological and virological hypotheses on multiple sclerosis, such patients should not be accepted as blood donors. An effort is being made to determine whether multiple sclerosis has been transmitted to the recipients of this blood.

Primate model for testing periodontal treatment procedures: I. Histologic investigation of localized periodontal pockets produced by orthodontic elastics.

Experimental periodontal lesions have been produced in Rhesus monkeys using orthodontic elastics. These lesions are characterized by an irreversible apical positioning of the junctional epithelium and both horizontal and angular bone loss. It was concluded that this lesion is suitable for testing the effect of periodontal treatment.

Effect of periodontal trauma upon intrabony pockets.

Conflicting results have been reported regarding the effect of periodontal trauma upon progression of periodontitis. In these studies, different initial pocket morphologies were present. This study investigated the effect of trauma superimposed upon existing intrabony pockets. Localized intrabony pockets were produced adjacent to the mesial and distal surfaces of the mandibular third bicuspids in 10 squirrel monkeys. Two animals were killed after 10 weeks of periodontitis. In four (experimental) of the remaining eight animals, mesio-distal jiggling of the third bicuspid was begun 10 weeks after induction of periodontitis, and continued for another 10 weeks. The other four animals (control) were killed 20 weeks after initiation of periodontitis. Step-serial histologic sections were selected from experimental and control specimens and analyzed for loss of connective tissue attachment, loss of crestal alveolar bone and percentage of bone in the coronal interproximal periodontium. When corresponding dimensions from experimental and control surfaces were compared statistically, there were no differences in loss of connective tissue attachment but a greater loss of bone had occurred in specimens with the combination of periodontitis and trauma. In addition, there was a marked difference in osseous morphology between the experimental and control specimens. It was concluded that trauma superimposed upon existing intrabony pockets increased loss of alveolar bone and altered osseous morphology, but did not affect the loss of connective tissue attachment.

The attachment between tooth and gingival tissues after periodic root planing and soft tissue curettage.

Utilizing a nonhuman primate model, a study was carried out to determine the nature of the attachment between the tooth and the gingival tissues following periodic root planing and soft tissue curettage. Under the conditions of this investigation, periodic root planing and soft tissue curettage combined with thrice weekly plaque control resulted in the formation of a long junctional epithelium with no new connective tissue attachment. In eight of the 22 experimental pockets, however, this procedure produced discontinuities or "windows" in the junctional epithelium. The coronal attachment of gingival tissues to the root surface (increased resistance to probing) commonly reported following root planing and soft tissue curettage appears to result from the formation of a long junctional epithelium rather than new connective tissue attachment.

Alveolar bone regeneration after removal of inflammatory and traumatic factors.

In this investigation periodontal destruction was produced by a combination of inflammatory and traumatic factors. After the inflammation was resolved and the trama stopped, a significant amount of alveolar bone regeneration took place. The implications of these findings for the management of advanced periodontal disease are discussed.

Conversion of chronic gingivitis to periodontitis in squirrel monkeys.

1. Acute exacerbation of gingivitis can lead to destructive periodontitis. 2. Such periods of acute inflammation may be associated with epithelial ulceration. 3. Bone loss in periodontal disease may occur in bursts of osteoclastic activity triggered by cells or factors generated during an acute phase. 4. Partial repair can follow an acute episode and a "stable lesion" may become re-established.

Interproximal and buccal cell populations apical to the sulcus before and during experimental periodontitis in squirrel monkeys.

The purpose of this investigation was to study inflammatory cell populations apical to the buccal and interproximal gingival sulcus during destructive experimental marginal periodontitis in squirrel monkeys. Specimens were obtained of the clinically healthy periodontium, and (after 2 and 10 weeks) of experimental periodontitis induced by the placement of plaque-retentive silk ligatures at the gingival margin. Cell populations were characterized and quantitated in a standard area of connective tissue immediately subjacent to the most apical cells of the junctional epithelium in buccal and interproximal locations. Comparisons of periodontitis cell populations showed there were no differences between the regions in relation to either total numbers of cells, or in the percentages of inflammatory cell types. The inflammatory cells consisted primarily of granulocytes and macrophages, with only small percentages of lymphoid and plasma cells. Mechanisms and consequences of these cell types relative to periodontal tissue destruction are discussed.

Cell populations in the transseptal fiber region before, during and after experimental periodontitis in squirrel monkeys.

A study was designed to enumerate cell populations before, during and after experimentally induced periodontitis in squirrel monkeys. The clinically healthy gingival connective tissue adjacent to the sulcus contained populations of macrophages, plasma cells, lymphoid cells, and granulocytes, indicating that immune responses were probably in operation. Although these cell populations have been associated with tissue destruction, it is possible that they may serve to confine the antigens to the tissue adjacent to the sulcus, and reduce their spread apically. Active periodontitis was associated with the presence of granulocytes and macrophages in the transseptal fiber region. These cells are capable of causing the localized collagen degradation and bone resorption that occur during the destructive phase of the disease. Eight weeks after etiologic agents were removed, the cell populations in the transseptal fiber area returned to a level comparable with those in the pre-experimental, clinically healthy. This indicates that active periodontitis within the transseptal fiber region had ceased and repair had occurred.