Europe: Oncology CHMP Minutes for December 2022

Summary: Minutes from the EMA’s Committee for Medicinal Products for Human Use (CHMP) meeting on 12-15 December 2022 released on the 8^th of February 2023. Items of interest listed below:

Oral Explanations

Post-authorisation procedure oral explanations

Zejula (niraparib) - GlaxoSmithKline (Ireland) Limited (Orphan)

• Update of sections 4.4 and 4.8 of the SmPC in order to amend an existing warning and add MDS/AML to the list of adverse drug reactions (ADRs) with frequency common, and update of section 5.1 based on final results from NOVA study (213356); this is a Phase 3 randomized double-blind trial of maintenance with niraparib versus placebo in patients with platinum sensitive relapsed ovarian cancer. In addition, the MAH took this opportunity to update sections 4.4 and 4.6 to update information on contraception based on EMA and CTFG recommendations and to make minor editorial changes in the SmPC. The Package Leaflet is updated accordingly. The RMP version 6.0 is approved.
• Request for Supplementary Information adopted on 19.05.2022, 10.02.2022.
• The CHMP agreed that an oral explanation was not needed at this time.

Initial applications

Initial applications; Opinions

Imjudo (tremelimumab) - AstraZeneca AB

• Indication: For use in combination with durvalumab for the treatment of adults with unresectable hepatocellular carcinoma.
• The Committee confirmed that all issues previously identified in this application had been and adopted a positive opinion recommending the granting of a marketing authorisation by consensus together with the CHMP assessment report and translation timetable.
• Furthermore, the CHMP considered that tremelimumab is a new active substance, as claimed by the applicant.
• The legal status was agreed as medicinal product subject to restricted medical prescription.

Tremelimumab AstraZeneca (tremelimumab) - AstraZeneca AB

• Indication: treatment of adults with metastatic NSCLC with no sensitising epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations.
• The Committee confirmed that all issues previously identified in this application had been addressed and adopted a positive opinion recommending the granting of a marketing authorisation by consensus together with the CHMP assessment report and translation timetable.
• Furthermore, the CHMP considered that tremelimumab is a new active substance, as claimed by the applicant.
• The legal status was agreed as medicinal product subject to restricted medical prescription.

Initial applications; List of outstanding issues (Day 180; Day 120 for procedures with accelerated assessment timetable)

Niraparib / Abiraterone acetate

• Indication: treatment of adult patients with prostate cancer
• The Committee was reminded of the status of this application and its remaining outstanding and adopted a list of outstanding issues with a specific timetable.

Trastuzumab

• Indication: treatment of metastatic and early breast cancer and metastatic gastric cancer (MGC)
• The Committee was reminded of the status of this application and its remaining outstanding issues and adopted a list of outstanding issues.
• The CHMP agreed to the request by the applicant for an extension to the clock stop to respond to the list of outstanding issues with a specific timetable.

Ivosidenib - Les Laboratoires Servier (Orphan)

• Indication: treatment of acute myeloid leukaemia and treatment of metastatic cholangiocarcinoma
• The Committee was reminded of the status of this application and its remaining outstanding issues.
• The Committee adopted a list of outstanding issues with a specific timetable.

Ivosidenib - Les Laboratoires Servier (Orphan)

• Indication: treatment of acute myeloid leukaemia
• The Committee was reminded of the status of this application and its remaining outstanding issues.
• The Committee adopted a list of outstanding issues with a specific timetable.

Initial applications; List of questions (Day 120; Day 90 for procedures with accelerated assessment timetable)

Decitabine / cedazuridine - Otsuka Pharmaceutical Netherlands B.V (Orphan)

• Indication: treatment of myeloid leukaemia
• The Committee discussed the issues identified in this application.
• The Committee adopted the CHMP recommendation and scientific discussion together with the list of questions.

Elacestrant

• Indication: treatment of postmenopausal woman and men with breast cancer
• The Committee discussed the issues identified in this application.
• The Committee adopted the CHMP recommendation and scientific discussion together with the list of questions.

Quizartinib - Daiichi Sankyo Europe GmbH (Orphan)

• Indication: Treatment of adult patients with diagnosed acute myeloid leukaemia (AML)
• The Committee discussed the issues identified in this application.
• The Committee adopted the CHMP recommendation and scientific discussion together with the list of questions.

Trastuzumab duocarmazine

• Indication: treatment of HER2 (Human Epidermal Growth Factor Receptor 2)-positive metastatic breast cancer
• The CHMP agreed to the request by the applicant for an extension to the clock stop to respond to the list of questions adopted in November 2022.

Extension of marketing authorisation

Extension of marketing authorization; Opinion

Calquence (acalabrutinib) - AstraZeneca AB

• Extension application to introduce a new pharmaceutical form, film-coated tablet. A.6 - To change the ATC Code of acalabrutinib from L01XE51 to L01EL02.
• The Committee confirmed that all issues previously identified in this application had been addressed. And adopted a positive opinion by consensus together with the CHMP Assessment Report and translation timetable.

Type II variations - variation of therapeutic indication

Type II variations - variation of therapeutic indication procedure; Opinions or Requests for supplementary information

Enhertu (trastuzumab deruxtecan) - Daiichi Sankyo Europe GmbH

• Extension of indication to include treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy; for Enhertu, based on final results from study DS8201-A-U303 (DESTINY-Breast04). This is a Phase III, multicentre, randomised, open-label, active-controlled trial of Trastuzumab Deruxtecan (T-DXd), an Anti-HER2-antibody Drug Conjugate (ADC), versus treatment of physician’s choice for HER2-low, unresectable and/or metastatic breast cancer subjects. As a consequence, sections 4.1, 4.2, 4.4, 4.8, 5.1 and 5.2 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 4.0 of the RMP has also been submitted. In addition, the marketing authorisation holder (MAH) took the opportunity to update section 4.4 of the SmPC to update the dosing recommendation for corticosteroid treatment (e.g. prednisolone) with a daily dose.
• The Committee confirmed that all issues previously identified in this application had been addressed and adopted a positive opinion by consensus together with the CHMP Assessment Report and translation timetable.

Imfinzi (durvalumab) -AstraZeneca AB

• Extension of indication to include first-line treatment, with Imfinzi in combination with tremelimumab and platinum-based chemotherapy, of adults with metastatic NSCLC with no sensitising epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) positive mutations, based on final results from study D419MC00004 (POSEIDON); This was a Phase III, randomised, multicentre, open-label, comparative global study to determine the efficacy and safety of tremelimumab and durvalumab or durvalumab in combination with platinum based chemotherapy for first-line treatment in patients with metastatic NSCLC. As a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8, 5.1 and 5.2 of the SmPC are updated. The Package Leaflet is updated in accordance. In addition, the marketing authorisation holder (MAH) took the opportunity to update the list of local representatives in the Package Leaflet. Furthermore, the PI is brought in line with the latest QRD template version 10.2. Version 8.1 of the RMP has also been submitted. The variation leads to amendments to the Summary of Product Characteristics and Package Leaflet and to the Risk Management Plan (RMP).
• The Committee confirmed that all issues previously identified in this application had been addressed and adopted a positive opinion by consensus together with the CHMP Assessment Report and translation timetable.

Imfinzi (durvalumab) - AstraZeneca AB

• Extension of indication to include Imfinzi in combination with tremelimumab for the first-line treatment of adults with advanced or unresectable hepatocellular carcinoma (uHCC), based on final results from study D419CC00002 (HIMALAYA); This was a randomized, open-label, multi-center phase III study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma. As a consequence, sections 4.1, 4.2, 4.4, 4.8, 5.1 and 5.2 of the SmPC are updated. The Package Leaflet is updated in accordance. In addition, the MAH took the opportunity to implement minor editorial changes in the SmPC and Package Leaflet. Version 68.1 of the RMP has also been submitted. The variation leads to amendments to the Summary of Product Characteristics and Package Leaflet and to the Risk Management Plan (RMP).
• The Committee confirmed that all issues previously identified in this application had been addressed and adopted a positive opinion by consensus together with the CHMP Assessment Report and translation timetable.

Libtayo (cemiplimab) - Regeneron Ireland Designated Activity Company (DAC)

• Extension of indication to include Libtayo in combination with platinum‐based chemotherapy for the first-line treatment of adult patients with locally advanced NSCLC who are not candidates for definitive chemoradiation or metastatic NSCLC with no EGFR, ALK or ROS1 aberrations; as a consequence, sections 4.1, 4.4, 4.8 and 5.1 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 4.0 of the RMP has also been submitted.
• The Committee discussed the issues identified in this application, relating to clinical aspects and adopted a 3rd request for supplementary information and agreed to the request by the applicant for an extension to the clock-stop with a specific timetable.

Nubeqa (darolutamide) - Bayer AG

• Extension of indication to include treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel, based on final results from study 17777 (ARASENS); this is a randomized, double-blind, placebo-controlled Phase 3 study designed to demonstrate the superiority of darolutamide in combination with docetaxel over placebo in combination with docetaxel in OS in patients with mHSPC. As a consequence, sections 4.1, 4.2, 4.5, 4.8 and 5.1 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 2.1 of the RMP has also been submitted. As part of the application, the MAH is also requesting one additional year of market protection; Request for 1 year of market protection for a new indication
• The Committee discussed the issues identified in this application, relating to non-clinical and clinical aspects and adopted a 3rd request for supplementary information with a specific timetable.

Opdivo (nivolumab) - Bristol-Myers Squibb Pharma EEIG

• Extension of indication to include adolescent patients aged 12 years and older in treatment of advanced (unresectable or metastatic) melanoma (nivolumab monotherapy), treatment of advanced (unresectable or metastatic) melanoma (nivolumab in combination with ipilimumab) and adjuvant treatment of melanoma (nivolumab monotherapy) for Opdivo, based on results from a nonclinical biomarker study (Expression of PD-L1 (CD274), and characterisation of tumour infiltrating immune cells in tumours of paediatric origin), also based on results from a Phase 1/2 clinical study (CA209070, A Phase 1/2 Study of Nivolumab (Ind# 124729) In Children, Adolescents, And Young Adults With Recurrent Or Refractory Solid Tumors As A Single Agent And In Combination With Ipilimumab) and a modelling and simulation study. As a consequence, sections 4.1, 4.2, 4.8, 5.1, 5.2 and 6.6 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 30.0 of the RMP has also been submitted.
• The Committee discussed the issues identified in this application, relating to clinical aspects as well as the RMP and adopted a request for supplementary information with a specific timetable.

Rubraca (rucaparib) - Clovis Oncology Ireland Limited

• Extension of indication to include maintenance treatment of adult patients with advanced (FIGO Stages III and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to first-line platinum-based chemotherapy for Rubraca, based on interim results from study CO-338-087 (ATHENA); this is a Phase III, randomized, double-blind, dual placebo controlled study of rucaparib as monotherapy and in combination with nivolumab in patients with newly diagnosed EOC, FTC or PPC who have responded to their first-line treatment (surgery and platinum-based chemotherapy). As a consequence, sections 4.1, 4.2, 4.4, 4.8 and 5.1 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 6.3 of the RMP has also been submitted. As part of the application the MAH is requesting a 1 year extension of the market protection; Request for 1 year of market protection for a new indication.
• The Committee discussed the issues identified in this application, relating to clinical aspects and the request for 1 year of market protection and adopted a request for supplementary information with a specific timetable.

Yervoy (ipilimumab) - Bristol-Myers Squibb Pharma EEIG

• Extension of indication to include in combination with nivolumab the treatment of adolescents (12 years of age and older) for advanced (unresectable or metastatic) melanoma, based on the pivotal study CA209070; this is a multicentre, open-label, single arm, phase 1/2 trial of nivolumab +/- ipilimumab in children, adolescents and young adults with recurrent or refractory solid tumours or lymphomas. As a consequence, sections 4.1, 4.2, 4.8, 5.1 and 5.2 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 38.0 of the RMP has also been submitted.
• The Committee discussed the issues identified in this application, relating to clinical aspects as well as the RMP and adopted a request for supplementary information with a specific timetable.

Pre-submission issues

Pre-submission issue

Elranatamab - Pfizer Europe MA EEIG (Orphan)

• Indication: Multiple Myeloma. Indicated as monotherapy for the treatment of relapsed or refractory multiple myeloma in adult patients who have received at least 3 prior therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD-38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
• The CHMP did not agree to the request for accelerated assessment and adopted the briefing note and Rapporteurs’ recommendation on the Request for Accelerated Assessment.

Post-authorisation issues

Post-authorisation issues

Rubraca (rucaparib) - Clovis Oncology Ireland Limited

• Update of sections 4.8 and 5.1 of the SmPC in order to update the efficacy and safety information and the list of adverse drug reactions (ADRs) based on the final results from study CO-338-014 (ARIEL 3) listed as a category 1 PAES in the Annex II; this is a phase 3, multicenter, randomized, double-blind, placebo-controlled study of rucaparib as switch maintenance following platinum-based chemotherapy in patients with platinum-sensitive, high grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube cancer. The Package Leaflet is updated accordingly. The RMP version 6.4 has also been submitted. In addition, the MAH took the opportunity to introduce minor editorial changes to the PI.
• The Committee discussed the issues identified in this application, relating to clinical aspects and adopted a request for supplementary information with a specific timetable.

Zejula (niraparib) - GlaxoSmithKline (Ireland) Limited (Orphan)

• Update of sections 4.4 and 4.8 of the SmPC in order to amend an existing warning and add MDS/AML to the list of adverse drug reactions (ADRs) with frequency common, and update of section 5.1 based on final results from NOVA study (213356); this is a Phase 3 randomized double-blind trial of maintenance with niraparib versus placebo in patients with platinum sensitive relapsed ovarian cancer. In addition, the MAH took this opportunity to update sections 4.4 and 4.6 to update information on contraception based on EMA and CTFG recommendations and to make minor editorial changes in the SmPC. The Package Leaflet is updated accordingly. The RMP version 6.0 is approved.
• The Committee confirmed that all issues previously identified in this application had been addressed and adopted a positive opinion by consensus together with the CHMP Assessment Report and translation timetable.

Imbruvica (ibrutinib) - Janssen-Cilag International N.V.

• Extension of indication to include treatment with IMBRUVICA in combination with bendamustine and rituximab (BR) of adult patients with previously untreated mantle cell lymphoma (MCL) who are unsuitable for autologous stem cell transplantation, based on final results from the category 3 Study PCI-32765MCL3002 (SHINE); this is a randomized, double-blind, placebo-controlled phase 3 study of ibrutinib in combination with BR in subjects with newly diagnosed MCL. As a consequence, sections 4.1, 4.2, 4.8 and 5.1 of the SmPC are updated. The Package Leaflet is updated in accordance. Version 19.1 of the RMP has also been submitted.
• The CHMP noted the withdrawal of the extension of indication application.

ANNEX

RENEWALS OF MARKETING AUTHORISATIONS OUTCOMES

Carmustine Obvius (carmustine) Obvius Investment B.V (Generic)

• Request for supplementary information adopted with a specific timetable.

KANJINTI (trastuzumab) - Amgen Europe B.V., BREDA

• Positive opinion adopted by consensus together with the CHMP assessment report and translation timetable.
• Based on the review of the available information, the CHMP was of the opinion that the renewal of the marketing authorisation can be granted with unlimited validity.

Pemetrexed Krka (pemetrexed) KRKA, d.d., Novo mesto (Generic; Generic of Alimta)

• Positive opinion adopted by consensus together with the CHMP assessment report and translation timetable.
• Based on the review of the available information, the CHMP was of the opinion that the renewal of the marketing authorisation can be granted with unlimited validity.

JEMPERLI (dostarlimab) GlaxoSmithKline (Ireland)

• Positive opinion adopted by consensus together with the CHMP assessment report.
• The CHMP was of the opinion that the renewal for this conditional Marketing Authorisation can be granted. The Marketing Authorisation remains conditional.

POST-AUTHORISATION PHARMACOVIGILANCE OUTCOMES

Atezolizumab

Tecentriq (atezolizumab) - Roche Registration GmbH

• The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004, the PSUR on the basis of the PRAC recommendation the PRAC assessment report as appended,recommends by consensus the variation to the terms of the marketing authorisation for the above-mentioned medicinal product, concerning the following change: Update of sections 4.2, 4.4 and 4.8 of the SmPC to include haemophagocytic lymphohistiocytosis (HLH) with a frequency “Rare”. The package leaflet is updated accordingly.

Tucatinib

TUKYSA (tucatinib) - Seagen B.V

• The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended, recommends by consensus, the variation to the terms of the marketing authorisation(s) for the above-mentioned medicinal product(s), concerning the following change(s): Update of section 4.4 of the SmPC to add a warning/precaution regarding grade ≥2 nausea and/or vomiting. The package leaflet is updated accordingly. In addition, the MAH took the to make minor changes in the product information for clarity.

Pemigatinib

Pemazyre (pemigatinib)

• The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended, recommends by consensus, the variation to the terms of the marketing authorisation(s) for the above mentioned medicinal product(s), concerning the following change(s): Update of section 4.4 of the SmPC to add the adverse reaction non-uraemic calciphylaxis as possible outcome regarding (untreated) hyperphosphatemia.

Zanubrutinib

Brukinsa (zanubrutinib) BeiGene Ireland Ltd

• The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended recommends by consensus the variation to the terms of the marketing authorisation(s) for the above mentioned medicinal product(s), concerning the following change(s): Updates of section 4.8 of the SmPC to add the adverse reactions dermatitis exfoliative generalised with frequency unknown and febrile neutropenia with frequency common. The package leaflet is updated accordingly.

Ripretinib

QINLOCK (ripretinib) - Deciphera Pharmaceuticals (Netherlands) B.V.

• The CHMP, having considered in accordance with Article 28 of Regulation (EC) No 726/2004 the PSUR on the basis of the PRAC recommendation and the PRAC assessment report as appended recommends by consensus the variation to the terms of the marketing authorisation(s) for the above-mentioned medicinal product(s), concerning the following change(s): Update of section 4.4 of the SmPC to amend a warning regarding skin cancer to include malignant melanoma. Update of section 4.8 of the SmPC to amend existing information on malignant melanoma to be in line with the available data. The package leaflet is already updated accordingly.

CHMP assessed procedures scope: Pharmaceutical aspects

Armisarte (pemetrexed) - Actavis Group PTC ehf

• Request for supplementary information adopted with a specific timetable.

Bavencio (avelumab) - Merck Europe B.V

• Positive opinion adopted by consensus on 17.11.2022.

Caelyx pegylated liposomal (doxorubicin) - Baxter Holding B.V

• Positive opinion adopted by consensus on 15.12.2022.

Padcev (enfortumab vedotin) - Astellas Pharma Europe B.V

• Request for supplementary information adopted with a specific timetable.

SARCLISA (isatuximab) - sanofi-aventis groupe

• Positive opinion adopted by consensus on 15.12.2022.

Spectrila (asparaginase) - medac Gesellschaft fur klinische Spezialpraparate mbH

• Positive opinion adopted by consensus on 08.12.2022

Zaltrap (aflibercept) Sanofi Winthrop Industrie

• Positive opinion adopted by consensus on 15.12.2022.

Zercepac (trastuzumab) - Accord Healthcare S.L.U

• Positive opinion adopted by consensus on 24.11.2022.

Zercepac (trastuzumab) Accord Healthcare S.L.U., Rapporteur: Sol Ruiz

• Request for Supplementary Information adopted on 01.12.2022.

CHMP assessed procedures scope: Non-Clinical and Clinical aspects

Calquence (acalabrutinib) - AstraZeneca AB

• Update of section 5.1 of the SmPC based on the interim report of study ACE-CL-007; a randomized, multicenter, open-Label, 3-arm phase 3 study of obinutuzumab in combination with chlorambucil, ACP-196 in combination with obinutuzumab, and ACP-196 monotherapy in subjects with previously untreated chronic lymphocytic leukaemia.
• Request for supplementary information adopted with a specific timetable.

Cotellic (cobimetinib) - Roche Registration GmbH

• Update of section 4.8 of the SmPC in order to add ”Pruritus”, “Dry skin” and “Oedema peripheral” to the list of adverse drug reactions (ADRs) with frequency “Very common” based on post-marketing experience and the final results from study ML29733; this is an Open-label, single-center, Phase II study evaluating the efficacy and safety of singleagent cobimetinib in patients with histiocytic disorders whose tumours were 1) BRAF V600 wildtype or 2) BRAF V600E mutant and were intolerant to, or unable to access, BRAF inhibitors. The Package Leaflet is updated accordingly.
• Positive opinion adopted by consensus on 24.11.2022.

Imfinzi (durvalumab) - AstraZeneca AB

• Update of section 4.2 of the SmPC in order to update the recommendation for dose modification for ‘other immune-mediated adverse reactions’ as well as immune-mediated encephalitis, meningitis, Guillain-Barré syndrome and myasthenia gravis based on the National Comprehensive Cancer Network (NCCN) guideline recommendations (2022).
• Positive opinion adopted by consensus on 15.12.2022.

Lysodren (mitotane) - HRA Pharma Rare Diseases

• Update of section 4.8 of the SmPC with new safety information regarding hypersensitivity reactions and oestrogenic-like effects based on post-marketing safety report and literature. The Package Leaflet is updated accordingly.
• Positive opinion adopted by consensus on 01.12.2022.

Myocet liposomal (doxorubicin hydrochloride) - Teva B.V

• Update of section 4.6 of the SmPC, upon request by PRAC following the assessment of to align the wording with the published CHMP SWPadvice on the duration of contraception in female patients after cessation of treatment genotoxic drug. The Package Leaflet has been updated accordingly.
• Positive opinion adopted by consensus on 15.12.2022.

SARCLISA (isatuximab) - sanofi-aventis groupe

• I.4: Update of sections 4.5, 5.1 and 5.2 of the SmPC in order to update the efficacy and pharmacokinetic data based on final progression-free survival (PFS) efficacy results from IKEMA study (EFC15246) and to introduce the Sebia Hydrashift assay, a validated assay to determine the complete response rate. IKEMA study (EFC15246) is a phase 3 randomized, open label, multicenter study assessing the clinical benefit of isatuximab combined with carfilzomib (Kyprolis) and dexamethasone versus carfilzomib with dexamethasone in patients with relapsed and/or refractory multiple myeloma previously treated with 1 to 3 prior lines. A.6: Update of section 5.1 of the SmPC in order to update the ATC code following amendment by WHO.
• Positive opinion adopted by consensus on 15.12.2022.

Tabrecta (capmatinib) - Novartis Europharm Limited

• Update of section 4.8 of the SmPC in order to add hypersensitivity to the list of adverse drug reactions (ADRs) with frequency uncommon, based on cumulative assessment of hypersensitivity cases in studies CINC280A2201, CINC280X1101, CINC280X2102, CINC280A2108, CINC280A2103 (post-DDI phase only), and CINC280A2105 (post-DDI phase only) and MAH global safety database. The Package Leaflet is updated accordingly.
• Positive opinion adopted by consensus on 01.12.2022.

Taxotere (docetaxel) - Sanofi Mature IP

• Update of sections 4.4, 4.6 and 5.3 of the SmPC to include further information regarding genotoxicity, pregnancy/lactation exposure with associated adverse outcomes and recommendations regarding use of contraception, and update of section 5.2 of the SmPC regarding the pharmacokinetic terminal elimination half-life (t1/2). The Package Leaflet is updated accordingly.
• Positive opinion adopted by consensus on 15.12.2022.

CHMP-PRAC assessed procedures

JEMPERLI (dostarlimab) - GlaxoSmithKline (Ireland) Limited

• Update of section 5.1 of the SmPC in order to update efficacy and safety information based on interim results from study 4010-01-001 (GARNET) listed as a specific obligation (SOB) in the Annex II; This is a single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumours. Update of Annex II to remove the specific obligation. In addition, the MAH took the opportunity to update Annex II in line with the QRD template version 10.3. The RMP version 2.1 is approved.
• Positive opinion adopted by consensus on 15.12.2022.

NUBEQA (darolutamide) - Bayer AG

• Submission of the final report of carcinogenicity study T104877-7 listed as a category 3 study in the RMP. This is a non-clinical study to assess the carcinogenic potential in mice. The study evaluates the effects of daily oral administration of darolutamide for a period of 6 months in tgrasH2 transgenic mouse model. The updated RMP version 3.1 has also been submitted.
• Request for supplementary information adopted with a specific timetable.

Rubraca (rucaparib) - Clovis Oncology Ireland Limited

• Update of sections 4.8 and 5.1 of the SmPC in order to update the efficacy and safety information and the list of adverse drug reactions (ADRs) based on the final results from study CO-338-014 (ARIEL 3) listed as a category 1 PAES in the Annex II; this is a phase 3, multicenter, randomized, double-blind, placebo-controlled study of rucaparib as switch maintenance following platinum-based chemotherapy in patients with platinumsensitive, high grade serous or endometrioid epithelial ovarian, primary peritoneal orfallopian tube cancer. The Package Leaflet is updated accordingly. The RMP version 6.4 has also been submitted. In addition, the MAH took the opportunity to introduce minor editorial changes to the PI.
• Request for supplementary information adopted with a specific timetable.

PRAC assessed procedures

Neulasta (pegfilgrastim) - Amgen Europe B.V.

• Submission of the final report from PASS study 20170701 listed as a category 3 study in the RMP. This is a cross-sectional survey study to Assess the Effectiveness of the Neulasta Patient Alert Card and to Measure Medication Errors Related to the Use of the Neulasta On-Body Injector. The RMP version 9.0 has also been submitted.
• Request for supplementary information adopted with a specific timetable.

CHMP-CAT assessed procedures

Breyanzi (lisocabtagene maraleucel / lisocabtagene maraleucel) - Bristol-Myers Squibb Pharma EEIG (ATMP)

• Positive opinion adopted by consensus on 15.12.2022.

Breyanzi (lisocabtagene maraleucel / lisocabtagene maraleucel) - Bristol-Myers Squibb Pharma EEIG

• Request for supplementary information adopted with a specific timetable.

Breyanzi (lisocabtagene maraleucel / lisocabtagene maraleucel) - Bristol-Myers Squibb Pharma EEIG (ATMP)

• Request for supplementary information adopted with a specific timetable.

CHMP-PRAC-CAT assessed procedures

CARVYKTI (ciltacabtagene autoleucel) -Janssen-Cilag International NV (ATMP) (Orphan)

• Update of sections 4.4 and 4.8 of the SmPC in order to update the existing warnings on cytokine release syndrome (CRS), neurologic toxicities and grading of related events and to update the list of adverse drug reactions (ADRs) based on previously reviewed data from studies MMY2001 and MMY2003, and an additional internal characterisation of neurotoxicity risk; the Package Leaflet is updated accordingly. The RMP version 2.1 has also been submitted. In addition, the MAH took the opportunity to introduce minor editorial changes to the PI.
• Positive opinion adopted by consensus on 15.12.2022.

CARVYKTI (ciltacabtagene autoleucel) - Janssen-Cilag International NV (ATMP) (Orphan)

• Grouped application comprising two type II variations as follows: - Update of section 4.4 of the SmPC in order to add a new warning on increased risk of severe/fatal COVID-19 infections following COVID-19 signal evaluation from the ongoing study 68284528MMY3002 (CARTITUDE-4) based on a cumulative review of all clinical trials, registries and literature. - Update of section 4.4 of the SmPC in order to add a new warning Risk of severe bleeding in the context of hemophagocytic lymphohistiocytosis syndrome (HLH) following a signal evaluation from the ongoing study 68284528MMY3002 (CARTITUDE-4) based on cumulative review of all clinical trials, registries and literature. The Package Leaflet is updated accordingly. The RMP version 2.2 has also been submitted.
• Positive opinion adopted by consensus on 15.12.2022.

PRAC assessed ATMP procedures

Imlygic (talimogene laherparepvec) - Amgen Europe B.V (ATMP)

• Submission of the final report from study 20120139 listed as a category 3 study in the RMP in order to fulfil MEA/004. This is a multicenter, observational registry study to evaluate the survival and long-term safety of subjects who previously received talimogene laherparepvec in Amgen or BioVEX sponsored clinical trials.
• Positive opinion adopted by consensus on 15.12.2022.

Unclassified procedures and worksharing procedures of type I variations

Blitzima, Truxima - Celltrion Healthcare Hungary Kft

• Positive opinion adopted by consensus on 24.11.2022

Herceptin, MabThera - Roche Registration GmbH

• Positive opinion adopted by consensus on 15.12.2022.

START OF THE PROCEDURES

Aumolertinib

• Indication: treatment of adult patients with locally advanced or metastatic non-small cell lung cancer

Toripalimab

• Indication: Combination treatment for metastatic or recurrent locally advanced nasopharyngeal carcinoma and for metastatic or recurrent oesophageal squamous cell carcinoma

Erleada (apalutamide) - Janssen-Cilag International N.V

• Extension application to add a new strength (240 mg) film-coated tablets grouped with the IB variation (C.I.z). The RMP (version 6.1) has also been submitted. C.I.z (IB): to align the SmPC/PL for Erleada 60 mg with the SmPC/PL proposed for the registration of the new Erleada film-coated tablet strength, 240 mg. The PL for Erleada 60 mg is proposed to be updated to ensure consistency. In addition, few minor revisions are proposed to the SmPC for Erleada 60 mg, to align the SmPC proposed for the 240 mg strength: - SmPC sections 5.1 and 5.2 Orthographic corrections - SmPC section 6.5: Further details on the description of the current packaging have been added, this change does not result from a change to the container. - SmPC section 6.6: The title of the section has been aligned with the QRD template.

Tecentriq (atezolizumab) - Roche Registration GmbH

• Extension application to introduce a new pharmaceutical form (solution for injection) associated with a new strength (1875 mg) and new route of administration (subcutaneous use). The RMP (version 24.0) is updated in accordance.

Renewals of Marketing Authorisations

Braftovi (encorafenib) - Pierre Fabre Medicament

Imfinzi (durvalumab) - AstraZeneca AB

Kymriah (tisagenlecleucel) - Novartis Europharm Limited (ATMP) (Orphan)

Lorviqua (lorlatinib) - Pfizer Europe MA EEIG

Mektovi (binimetinib) - Pierre Fabre Medicament

Yescarta (axicabtagene ciloleucel) - Kite Pharma EU B.V (Orphan) (ATMP)

VARIATIONS – START OF THE PROCEDURE

Aybintio (bevacizumab) - Samsung Bioepis NL B.V

Oyavas (bevacizumab) - STADA Arzneimittel AG (Duplicate; Duplicate of Alymsys)

Padcev (enfortumab vedotin) - Astellas Pharma Europe B.V

Tabrecta (capmatinib) - Novartis Europharm Limited

Zercepac (trastuzumab) - Accord Healthcare S.L.U.

CHMP assessed procedures scope: Non-Clinical and Clinical aspects

Imfinzi (durvalumab) - AstraZeneca AB

• Submission of the final report from non-clinical study ONC4736-PB-0401 (Profiling of Biomarkers Relevant to Immunotherapies in Paediatric Solid Tumours).

IBRANCE (palbociclib) - Pfizer Europe MA EEIG

• Update of section 5.1 of the SmPC in order to update efficacy and safety information based on final OS results from study A5481008 (PALOMA-2, “A Randomized, Multicenter, Double-blind Phase 3 Study of PD- 0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women with ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For Advanced Disease”) to fulfil REC 2. In addition, the MAH took the opportunity to align Annex II with the current QRD template.

Keytruda (pembrolizumab) - Merck Sharp & Dohme B.V.

• Update of section 5.1 of the SmPC in order to update information based on the final OS data for the overall population as well as for MMR subgroups from study 309/KEYNOTE-775 in order to fulfil the Recommendation: REC/033. This recommendation was agreed with the approval of study 309/KEYNOTE-775; this is a multicenter, open-label, randomized, phase 3 trial to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in with advanced endometrial cancer.

Kisplyx (lenvatinib) - Eisai GmbH

• Submission of the latest Modelling and Simulation related data (such as PopPK and PK/PD Analyses) following the assessment of procedure II/52 to fulfil MEA/FSR 008.1, MEA/FSR 007.3 and MEA/FSR 013.2.

Lenvima (lenvatinib) - Eisai GmbH

• Update of section 5.1 of the SmPC in order to update the efficacy information of "Endometrial carcinoma" based on the final OS analysis data for the overall population as well as for MMR subgroups from study E7080-G000- 309 / KEYNOTE-775. This is a Multicenter, Open-label, Randomized, Phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician’s choice in participants with advanced endometrial cancer. In addition, the MAH took the opportunity to implement editorial changes in the SmPC.

Lynparza (olaparib)- AstraZeneca AB

• Update of sections 4.8 and 5.1 of the SmPC in order to update the long-term safety data and the final OS analysis from the PAOLA-1 study (D0817C00003). This is a Randomized, Double- Blind, Phase III Trial of Olaparib vs. Placebo in Patients with Advanced FIGO Stage IIIB – IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer Treated with Standard First Line Treatment, Combining Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy and in Maintenance. The Package Leaflet is updated accordingly.

Lynparza (olaparib) - AstraZeneca AB

• Update of section 5.1 of the SmPC in order to provide the Final Overall Survival (OS) Analysis from study D0816C00020 (OPINION). This is a Phase IIIb single-arm, open-label, multicentre study of maintenance therapy in PSR nongermline BRCA mutated ovarian cancer patients who are in complete or partial response following platinum-based chemotherapy.

Nexpovio (selinexor) - Stemline Therapeutics B.V

• Update of section 4.5 of the SmPC in order to add drug-drug interaction information regarding the strong CYP3A4 inhibitor, clarithromycin, based on results from the drug-drug interaction (DDI) pharmacokinetic (PK) portion of study KCP 330- 017 (STOMP) following procedure EMEA/H/C/005127/REC/003.1. This is a Phase 1b/2, multi-center, open-label, clinical study with Dose Escalation (Phase 1) and Expansion (Phase 2) to independently assess the MTD, efficacy, and safety of 10 combination therapies in 11 arms in patients with RRMM (Relapsed/Refractory Multiple Myeloma) and NDMM (Newly Diagnosed Multiple Myeloma).

Orgovyx (relugolix) - Accord Healthcare S.L.U

• Submission of the bioanalytical report of testosterone.

Orgovyx (relugolix) - Accord Healthcare S.L.U

• Submission of the final report from study MVT-601-055; this is an open-label, fixed (single)-sequence crossover phase 1 study to assess the sufficiency of dose separation to mitigate absorption-mediated increases in exposure to relugolix resulting from inhibition of intestinal P-gp by azithromycin in healthy adult men.

Orgovyx (relugolix) - Accord Healthcare S.L.U

• Submission of the final report from study MVT-601-057. This is a Phase I, two-part, open-label, fixed (single)-sequence, two-treatment, two-period crossover study to assess the effects of relugolix on the pharmacokinetics of total dabigatran upon coadministration of relugolix and the P-gp substrate dabigatran etexilate in healthy adult men and women.

Piqray (alpelisib) - Novartis Europharm Limited

• Update of section 5.3 of the SmPC in order to update non-clinical information based on data from two skin toxicology studies conducted in rats: study 1770766 and study 1870156.

Revlimid (lenalidomide) - Bristol-Myers Squibb Pharma EEIG

• Update of section 5.1 of the SmPC in order to update 5-year Overall Survival data following the assessment of procedure II/107 based on study CC-5013-NHL-007, A Phase 3, Double-Blind Randomized Study To Compare The Efficacy And Safety Of Rituximab Plus Lenalidomide (Cc-5013) Versus Rituximab Plus Placebo In Subjects With Relapsed/Refractory Indolent Lymphoma.

Spectrila (asparaginase) - medac Gesellschaft fur klinische Spezialpraparate mbH

• Grouped Variation (Type II & Type IB): C.I.4: Update of sections 4.4 and 4.6 of the SmPC in order to include the recommendations from the SWP regarding genotoxic medicinal products and contraception duration period; the Package Leaflet is updated accordingly. In addition, the MAH took the opportunity to introduce minor editorial changes to the PI. C.I.6.b: Deletion of the indication lymphoblastic lymphoma (LBL) in section 5.3 of the SmPC, as Spectrila is not approved for LBL.

TEPMETKO (tepotinib) - Merck Europe B.V.

• Update of sections 4.5 and 5.2 of the SmPC in order to remove interactions with ‘CYP and P-gp inducers’ and ‘dual strong CYP3A and P-gp inhibitors, and P-gp inhibitors’ and to update pharmacokinetic information based on final results from the drug-drug interaction (DDI) studies MS200095-0051 and MS200095-0053. Study MS200095-0051 is a phase 1, open-label, single-sequence, cross-over study to evaluate the effect of multiple doses of carbamazepine on single-dose tepotinib pharmacokinetics in healthy participants, while study MS200095- 0053 is a phase 1, open-label, single-sequence, cross-over study to evaluate the effect of multiple doses of itraconazole on single-dose tepotinib pharmacokinetics in healthy participants. The Package Leaflet is updated accordingly. In addition, the MAH took the opportunity to introduce minor changes to the PI.

Vargatef (nintedanib) - Boehringer Ingelheim International GmbH

• Grouped application containing: C.I.4: Update of sections 4.2, 5.1 and 5.2 of the SmPC in order to update information regarding the paediatric population based on results from study 1199-0337; this is a double blind, randomised, placebo-controlled trial to evaluate the dose-exposure and safety of nintedanib on top of standard of care for 24 weeks, followed by open label treatment with nintedanib of variable duration, in children and adolescents (6 to 17 year-old) with clinically significant fibrosing interstitial lung disease. The Package Leaflet is updated accordingly. C.I.4: Update of sections 4.2 and 5.2 of the SmPC in order to improve the recommendation for the administration of nintedanib based on food compatibility data. The Package Leaflet is updated accordingly. In addition, the MAH took the opportunity to update the list of local representatives in the Package Leaflet and to introduce minor editorial changes to the PI.

Verzenios (abemaciclib)  - Eli Lilly Nederland B.V

• Update of section 5.1 of the SmPC in order to include overall survival data based on final results from study MONARCH 2; this is a A Randomized, Double-Blind, Placebo- Controlled, Phase 3 Study of Fulvestrant with or without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone Receptor-Positive, HER2- Negative Locally Advanced or Metastatic Breast Cancer.

XALKORI (crizotinib) - Pfizer Europe MA EEIG

• Submission of the final report from study A8081001 (A Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study Of PF-02341066, A MET/HGFR Selective Tyrosine Kinase Inhibitor, Administered Orally to Patients with Advanced Cancer), to fulfil recommendation 8 of the Xalkori MAA to further investigate the role of c-Met status in ALKnegative patients.

CHMP-PRAC assessed procedures

Rozlytrek (entrectinib) - Roche Registration GmbH

• Update of sections 4.2 and 5.2 of the SmPC in order to update pharmacokinetic information based on final results from study GP411174 listed as an additional pharmacovigilance activity in the RMP; this is a Phase I, non-randomized, single-dose, openlabel study to investigate the effect of impaired hepatic function on the pharmacokinetics of entrectinib in volunteers with different levels of hepatic function. The RMP version 4.0 has also been submitted. In addition, the MAH took the opportunity to update in Annex II section C and to update the list of local representatives in the Package Leaflet.

Tecentriq (atezolizumab) - Roche Registration GmbH

• Submission of the final report from study MO39171 listed as a category 3 study in the RMP in order to fulfil MEA/008. This is a Phase III/IV, Single Arm, multicenter, interventional study of Atezolizumab to Investigate Long-term Safety and Efficacy in previously treated Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer. The RMP version 23 has also been submitted.

Tecentriq (atezolizumab) - Roche Registration GmbH

• Update of sections 4.2, 4.4 and 4.8 of the SmPC in order to add ‘pericardial disorders’ to the list of adverse drug reactions (ADRs) with frequency common in monotherapy and uncommon in combination therapy/based on final results from Drug Safety Report (DSR 1115896) including review of available clinical trial data, post-marketing data and literature. In addition, the MAH took the opportunity to update Annex II section D of the SmPC and to implement editorial changes in the SmPC. The Package Leaflet was updated accordingly. The RMP version 23.1 has also been submitted.

PRAC assessed procedures

Alecensa (alectinib) - Roche Registration GmbH

• Submission of an updated RMP version 3.2 in order to remove the important identified risks of Interstitial Lung Disease (ILD)/Pneumonitis, Hepatotoxicity, Photosensitivity, Bradycardia, Severe myalgia and Creatine Phosphokinase (CPK) elevations as safety concerns. Furthermore, template updates in line with the GVP Product or Population- Specific Considerations III: Pregnant and breastfeeding women are made.

Stivarga (regorafenib) - Bayer AG

• Update of section 4.4 of the SmPC in order to remove the disease specific precaution for hepatocellular carcinoma based on final results from study REFINE (study number 19244) listed as a category 3 study in the RMP; this is an international, prospective, open-label, multi-center, observational study to describe the safety and effectiveness of treatment with regorafenib in real-world settings. The RMP version 6.1 has also been submitted.

Tarceva (erlotinib) - Roche Registration GmbH

• Update of section 4.8 of the SmPC in order to provide a single table listing all ADRs following PSUSA/00001255/202111. The Package Leaflet is updated accordingly.

PRAC assessed ATMP procedures

Imlygic (talimogene laherparepvec) - Amgen Europe B.V (ATMP)

• Submission of an updated RMP version 10 in order to update and reclassify identified risk of ‘Disseminated herpetic infection’ based on the cumulative assessment of literature review and MAH Global Safety Database and to remove studies 20180062 and 20180099 from Planned and Ongoing Studies from the list of Pharmacovigilance Plan studies in the Annex II.

Unclassified procedures and worksharing procedures of type I variations

Herceptin, Phesgo - Roche Registration GmbH

List of procedures concluding at 12-15 December 2022 CHMP plenary

Oncology - AMB-05X

• Tenosynovial giant cell tumour (SME)
• The CHMP granted eligibility to PRIME and adopted the critical summary report.