Keytruda - Europa

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 Keytruda Procedural steps taken and scientific information after the authorisation Application number Scope Opinion/ Notification1 issued on Commission Decision Issued2 / amended on Product Information affected3 Summary IB/0119 - Deletion of - a pharmaceutical form 04/01/2022 SmPC, Labelling and PL II/0105 Extension of indication to include pembrolizumab in combination with lenvatinib for the treatment of 14/10/2021 15/11/2021 SmPC and PL Please refer to Scientific Discussion Keytruda -H -C -003820-II-0105 1 Notifications are issued for type I variations and Article 61(3) notifications (unless part of a group including a type II variation or extension application or a worksharing application). Opinions are issued for all other procedures.

2 2 A Commission decision (CD) is issued for procedures that affect the terms of the marketing authorisation ( summary of product characteristics, annex II, labelling, package leaflet). The CD is issued within two months of the opinion for variations falling under the scope of Article (a) of Regulation (EU) No. 712/2012, or within one year for other procedures. 3 SmPC (Summary of Product Characteristics), Annex II, Labelling, PL (Package Leaflet). Page 2/43 advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation; as a consequence, sections , , and of the SmPC are updated. The Package Leaflet is updated in accordance. Version of the RMP has also been agreed. - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one II/0104 Extension of indication to include Keytruda in combination with lenvatinib first line treatment of adults with advanced renal cell carcinoma (RCC); as a consequence, sections , , and of the SmPC are updated.

3 The Package Leaflet is updated in accordance. Version of the RMP has also been submitted. - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one 14/10/2021 15/11/2021 SmPC and PL Please refer to Scientific Discussion Keytruda -H-C-Product Number-II- 3820-104 II/0099 Extension of indication for Keytruda to include in combination with chemotherapy, treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD L1 with a CPS 10 and who have not received prior chemotherapy for metastatic disease; as a 16/09/2021 19/10/2021 SmPC and PL Please refer to Scientific Discussion Keytruda -H-C-3820-II-99 Page 3/43 consequence, sections , , , and of the SmPC are updated. The Package Leaflet is updated in accordance. Version 32 of the RMP has also been submitted. - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one IB/0113 - Change in test procedure for AS or starting material/reagent/intermediate - Deletion of a test procedure for the AS or a starting material/reagent/intermediate, if an alternative test procedure is already authorised 30/09/2021 n/a IAIN/0112 - Changes (Safety/Efficacy) of Human and Veterinary Medicinal Products - Other variation 19/08/2021 19/10/2021 SmPC and PL II/0097 Extension of indication to include in combination with platinum and fluoropyrimidine based chemotherapy, first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD L1 with a CPS 10, based on the results from the pivotal KEYNOTE-590 (KN590) trial.

4 As a consequence, sections , , , , and of the SmPC are updated. The Package Leaflet is updated in accordance. Minor updates are also included in Annex II of the Product Information. Version of the RMP (Version ) has also been submitted. 20/05/2021 24/06/2021 SmPC, Annex II and PL Please refer to Scientific Discussion Keytruda -H-C-3820-II-97 Page 4/43 - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one PSUSA/10403/202009 Periodic Safety Update EU Single assessment - pembrolizumab 22/04/2021 17/06/2021 SmPC and PL Refer to Scientific conclusions and grounds recommending the variation to terms of the Marketing Authorisation(s) for PSUSA/10403/202009. II/0107 - Introduction of a post approval change management protocol related to the finished product 03/06/2021 n/a II/0106/G This was an application for a group of variations. - Change to importer, batch release arrangements and quality control testing of the FP - Replacement/addition of a site where batch control/testing takes place for a biol/immunol product and any of the test methods at the site is a biol/immunol method - Change to importer, batch release arrangements and quality control testing of the FP - Replacement/addition of a site where batch control/testing takes place 28/05/2021 n/a II/0102 Update of sections , and of the SmPC in order to introduce an alternative dosing regimen of 400 mg every 6 weeks (Q6W) for all approved indications based on interim results from study KEYNOTE-555; this is an interventional, PK study in patients with advanced melanoma.

5 Additonal data/analysis from studies KEYNOTE-021, -048, -189, -407 and -426 22/04/2021 21/05/2021 SmPC The recommended dose of Keytruda in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. Page 5/43 were provided. - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data II/0100 Update of section of the SmPC in order to update efficacy data based on interim results from study KEYNOTE-054 listed as a PAES in the Annex II; this is a randomized, double-blind, placebo-controlled phase 3 study evaluating pembrolizumab in the adjuvant therapy of patients with resected high-risk melanoma. - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data 15/04/2021 21/05/2021 SmPC SmPC new text Updated efficacy results with a median follow-up time of months were provided, including distant metastases free survival (DMFS) analysis in the whole population and in the population with PD-L1 positive tumours (secondary outcome measure).

6 RFS and DMFS benefit was consistently demonstrated across subgroups, including tumour PD-L1 expression, BRAF mutation status, and stage of disease (using AJCC 7th edition). These results were consistent when reclassified in a post-hoc analysis according to the current AJCC 8th edition staging system. II/0094 Update of sections and of the SmPC in order to update efficacy information based on final results from study KEYNOTE-361 listed as a PAES in the Annex II; this is a Phase III Randomised, Controlled Clinical Trial of Pembrolizumab with or without Platinum-based Combination Chemotherapy versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma; Annex IID is updated accordingly. - Change(s) in the SPC, Labelling or PL due to new quality, preclinical, clinical or pharmacovigilance data 25/03/2021 21/05/2021 SmPC and Annex II SmPC new text In KEYNOTE-361, a higher number of deaths within 6 months of treatment initiation followed by a long-term survival benefit was observed with pembrolizumab monotherapy compared to chemotherapy (see section ).

7 No specific factor(s) associated with early deaths could be identified. Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with urothelial carcinoma who are considered eligible for carboplatin-based combination chemotherapy. Results of KEYNOTE 361 for pembrolizumab in combination with chemotherapy did not show statistically significant improvement in PFS as assessed by BICR using RECIST Page 6/43 (HR ; 95% CI: , ; p= ), and OS (HR ; 95% CI: , ; p= ) versus chemotherapy alone. Per the pre specified hierarchical testing order no formal tests for statistical significance of pembrolizumab versus chemotherapy could be performed. The key efficacy results of pembrolizumab monotherapy in patients for whom carboplatin rather than cisplatin was selected by the investigator as the better choice of chemotherapy were consistent with KEYNOTE 052 results. Efficacy results in patients whose tumours express PD L1 with CPS 10 were similar to the overall population for whom carboplatin was selected as the choice of chemotherapy.

8 IA/0103 - Administrative change - Deletion of manufacturing sites 04/03/2021 n/a II/0090 Extension of the currently approved therapeutic indication for the treatment of relapsed or refractory classical Hodgkin lymphoma (rrcHL) in adults to an earlier line of therapy and to include paediatric patients - as follows: Keytruda as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. As a consequence, sections , , , and of the SmPC are updated. The Package Leaflet is updated in accordance. The Annex II was revised to reflect extended deadline for the submission of the 28/01/2021 09/03/2021 SmPC, Annex II and PL Please refer to Scientific Discussion Keytruda -H-C-3820-II-0090. Page 7/43 PAES KN-204. Revised RMP Version 30 of the RMP has also been submitted.

9 - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one II/0091 Extension of indication to include first-line treatment of metastatic microsatellite instability-high (MSI H) or mismatch repair deficient (dMMR) colorectal cancer in adults for Keytruda based on the results from KEYNOTE-177 (an international, randomised, open-label Phase 3 trial of pembrolizumab versus chemotherapy in MSI-H or dMMR Stage IV Colorectal Carcinoma). As a consequence, sections , , , and of the SmPC are updated. The Package Leaflet is updated in accordance. In addition, a minor correction has been made in section , Immune related endocrinopathies subsection. Version of the RMP has also been submitted. - Change(s) to therapeutic indication(s) - Addition of a new therapeutic indication or modification of an approved one 10/12/2020 21/01/2021 SmPC, Annex II and PL Please refer to Scientific Discussion Keytruda -H-C-3820-II-0091.

10 IAIN/0101 - Changes (Safety/Efficacy) of Human and Veterinary Medicinal Products - Other variation 18/01/2021 09/03/2021 SmPC and PL IAIN/0098 - Changes (Safety/Efficacy) of Human and Veterinary Medicinal Products - Other variation 02/12/2020 21/01/2021 SmPC and PL Page 8/43 IA/0095/G This was an application for a group of variations. - Administrative change - Change in the name and/or address of a manufacturer or an ASMF holder or supplier of the AS, starting material, reagent or intermediate used in the manufacture of the AS or manufacturer of a novel excipient - Administrative change - Change in the name and/or address of a manufacturer or an ASMF holder or supplier of the AS, starting material, reagent or intermediate used in the manufacture of the AS or manufacturer of a novel excipient - Administrative change - Change in the name and/or address of a manufacturer/importer of the finished product, including quality control sites (excluding manufacturer for batch release) 10/11/2020 21/01/2021 Annex II and PL IAIN/0093/G This was an application for a group of variations.