PAGE 175 PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN BY PRODUCT Summary of risk management plan for pembrolizumab This is a summary of the risk management plan (RMP) for pembrolizumab. The RMP details important risks of pembrolizumab, how these risks can be minimised, and how more information will be obtained about pembrolizumab s risks and uncertainties (missing information). Pembrolizumab's Summary of product characteristics (SmPC) and its package leaflet give essential information to healthcare professionals and patients on how pembrolizumab should be used. I. The Medicine and What it is Used For Pembrolizumab is authorised for monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. Pembrolizumab as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. Pembrolizumab as monotherapy is indicated for the first-line treatment of metastatic nonsmall cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. Pembrolizumab, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. Pembrolizumab as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a 1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving pembrolizumab. Pembrolizumab as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin Lymphoma (chl) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV. Pembrolizumab as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. Pembrolizumab as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy.
PAGE 176 Pembrolizumab as monotherapy is indicated for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a 50% TPS and progressing on or after platinum-containing chemotherapy. It contains 50 mg lyophilized pembrolizumab in a 15 ml single-use vial or 100 mg liquid pembrolizumab in a 10 ml single-use vial as the active substance and it is given by intravenous infusion. The Recommended Dose of Pembrolizumab is: 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. Further information about the evaluation of pembrolizumab s benefits can be found in pembrolizumab s European Public Assessment Report (EPAR), including in its plainlanguage summary, available on the EMA website, under the s webpage link to product s EPAR summary landing page on the EMA webpage at the following link: http://www.ema.europa.eu/ema/index.jsp?curl=pages/s/human/s/003820/ human_med_001886.jsp&mid=wc0b01ac058001d124 II. Risks Associated With the Medicine and Activities to Minimise or Further Characterise the Risks Important risks of pembrolizumab, together with measures to minimise such risks and the proposed studies for learning more about pembrolizumab's risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals; Important advice on the s packaging; The s legal status the way a is supplied to the patient (e.g. with or without prescription) can help to minimise its risks. The authorised pack size the amount of in a pack is chosen so to ensure that the is used correctly; Together, these measures constitute routine risk minimisation measures. In the case of pembrolizumab, these measures are supplemented with additional risk minimisation measures mentioned under relevant important risks, below. In addition to these measures, information about adverse reactions is collected continuously and regularly analysed, including PSUR assessment - so that immediate action can be taken as necessary. These measures constitute routine pharmacovigilance. If important information that may affect the safe use of pembrolizumab is not yet available, it is listed under missing information below.
II.A PAGE 177 List of Important Risks and Missing Information Important risks of pembrolizumab are risks that need special risk management to further investigate or minimise the risk, so that the medicinal product can be safely administered. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of pembrolizumab. Potential risks are concerns for which an association with the use of this is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (e.g. on the long-term use of the ). Table II.A.1: List of Important Risks and Missing Information List of Important Risks and Missing Information Important identified risks Immune-Related Adverse Reactions Immune-related pneumonitis Immune-related colitis Immune-related hepatitis Immune-related nephritis Immune-related endocrinopathies - Hypophysitis (including hypopituitarism and secondary adrenal insufficiency) - Thyroid Disorder (hypothyroidism, hyperthyroidism, thyroiditis) - Type 1 diabetes mellitus Severe skin reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Other Immune-Related Adverse Reactions - Uveitis - Myositis - Pancreatitis - Myocarditis - Guillain-Barre Syndrome - Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients - Encephalitis - Sarcoidosis Infusion-Related Reactions Important potential risks Immune-Related Adverse Events Gastrointestinal perforation secondary to colitis Other Immune-Related Adverse Events
Table II.A.1: PAGE 178 List of Important Risks and Missing Information List of Important Risks and Missing Information For hematologic malignancies: increased risk of severe complications of allogeneic stem cell transplantation (SCT) in patients who have previously received pembrolizumab Graft versus host disease (GVHD) after pembrolizumab administration in patients with a history of allogeneic stem cell transplant (SCT) Immunogenicity Missing information Safety in patients with moderate or severe hepatic impairment Safety in patients with severe renal impairment Safety in patients with active systemic autoimmune disease Safety in patients with HIV or Hepatitis B or Hepatitis C Safety in pediatric patients Reproductive and lactation data Long term safety Safety in various ethnic groups Potential pharmacodynamic interaction with systemic immunosuppressants Safety in patients with previous hypersensitivity to another monoclonal antibody Safety in patients with severe (grade 3) immune-related (ir)aes on prior ipilimumab (ipi) requiring corticosteroids for > 12 weeks, or life-threatening iraes on prior ipi, or with ongoing ipi-related AEs
II.B PAGE 179 Summary of Important Risks Table II.B.1: Important Identified Risk: Immune-Related Pneumonitis regarding pneumonitis represent sufficient evidence of a causal association with pembrolizumab exposure. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis were excluded from the clinical trials. These patients are considered to be a risk group for the development of pneumonitis; in the interim analysis of the KN001 NSCLC cohort, possible risk factors identified that might predispose subjects to pneumonitis were a documented history of prior thoracic radiation to the chest ( 30Gy). According to the literature, risk factors for interstitial lung disease may include occupational exposure to toxins, chest irradiation, some chemotherapies, smoking and advanced age. Routine risk minimisation measures: The risk of the immune-related adverse reaction of pneumonitis associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.2: PAGE 180 Important Identified Risk: Immune-Related Colitis regarding colitis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for colitis and diarrhea associated with pembrolizumab were identified. Routine risk minimisation measures: The risk of the immune-related adverse reaction of colitis associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.3: PAGE 181 Important Identified Risk: Immune-Related Hepatitis regarding hepatitis represent sufficient evidence of a causal association with pembrolizumab exposure. Patients with moderate to severe liver dysfunction were excluded from clinical trials. No analysis of specific risk factors for immune-related hepatitis associated with pembrolizumab has been undertaken. Routine risk minimisation measures: The risk of the immune-related adverse reaction of hepatitis associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.4: PAGE 182 Important Identified Risk: Immune-Related Nephritis regarding nephritis represent sufficient evidence of a causal association with pembrolizumab exposure. Patients with severe renal dysfunction were excluded from clinical trials. No specific risk factors for nephritis associated with pembrolizumab have been identified. The risk of the immune-related adverse reaction of nephritis associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.5: PAGE 183 Important Identified Risk: Immune-Related EndocrinopathiesHypophysitis (Including Hypopituitarism and Secondary Adrenal Insufficiency) regarding endocrinopathies- hypophysitis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for hypophysitis (including hypopituitarism and secondary adrenal insufficiency) associated with pembrolizumab have been identified. The risk of the immune-related endocrinopathies [Hypophysitis (including hypopituitarism and secondary adrenal insufficiency); Thyroid Disorder ( Hypothyroidism, Hyperthyroidism, thyroiditis); Type 1 Diabetes Mellitus] associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4 and 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.6: PAGE 184 Important Identified Risk: Immune-Related EndocrinopathiesType 1 Diabetes Mellitus regarding endocrinopathies- type 1 diabetes mellitus represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for Type I DM associated with pembrolizumab have been identified. The risk of the immune-related endocrinopathies [Hypophysitis (including hypopituitarism and secondary adrenal insufficiency); Thyroid Disorder ( Hypothyroidism, Hyperthyroidism, thyroiditis); Type 1 Diabetes Mellitus] associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4 and 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.7: PAGE 185 Important Identified Risk: Severe Skin Reactions Including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrosis (TEN) regarding severe skin reactions including SJS and TEN represent sufficient evidence of a causal association with pembrolizumab exposure. A TEN-specific severity-of-illness score (SCORTEN) was developed in 2000 to estimate the mortality of patients with TEN. The score is designed to predict the mortality rate through seven independent factors, including age > 40 years, presence of malignancy, tachycardia above 120 per min, epidermal detachment of > 10% of body surface area (BSA) at admission, serum urea > 10 mmol L_1, serum glucose > 14 mmol L_1 and bicarbonate < 20 mmol L_1.1,8 Of the seven independent risk factors identified in SCORTEN analysis for patients with TEN, cancer or haematological malignancy was identified to have the highest odds ratio (OR) [Ref. 5.4: 04LDLY]. The risk of severe skin reactions including SJS and TEN associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.8: PAGE 186 Important Identified Risk: Other Immune-Related Adverse Reactions- Uveitis regarding uveitis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for uveitis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, encephalitis, sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. : Safety monitoring in all ongoing MAH-sponsored clinical trials for
Table II.B.9: PAGE 187 Important Identified Risk: Other Immune-Related Adverse Reactions- Myositis regarding myositis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for myositis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, encephalitis, sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.10: PAGE 188 Important Identified Risk: Other Immune-Related Adverse Reactions- Pancreatitis regarding pancreatitis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for pancreatitis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, myocarditis, and encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.11: PAGE 189 Important Identified Risk: Other Immune-Related Adverse Reactions- Myocarditis regarding myocarditis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for myocarditis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.12: PAGE 190 Important Identified Risk: Other Immune-Related Adverse Reactions- Guillain-Barre Syndrome regarding Guillain-Barre Syndrome represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for Guillain-Barre syndrome associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.13: PAGE 191 Important Identified Risk: Other Immune-Related Adverse Reactions- Solid Organ Transplant Rejection Following Pembrolizumab Treatment in Donor Organ Recipients Review of pembrolizumab post-marketing experience and literature regarding solid organ transplant rejection following pembrolizumab treatment in donor organ recepients represent sufficient evidence of a causal association with pembrolizumab exposure. Literature [Ref. 5.4: 04KMQG], [Ref. 5.4: 04KMQJ] Patients who have received solid organ transplants. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.14: PAGE 192 Important Identified Risk: Other Immune-Related Adverse Reactions - Encephalitis regarding encephalitis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for encephalitis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. : Cumulative review of literature, clinical trial and post-marketing cases of encephalitis to be included with PSUR submission in 2019.
Table II.B.15: PAGE 193 Important Identified Risk: Other Immune-Related Adverse Reactions - Sarcoidosis regarding sarcoidosis represent sufficient evidence of a causal association with pembrolizumab exposure. No specific risk factors for sarcoidosis associated with pembrolizumab have been identified. The risk of other immune-related adverse reactions (uveitis, myositis, pancreatitis, myocarditis, Guillain-Barre syndrome, Solid organ transplant rejection following pembrolizumab treatment in donor organ recipients, Encephalitis, Sarcoidosis) associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 (Guillain-Barre Syndrome, Myocarditis, Encephalitis are also described in Section 4.2) and appropriate advice is provided to the prescriber to minimize the risk. : Cumulative review of literature, clinical trial and post-marketing cases of sarcoidosis to be included with PSUR submission in 2019.
Table II.B.16: PAGE 194 Important Identified Risk: Infusion-Related Reactions regarding infusion-related reactions represent sufficient evidence of a causal association with pembrolizumab exposure. All patients are potentially at risk for this adverse reaction. The risk of infusion-related reactions associated with the use of pembrolizumab is described in the SmPC, Section 4.2, 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk :
Table II.B.17: PAGE 195 Important Potential Risk: Immune-Related Adverse EventsGastrointestinal Perforation Secondary to Colitis regarding gastrointestinal perforation secondary to colitis represent scientific evidence of a possible causal association with pembrolizumab exposure. No specific risk factors for gastrointestinal perforation secondary to colitis associated with pembrolizumab have been identified. The risk of the immune-related adverse event of gastrointestinal perforation secondary to colitis associated with the use of pembrolizumab is described in the SmPC, Section 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. :
Table II.B.18: PAGE 196 Important Potential Risk: Other Immune-Related Adverse Events- For Hematologic Malignancies: Increased Risk of Severe Complications of Allogeneic Stem Cell Transplantation (SCT) in Patients Who Have Previously Received Pembrolizumab Review of pembrolizumab literature regarding increased risk of severe complications of allogeneic stem cell transplantation in patients who have previously received pembrolizumab represents scientific evidence of a possible causal association with pembrolizumab exposure. Abstract [Ref. 5.4: 04FG2Z] Patients with hematologic malignancies undergoing allogeneic SCT who were previously treated with a PD-inhibitor. For Hematologic malignancies: the increased risk of severe complications of allogeneic SCT in patients who have previously received pembrolizumab is described in the SmPC, Section 4.4, 4.8 and appropriate advice is provided to the prescriber to minimize the risk. : Safety monitoring in the ongoing HL trials (KN013, KN087, KN204)
Table II.B.19: PAGE 197 Important Potential Risk: Other Immune-Related Adverse Events- - Graft Versus Host Disease (GVHD) After Pembrolizumab Administration in Patients With a History Of Allogeneic Stem Cell Transplant (SCT) Published literature [Ref. 5.4: 04PSFD] Patients with a history of allogeneic SCT treated with a PD-1 inhibitor. Postmarketing data GVHD after pembrolizumab administration in patients with a history of allogeneic SCT is described in the SmPC, Section 4.4 and appropriate advice is provided to the prescriber to minimize the risk. Routine pharmacovigilance including: Table II.B.20: Safety monitoring in all other ongoing MAH-sponsored clinical trials for pembrolizumab in various tumor types Cumulative review of literature, clinical trial and post-marketing cases of GVHD after pembrolizumab administration in patients with a history of allogeneic SCT with PSUR submission in Nov 2019. Important Potential Risk: Immunogenicity Review of pembrolizumab clinical trial data regarding immunogenicity represent scientific evidence of a possible causal association with pembrolizumab exposure., Data Cut off of 07-SEP-2016 None Identified The risk of immunogenicity associated with the use of pembrolizumab is described in the SmPC, Section 4.8. : Conducting anti-drug antibody (ADA) assessments in multiple MAH- sponsored clinical trials in different tumor types in the pembrolizumab program.
Table II.B.21: The missing information of safety in patients with patients with HIV or Hepatitis B or Hepatitis C is described in the SmPC, Section 4.4, 5.1. Missing Information: Safety in Pediatric Patients The missing information of safety in patients with active systemic autoimmune disease is described in the SmPC, Section 4.4, 5.1. Missing Information: Safety in Patients With HIV or Hepatitis B or Hepatitis C Table II.B.25: The missing information of safety in these patients is described in the SmPC, Section 4.2, 4.4. Missing Information: Safety in Patients With Active Systemic Autoimmune Disease Table II.B.24: The missing information of safety in these patients is described in the SmPC, Section 4.2, 4.4. Missing Information: Safety in Patients With Severe Renal Impairment Table II.B.23: Missing Information: Safety in Patients With Moderate To Severe Hepatic Impairment Table II.B.22: PAGE 198 The missing information of safety in pediatric patients is described in the SmPC, Section 4.2. : Safety monitoring in the paediatric investigation plan (PIP): A Phase I/II Study of Pembrolizumab () in Children with advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma (KN051)
Table II.B.26: Use during pregnancy and use in nursing mothers is described in the SmPC, Section 4.6, 5.3. Missing Information: Long Term Safety No risk Minimisation warranted : Table II.B.28: pembrolizumab in various tumor types Missing Information: Safety in Various Ethnic Groups No risk Minimisation warranted : Table II.B.29: The missing information of potential pharmacodynamic interaction with systemic immunosuppressants is described in the SmPC, Section 4.4, 4.5. Missing Information: Safety in Patients With Previous Hypersensitivity to Another Monoclonal Antibody Safety monitoring in ongoing global MAH-sponsored clinical trials for pembrolizumab Missing Information: Potential Pharmacodynamics Interaction With Systemic Immunosuppressants Table II.B.30: Missing Information: Reproductive and Lactation Data Table II.B.27: PAGE 199 The missing information of safety in patients with previous hypersensitivity to another monoclonal antibody is described in the SmPC, Section 4.4, 5.1.
Table II.B.31: II.C.1 Missing Information: Safety in Patients With Severe (Grade 3) Immune-Related (ir)aes on Prior Ipilimumab (ipi) Requiring Corticosteroids for >12 Weeks, or Life-Threatening iraes on Prior ipi, or With Ongoing ipi-related AEs II.C PAGE 200 The missing information of safety in patients with severe (grade 3) immunerelated (ir)aes on prior ipilimumab (ipi) requiring corticosteroids for > 12 weeks, or life-threatening iraes on prior ipi, or with ongoing ipi-related AEs is described in the SmPC, Section 4.4, 5.1. Post-Authorisation Development Plan Studies Which are Conditions of the Marketing Authorisation The following studies are conditions of the marketing authorisation: Table II.C.1.1: Studies Which are Conditions of the Marketing Authorisation Study Title Objectives Efficacy studies which are conditions of the marketing authorisation Phase I Study of Single Agent in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KN001) Phase II/III Randomized Trial of Two Doses of MK3475 (SCH900475) versus Docetaxel in Previously Treated Subjects with Non-Small Cell Lung Cancer (KN010) Randomized Open-Label Phase III Trial of Pembrolizumab versus Platinum based Chemotherapy in 1L Subjects with PD-L1 Strong Metastatic NonSmall Cell Lung Cancer (KN024) Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab () versus Platinum Based Chemotherapy in Treatment Naïve Subjects with PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (KN042) A Phase III Randomized Clinical Trial of Pembrolizumab () versus Paclitaxel, Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial Cancer (KN045) A Phase II Clinical Trial of Pembrolizumab (MK3475) in Subjects with Advanced/Unresectable or Metastatic Urothelial Cancer (KN052) A randomized, open-label Phase III clinical trial of Pembrolizumab versus the choice of 3 different standard treatment options in subjects with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) whose disease has progressed on or after prior platinum-containing chemotherapy (KN040) (on-going) The value of biomarkers to predict the efficacy of pembrolizumab should be further explored, specifically: Additional biomarkers other than PD-L1 expression status by Immunohistochemistry (IHC) (e.g. PD-L2, RNA signature, etc.) predictive of pembrolizumab efficacy should be investigated together with more information regarding the pattern of expression of PD L1 obtained in NSCLC studies (KN001, KN010, KN024 and KN042) as well as the urothelial carcinoma studies KN045 and KN052, HNSCC study KN040 and resected Stage II melanoma adjuvant study (KN716): Comparison between PD-L1 IHC staining in archival tissue vs newly obtained (melanoma studies only) Comparison of PD-L1 IHC between pre and post treatment tumour tissues (melanoma studies only) Genomic analyses using whole exome sequencing and/or RNAseq (e.g. Nanostring RNA gene signature) IHC staining for PD-L2 Data on RNA and proteomic serum profiling Data on Immune cell profiling (peripheral blood) (melanoma studies only)
Table II.C.1.1: PAGE 201 Studies Which are Conditions of the Marketing Authorisation Study Title A Phase II Clinical Trial of (Pembrolizumab) in Subjects with Relapsed or Refractory (R/R) Classical Hodgkin Lymphoma (chl) (KN087) Objectives To determine the safety and tolerability of pembrolizumab in subjects with relapsed or refractory classical Hodgkin Lymphoma (chl) and to evaluate overall response rate (ORR), progression free survival (PFS), duration of response (DOR) and overall survival (OS) of pembrolizumab in study subjects (on-going) A Phase Ib Multi-Cohort Trial of (pembrolizumab) in Subjects with Hematologic Malignancies (KN013) (on-going) To examine the safety and tolerability of pembrolizumab in subjects with hematologic malignancies including, Hodgkin lymphoma, mediastinal large B cell lymphoma (MLBCL), relapsed/refractory non-hodgkin lymphoma (NHL), myelodysplastic syndrome (MDS) and multiple myeloma A Phase III, Randomized, Open-label, Clinical Trial to Compare Pembrolizumab with Brentuximab Vedotin in Subjects with Relapsed or Refractory Classical Hodgkin Lymphoma (KN204) To compare overall survival (OS), progression free survival (PFS) and overall response rate (ORR) of pembrolizumab when compared to Brentuximab Vedotin in subjects with relapsed or refractory chl and to examine the safety and tolerability between treatment groups. (on-going) A Phase III Randomized Clinical Trial of Pembrolizumab () versus Paclitaxel, Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial Cancer (KN045) To examine overall survival (OS), progression free survival (PFS) and objective response rate (ORR) of pembrolizumab in subjects with recurrent or progressive metastatic urothelial cancer when compared to chemotherapy and to evaluate the safety and tolerability profile in treatment groups. (on-going) A Phase II Clinical Trial of Pembrolizumab (MK3475) in Subjects with Advanced/Unresectable or Metastatic Urothelial Cancer (KN052) To evaluate the safety and tolerability of pembrolizumab and to evaluate the antitumor activity of it as 1L therapy in subjects with advanced/ unresectable or metastatic urothelial cancer. (on-going) A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without Platinum-Based Combination Chemotherapy versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma (KN361) To compare progression free survival (PFS) and objective response rate (ORR) in all three treatment groups; pembrolizumab only, pembrolizumab + chemotherapy and chemotherapy only and to evaluate the safety and tolerability profile among the three treatment groups. (on-going) Adjuvant immunotherapy with anti-pd-1 monoclonal antibody Pembrolizumab () versus placebo after complete resection of high-risk Stage III melanoma: A randomized, double-blind Phase 3 trial of the EORTC Melanoma Group (KN054) (on-going) To prospectively assess whether post-operative adjuvant therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo in high-risk patients with complete resection of Stage IIIA (> 1 mm metastasis), IIIB and IIIC melanoma. To prospectively assess whether in the subgroup of patients with PDL1- positive tumor expression, pembrolizumab improves recurrence-free survival as compared to placebo (primary endpoint); distant metastasis free survival (DMFS) and overall survival (OS) in all-subjects and subjects with PD-L1-positive tumors (secondary endpoints for final study report).
II.C.2 PAGE 202 Other Studies in Post-Authorisation Development Plan Table II.C.2.1: Other Studies in Post-Authorisation Development Plan Study title and category Objectives Clinical trial A Phase II/III Randomized Trial of Two Doses of (SCH900475) versus Docetaxel in Previously Treated Subjects with Non-Small Cell Lung Cancer (KN010) (Category 3) To examine the overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and long term efficacy and safety of MK3475 in previously treated subjects with NSCLC whose tumors express PD-L1 Clinical trial A Randomized Open-Label Phase III Trial of Pembrolizumab versus Platinum based Chemotherapy in 1L Subjects with PD-L1 Strong Metastatic Non-Small Cell Lung Cancer (KN024) (Category 3) To evaluate the overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) and the safety and tolerability profile of pembrolizumab in subjects with 1L metastatic NSCLC, whose tumors express PD-L1, treated with pembrolizumab compared to standard of care (SOC) chemotherapies. Clinical trial A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab () versus Platinum Based Chemotherapy in Treatment Naïve Subjects with PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (KN042) (Category 3) To evaluate the overall survival (OS) and progression free survival (PFS) and to examine the safety and tolerability profile of pembrolizumab in subjects with PD-L1 positive 1L advanced/metastatic NSCLC, treated with pembrolizumab compared to standard of care (SOC) chemotherapies. Clinical Trial A Phase Ib Multi-Cohort Trial of (pembrolizumab) in Subjects with Hematologic Malignancies (KN013) (Category 3) To examine the safety and tolerability of pembrolizumab in subjects with hematologic malignancies including, Hodgkin lymphoma, mediastinal large B cell lymphoma (MLBCL), relapsed/refractory non-hodgkin lymphoma (NHL), myelodysplastic syndrome (MDS) and multiple myeloma Clinical Trial A Phase II Clinical Trial of (Pembrolizumab) in Subjects with Relapsed or Refractory (R/R) Classical Hodgkin Lymphoma (chl) (KN087) (Category 3) To determine the safety and tolerability of pembrolizumab in subjects with relapsed or refractory classical Hodgkin Lymphoma (chl) and to evaluate overall response rate (ORR), progression free survival (PFS), duration of response (DOR) and overall survival (OS) of pembrolizumab in study subjects
Table II.C.2.1: PAGE 203 Other Studies in Post-Authorisation Development Plan Study title and category Objectives Clinical Trial A Phase III, Randomized, Open-label, Clinical Trial to Compare Pembrolizumab with Brentuximab Vedotin in Subjects with Relapsed or Refractory Classical Hodgkin Lymphoma (KN204) (Category 3) To compare overall survival (OS), progression free survival (PFS) and overall response rate (ORR) of pembrolizumab when compared to Brentuximab Vedotin in subjects with relapsed or refractory chl and to examine the safety and tolerability between treatment groups. Clinical Trial A Phase I/II Study of Pembrolizumab (MK3475) in Children with advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma (KN051) (Category 3) To define the toxicities and maximum tolerated, maximum administered dose of pembrolizumab when administered as monotherapy to children between 6 months to 18 years of age with advanced melanoma, advanced, relapsed or refractory solid tumors or lymphoma. Study is designed to determine the safety and tolerability of pembrolizumab in all children between 6 months to 18 years of age. Cumulative review of literature, clinical trial and post-marketing cases for the risks of encephalitis, sarcoidosis and GVHD after pembrolizumab administration in patients with a history of allogeneic stem cell transplant (SCT) (Category 3) To monitor, identify and evaluate reports of encephalitis, sarcoidosis and GVHD after pembrolizumab administration in patients with a history of allogeneic SCT Clinical trial A Phase I/II Study of ) in Combination with Chemotherapy or Immunotherapy in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma (KN021) (Category 3) To determine the recommended Phase II dose for in combination with chemotherapy or immunotherapy in subjects with unresectable or metastatic NSCLC Clinical Trial A Randomized, Double-Blind, Phase III Study of Platinum+ Pemetrexed Chemotherapy with or without Pembrolizumab () in First Line Metastatic Non-squamous Non-small Cell Lung Cancer Subjects (KN189) (Category 3) To evaluate the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with chemotherapy using OS Clinical Trial A randomized, active-controlled, multicenter, open-label Phase III clinical trial to examine the efficacy and safety of Pembrolizumab versus the choice of 3 different standard treatment options in subjects with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) whose disease has progressed on or after prior platinum-containing chemotherapy (KN040) (Category 3) To compare the overall survival (OS) in subjects with R/M HNSCC treated with pembrolizumab compared to standard treatment.