these trials. For the purpose of providing safety updates from clinical trials to the TGA, the sponsor confirms that Periodic Safety Update Reports (PSUR), as outlined in the EMA ‘Guideline will be provided on a 6 monthly basis. The PSURs will contain all safety data collected by the sponsor, including data from clinical trials and in-market use in territories where Keytruda is approved. Changes to the safety profile of Keytruda will be communicated via changes in labelling, individual case reporting and the periodic PSURs. It appears that safety related data which will be collected during ongoing clinical studies will address some of the ongoing safety concerns. Consequently, it is recommended that the sponsor amends table 46 of the EU-RMP (Overview of Pharmacovigilance Actions), and any other table as appropriate, to assign safety concerns to the ongoing clinical studies. The sponsor agrees to update Table 46 ‘Overview of Pharmacovigilance Actions’ in the current EU RMP v1.1 to reflect generally the current clinical trials as they will contribute important safety data to the overall understanding of ongoing safety concerns The sponsor’s response cannot be verified because no updated RMP was provided with the response. It is recommended that the sponsor provides the updated RMP for review prior to approval. The study protocols for the PIP have not been attached to the RMP, and it is recommended that the sponsor provides these as annex to the Furthermore, these studies should be assigned to the ongoing safety concerns of safety in paediatrics in the Section SIV.3 ‘Limitations in Respect to Populations Typically Under-represented in Clinical Development Programmes’ and Table 49 ‘Overview of Pharmacovigilance Actions’ of the EU RMP v.1.1 have been updated The sponsor’s response cannot be verified because no updated RMP was provided with the response. It is recommended that the sponsor provides the updated RMP for review prior to approval.
pharmacovigilance plan of the RMP. to include the PIP study as a pharmacovigilance activity to address the missing information of ‘Safety in use in paediatric patients’. Furthermore, the sponsor agrees to include the available study protocol for the PIP in an annex to the EU RMP v1.1, and future PIP study protocols will be added when available. As the safety data base is relatively small, it is recommended that the sponsor implements further pharmacovigilance activities, to ensure the safe use of the product, should it be approved. This includes, but is not limited to: A.) Implementation of follow-up forms for all identified and potential risks, in order to collect comprehensive information about the causality and outcome of adverse events. B.) Implementation of a Post Authorisation Safety Study (PASS) to collect detailed information about the safety profile of the product. The sponsor requests follow up information on spontaneous adverse event reports received for pembrolizumab utilizing Standard Operating Procedures. In addition, the sponsor agrees to utilise an additional follow-up form to collect important information on the identified and potential risks, immune related events and infusion related reactions, reported with pembrolizumab as part of routine pharmacovigilance activities. Although the initial cohort for which safety assessments have been the basis of the RMP is generally small, the sponsor believes that a PASS is not necessary at this time given the number of on-going clinical trials with pembrolizumab and the planned studies across all indications from which valuable safety information will be obtained. Specifically, A.) The sponsor’s commitment to implement additional follow-up forms to collect important information on the identified and potential risks, immune related events and infusion related reactions, reported with pembrolizumab has been noted. It is recommended that these additional follow-up forms are included in the pharmacovigilance plan of the RMP, and are attached to an updated RMP as an annex. B.) The recommendation to implement additional pharmacovigilance activities remains and is supported by ACSOM.
Patient Information Brochures including alert cards. minimization (the PI) adequate for the pembrolizumab RMP. Based on the current benefit: risk profile for pembrolizumab, there is no evidence that additional risk minimization activities beyond those planned by the sponsor are warranted. The PI comprehensively communicates risks for pembrolizumab and provides clear guidance for identification, treatment of the risks associated with pembrolizumab, and recommendations for discontinuation or temporary interruption of therapy accordingly to the severity by observed risk. The sponsor will be providing educational materials to prescribers and patient information that will enhance the product labelling awareness for pembrolizumab. The sponsor also considers that the oncology community is now familiar with immunotherapy for melanoma. Adoption of appropriate patient management for a new oncology product into treatment practices will be adequately supported by labelling with product specific educational materials provided by the sponsor to support product launch. considers routine risk minimization (the PI) adequate for the pembrolizumab RMP. In contrast the sponsor also states: The sponsor will be providing educational materials to prescribers and patient information that will enhance the product labelling awareness for pembrolizumab. The sponsor should clarify if educational materials for physicians and patients will form part of the RMP, and if so, this activity should be incorporated in the risk-minimisation plan of the RMP and these documents attached to the updated RMP as an annex. B.) Pending the clarification by the sponsor, the recommendation to implement additional risk-minimisation activities remains and is supported by It is recommended that the sponsor amends table 65 of the EU-RMP Part V ‘Risk Minimization Measures’, V.3 ‘Summary Table of The sponsor’s response cannot be verified because no updated
(Summary of Safety Concerns and Risk Minimization Activities) to describe only activities but not pharmacovigilance activities. Risk Minimization Measures’, Table 73 ‘Summary of Safety Concerns and Risk Minimization Activities’ of the EU-RMP has been modified and includes the routine risk minimization activities for each listed safety concern. RMP was provided with the response. It is recommended that the sponsor provides the updated RMP for review to approval. A table comparing the wording in the Australian-PI with the EU-SmPC should be provided as annex to the ASA. A table comparing the proposed EU SmPC, US monograph and the proposed Australian PI is provided as an attachment to the ASA. The documents are generally consistent, and any differences between the relevant sections are typically due to the different layouts of the documents. The has been provided by the sponsor. This is considered acceptable. It is recommended that the sponsor outlines the wording, by which important safety concerns are addressed in the US monograph compared to the proposed Australian PI, and material differences in the Australian PI should be justified. A table comparing the US monograph, the proposed Australian PI and the proposed EU SmPC is provided as an attachment to the Australian-Specific Annex. The documents are generally consistent, and any differences between the relevant sections are typically due to the different layouts of the documents. The sponsor’s response has been noted. The following is brought to the delegate’s attention. The following statement is included in the Australian PI in section ‘dosage and administration’: The recommended dose of Keytruda is 2 mg/kg administered intravenously over 30 minutes every 3 weeks. Merck proposes to inform prescribers that atypical responses can occur to Keytruda, and that prescribers should confirm progression in patients who are clinically stable so that they do not prematurely discontinue treatment. In P001, patients were allowed to remain on It appears that the writing in bold was initially included in the US prescribing information, but was subsequently removed, and more detailed information was included in the clinical trial section. This is in line with the recommendations made trial
A.) The sponsor should add a statement in the PI describing that the product has been derived mammalian cells of Hamster origin. B.) The sponsor should add a statement informing health care professionals that patients with active infections should be appropriately treated prior to commencement of therapy with Keytruda. C.) The sponsor should amend the PI to include a statement describing that only experienced oncologists should administer the product. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft CMI document be revised as follows: D.) The sponsor should add a statement in the CMI informing patients with a known allergy to Hamster protein to be more cautious when receiving Keytruda. recommended. Of relevance the sponsor states in their response: it was recommended that the patient’s active infection be treated prior to the start of therapy with pembrolizumab in study P001. As such a recommendation was made during the clinical development program, and there is no safety data available for patients being treated with an active infection, this recommendation to the Delegate remains. C.) The sponsor has added the following statement: Treatment must be initiated and supervised by healthcare professionals experienced in the treatment of cancer. It is recommended to the Delegate that this statement be amended to: Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer. D.) The sponsor has not included a statement as recommended. This recommendation remains. Summary of recommendations Outstanding issues RMP related issues remaining from the round 1 RMP report The sponsor should provide justification as to why ‘Skin disorders’ was added as potential risk rather than an identified risk to the table of ongoing safety concerns. It is recommended that ‘Safety in patients with an active infection’ be added as missing information to the table of ongoing safety concerns.
10. Pembrolizumab clinical development programme Phase Design of of up / Actual Updated description (data cut off 31 July 2014) Melanoma P001 Parts B and D Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non- Small Cell Lung Carcinoma; Phase I 1246 pts 1191 pts (for all P001) 24 m1 December 2016 KEYNOTE001 was the initial phase I study that was expanded to include cohorts of melanoma and NSCLC patients. Cohort B and D include 656 melanoma patients including and patients. P002 Phase II Study of versus in Patients with Advanced Melanoma; Phase II Open label (MK dose is 510 pts; 540 pts 24 m June 2016 KEYNOTE002 is an ongoing clinical comparing two doses of pembrolizumab (2 mg/kg Q3W or 10 mg/kg Q3W) versus investigator’s choice of standard of care chemotherapy in patients who have failed prior ipilimumab treatment. These data include 449 patients who received pembrolizumab including 91 patients who crossed over to pembrolizumab after Randomised blinded Label naïve Description d
progressing on the comparator. P006 A Multicentre, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of MK-3475 Compared to Ipilimumab in Patients with Advanced Melanoma; Phase III 645 pts; 831 pts 36 m July 2016 KEYNOTE006 is an ongoing study of two doses of pembrolizumab (10 mg/kg Q2W or 10 mg/kg Q3W) versus ipilimumab. Of note, cross over to pembrolizumab is not permitted in this study compared to KEYNOTE002 above. A total of 556 patients have been treated with pembrolizumab in KEYNOTE006. NSCLC P001 Parts C and F Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non- Small Cell Lung Carcinoma; Phase I 1246 pts 1191 pts (for all P001) 24 m December 2016 KEYNOTE001 is the phase I study that included two cohorts with NSCLC patients. Cohort C was the preliminary NSCLC 3rd line cohort. Cohort F includes NSCLC patients with various lines of therapy including patients without prior chemotherapy. A total of 549 NSCLC patients have been treated in Randomised
KEYNOTE001 (39 in C, 510 in F). P010 A Phase II/III of Two Doses of MK-3475 versus Docetaxel in Previously Treated Subjects with Squamous Histology Non-Small Cell Lung Cancer; Phase II/III for study PDL1 level = 920 pts; 170 pts 30 days and 2015 KEYNOTE010 is an ongoing randomised trial of pembrolizumab two doses (2 mg/kg Q3W or 10 mg/kg Q3W) versus docetaxel 75 mg/m2. Patients were required to have had progression on or after prior platinum-based chemotherapy. Cases are included for patients who had at least one dose of pembrolizumab. Approximately 323 NSCLC patients had been treated in KEYNOTE010. are ongoing NSCLC studies in Japan using a range of doses. A total of 40 patients have been enrolled to date. P021 A Phase I/II Study of in Combination with or in Patients with Locally Advanced or Open 320 pts; 1 pts May 2016 al al
Metastatic NSCLC; Phase I/II Other P001 Part A Phase I Study of Single Agent MK-3475 in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non- Small Cell Lung Carcinoma; Phase I 1246 pts 1191 pts (for all P001) 24 m December 2016 KEYNOTE001 Cohort A included 30 patients with different solid tumour types for dose ranging. A total of 30 patients received pembrolizumab in this cohort. P012 A Phase Ib Study of in Subjects with Advanced Solid Tumours; Phase I open label study 114 pts 160 pts follow up 12 weeks until death or end of study May 2015 KEYNOTE012 is a II study of pembrolizumab in patients with triple negative breast cancer, head and neck cancer, urothelial cancer, or gastric cancer. A total of 225 patients have been treated with pembrolizumab. P013 A Ib Study of in Subjects with Hematologic Phase I 106 pts; 36 pts 12 weeks 2016 KEYNOTE013 is a phase II study in patients with hematologic malignancies. A total of 69 patients have been enrolled in this trial. P016 Phase 2 Study of in Patients with 71 pts; 3 m 2017 al trial
Table 20. Overall response rates in patients from P001 (18 October 2013 cut off). BRAF status 2 mg/kg Q3W 10 mg/kg Q3W 10 mg/kg Q2W Mutant 8 out of 38 (21%) 9 out of 45 (20%) 7 out of 14 (50%) 24 out of 97 (25%) Mutant, use of BRAFi/MEKi 13 out of 66 (20%) Mutant, no use of BRAFi/MEKi 11 out of 31 (35%) Wild-type 39 out of 124 (31%) 46 out of 147 (31%) 19 out of 39 (49%) 104 out of 310 (34%) In the 18 April 2014 cut off analysis of B1+B2+B3+D, there were 308 IPI naïve subjects and 342 IPI exposed subjects (many of whom were included in the above analysis). In Table 21 is presented the analysis of ORRs is by BRAF status and ipilimumab exposure. Table 21. Analysis of overall response rates is by BRAF status and ipilimumab exposure BRAF status IPI-naive IPI-exposed total Mutant n=91 ORR = 27.5% n=64 ORR = 17% n=155 ORR = 23% - Mutant, use of BRAFi/MEKi n=45 ORR = 24% n=56 ORR = 18% n=101 ORR = 21% - Mutant, no use of BRAFi/MEKi n=46 ORR = 30% n=8 ORR = 12.5% n=54 ORR = 28% Wild-type n=217 ORR = 40% n=277 ORR = 28.5% n=494 ORR = 34% Total n=308 ORR = 36% n=342 ORR = 27% n=650 ORR = 31% Safety results Exposure Exposure to pembrolizumab in 411 subjects with advanced melanoma within sub-studies B1, B2 and D was as follows, based on the 18 October 2013 cut off (values from the 18 April 2014 cut off follow, in bold and parentheses)
Table 43. Cross study comparison of the safety profiles of pembrolizumab and BRAF + MEK inhibition P006 data) P001 [18 April 2014; 2 mg/kg Q3W] P002 (interim data) COMBI-D arm) COMBI-V arm) due to AEs 7 to 11% 11% 10% 9% 13% Severe AEs 43% 47% 35% 52% Top 5 AEs not fatigue (43%), nausea (32%), (30%), (28%), pruritus and rash (26%) fatigue (39%), pruritus (25%), (21%), diarrhoea (21%), nausea (20%) pyrexia (51%), fatigue (35%), headache (30%), nausea (30%), chills (30%) pyrexia (53%), nausea (35%), diarrhoea (32%), chills (31%), vomiting (29%) For BRAF monotherapy, discontinuation due to AEs was reported in 5% (COMBI-D) and 12% (COMBI-V); and severe AEs in 37% (COMBI-D) and 63% (COMBI-V). Other comparisons Summary data from P002 are useful in the comparison of pembrolizumab and chemo. Differences in exposure across arms and the mix of control chemotherapies make head to head comparisons difficult, but pembrolizumab’s safety profile seems very different and relatively good (especially for the 2 mg/kg arm). Other Viral infection PD-1’s role in human biology is not limited to the maintenance of tolerance. It regulates antibody responses and the response to viruses (as well as tumours). Some plausible effects related to these roles were not well-examined. For example, in HCV positive patients, it would have been useful to search for any evidence of altered control of the infection. There were cases of elevated LFTs and / or hepatitis, but no attempt to relate these cases to a history of HCV or HBV. It is possible that blockade of PD-1 – PD-L signalling might trigger immunopathology as previously exhausted virus-specific T cells are reactivated. The FDA Summary Review states:
The ACPM advised that implementation by the sponsor of the recommendations outlined above to the satisfaction of the TGA, in addition to the evidence of efficacy and safety provided would support the safe and effective use of this product. Outcome on a review of quality, safety and efficacy, TGA approved the registration of Keytruda pembrolizumab (rch) 50 mg powder for injection vial indicated for: Keytruda (pembrolizumab (rch)) is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults. Specific conditions of registration applying to these goods Keytruda European Risk Management Plan (version 1.1, dated 9 February 2015) with Australian Specific Annex, dated August 2014 and revised to the satisfaction of the TGA, or any updates to these documents that are agreed by the TGA, must be implemented. It is a condition of registration that, as a minimum, the first five independent batches of Keytruda pembrolizumab (rch) 50 mg vial imported into in Australia are not released for sale until samples and/or the manufacturer's release data have been assessed and endorsed for release by the TGA Laboratories Branch (LB). Attachment 1. Product Information The PI for Keytruda approved with the submission is described in this AusPAR is at Attachment 1. For the most recent PI, please refer to the TGA website at <>. Attachment 2. Extract from the Clinical Evaluation Report