Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma Meredith K

Published OnlineFirst February 24, 2017; DOI: 10.1158/1078-0432.CCR-16-0663

CCR Drug Updates Clinical Cancer Research FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma Meredith K. Chuk1, Jennie T. Chang1, Marc R. Theoret1, Emmanuel Sampene2, Kun He2, Shawna L. Weis1, Whitney S. Helms1, Runyan Jin3, Hongshan Li3, Jingyu Yu3, Hong Zhao3, Liang Zhao4, Mark Paciga5, Deborah Schmiel5, Rashmi Rawat5, Patricia Keegan1, and Richard Pazdur1

Abstract

On September 4, 2014, the FDA approved pembrolizumab responses were ongoing. The most common (20%) adverse (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended reactions were fatigue, cough, nausea, pruritus, rash, decreased dose of 2 mg/kg every 3 weeks by intravenous infusion for the appetite, constipation, arthralgia, and diarrhea. Immune-mediated treatment of patients with unresectable or metastatic melanoma adverse reactions included pneumonitis, colitis, hepatitis, hypo- who have progressed following treatment with ipilimumab and, if physitis, and thyroid disorders. The benefits of the observed ORR BRAF V600 mutation positive, a BRAF inhibitor. Approval was with prolonged duration of responses outweighed the risks of based on demonstration of objective tumor responses with pro- immune-mediated adverse reactions in this life-threatening dis- longed response durations in 89 patients enrolled in a random- ease and represented an improvement over available therapy. ized, multicenter, open-label, dose-finding, and activity-estimat- Important regulatory issues in this application were role of dura- ing phase 1 trial. The overall response rate (ORR) by blinded bility of response in the evaluation of ORR for accelerated approv- independent central review per RECIST v1.1 was 24% (95% al, reliance on data from a first-in-human trial, and strategies for confidence interval, 15–34); with 6 months of follow-up, 86% of dose selection. Clin Cancer Res; 23(19); 1–5. 2017 AACR.

Introduction these therapies represented a patient population with an unmet medical need. Historically, patients with metastatic melanoma have had an Alterations in the immune response have been shown to play a estimated median overall survival (OS) of less than 1 year (1). role in the pathogenesis of melanoma. One method of exploiting Older treatments approved by the FDA include dacarbazine and relevant immune pathways is to block inhibitory signals of T-cell IL2, which demonstrate low response rates, and for IL2, consid- activation to enhance the endogenous antitumoral immune erable toxicity. The FDA approved ipilimumab and vemurafenib response (2, 3). The programmed death-1 (PD-1) pathway, in 2011 based on improvements in OS over dacarbazine. In 2013, including PD-1 and its ligands, PD-L1 and PD-L2, functions to the FDA approved dabrafenib and trametinib as single agents on maintain self-tolerance, prevents the development of autoimmu- the basis of improvement in progression-free survival (PFS) over nity, and protects normal tissues during an infectious/inflamma- dacarbazine or paclitaxel. At the initial approval of pembrolizu- tory response. Interruption of this pathway, which can be upre- mab, these six drugs represented available therapy for patients gulated in a variety of tumors, attempts to restore antitumor with advanced melanoma. Patients who progressed following immune reactivity (4–6). Pembrolizumab, an anti–PD-1 monoclonal antibody, received FDA's breakthrough therapy designation in January 1Office of Hematology and Oncology Products (OHOP), Center for Drug Eval- 2013 for the treatment of patients with unresectable or meta- uation and Research, U.S. Food and Drug Administration, Silver Spring, Mary- land. 2Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food static melanoma that is refractory to ipilimumab and for the and Drug Administration, Silver Spring, Maryland. 3Office of Clinical Pharma- treatment of patients who are ipilimumab-na€ve based on data cology, Center for Drug Evaluation and Research, U.S. Food and Drug Admin- from 85 patients (ipilimumab-na€ve, N ¼ 58; refractory to istration, Silver Spring, Maryland. 4Office of Generic Drugs, Center for Drug ipilimumab, N ¼ 27) treated with 10 mg/kg of pembrolizu- Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, mab. The overall response rate (ORR) was 40% (95% confi- Maryland. 5Office of Biotechnology Products, Center for Drug Evaluation and dence interval, 29–51) as assessed by central independent Research, U.S. Food and Drug Administration, Silver Spring, Maryland. review per RECIST v1.1. Duration of response (DOR) ranged Note: This is a U.S. government work. There are no restrictions on its use. from 0.9 to 7.9 months. Breakthrough therapy designation is Corresponding Author: Meredith K. Chuk, U.S. Food and Drug Administration, given for a drug that is intended to treat a serious condition 10903 New Hampshire Avenue, Silver Spring, MD 20903. Phone: 301-796-5006; where there is preliminary clinical evidence that the drug may Fax: 301-796-9849; E-mail: [email protected] demonstrate substantial improvement on a clinically signifi- doi: 10.1158/1078-0432.CCR-16-0663 cant endpoint over available therapies.TheFDAreviewofthe 2017 American Association for Cancer Research. Biologics License Application (BLA) for pembrolizumab for the

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treatment of patients with unresectable or metastatic melano- postmarketing study to characterize the effect of pembrolizumab ma who have progressed following treatment with ipilimumab on the magnitude of the recall immune response in mice. and, if BRAF V600 mutation positive, a BRAF inhibitor, which was approved under the provisions of 21 C.F.R., 601, Subpart E Clinical Pharmacology (accelerated approval; ref. 7), is summarized below. The pharmacokinetics (PK) of pembrolizumab was studied in 479 patients with advanced melanoma or carcinoma at the dose Chemistry range of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 Pembrolizumab is an IgG4k humanized monoclonal antibody weeks. Based on a population PK analysis, the mean clearance and that binds to the PD-1 receptor and blocks the interaction with its elimination half-life with percent coefficient of variation (CV%) ligands, PD-L1 and PD-L2. Each heavy chain contains 447 amino are 0.22 L/day (28%) and 26 days (24%), respectively. Steady- acids, and each light chain contains 218 amino acids. There are 32 state concentrations of pembrolizumab were reached by 18 weeks cysteine residues that form four disulfide linkages as intrachain of repeated dosing with an every-3-weeks regimen, and the bonds and 12 intrachain disulfide bonds. The molecular weight of increase in the systemic exposure was dose proportional with glycosylated pembrolizumab is approximately 149 kDa. accumulation of 2.1-fold. No clinically important differences in the clearance of pem- Nonclinical Pharmacology and Toxicology brolizumab were found between patients with renal impairment or mild hepatic impairment and those with normal hepatic and Pembrolizumab bound to PD-1 in humans and cynomolgus renal function. The PK of pembrolizumab was not studied in monkeys to a similar extent but did not bind to PD-1 in rodents; patients with moderate to severe hepatic impairment. therefore, Merck evaluated the potential for antitumor activity of pembrolizumab in a murine tumor model using a surrogate anti- Clinical Trial Design mouse PD-1 monoclonal antibody. Pembrolizumab was tested in 4- and 26-week toxicity studies in Trial MK3475-P001 (P001) was a first-in-human, internation- cynomolgus monkeys. Effects were limited to an increased fre- al, open-label trial consisting of multiple cohorts evaluating the quency of alopecia and liquid/unformed feces in treated animals tolerability and preliminary activity of several doses and sche- compared with controls, and a diffuse pattern of immune cell dules of pembrolizumab in patients with a variety of advanced infiltration that lacked clear clinical correlates. No evidence of solid tumors, as outlined in Table 1. The primary clinical data autoimmune disease was observed. supporting the FDA's decision were obtained in the patients Published data in other animal models raise concerns about the enrolled in cohort B2, supported by patients enrolled in cohorts toxicity of pembrolizumab in patients with chronic infections; B1 and D. Patients in cohort B2 were randomized (1:1) to receive infection of PD-1–deficient mice with Mycobacterium tuberculosis either 2 or 10 mg/kg of pembrolizumab by intravenous infusion resulted in a marked decrease in survival compared with similarly every 3 weeks until disease progression or unacceptable toxicity. infected wild-type animals, which correlated with increases in Ipilimumab-refractory was defined as receipt of at least two doses both bacterial proliferation and florid and destructive inflamma- of ipilimumab (minimum 3 mg/kg) and documented disease tory responses in the lungs of PD-1–deficient animals compared progression by immune-related response criteria (irRC) within 24 with wild-type controls (8). Because PD-1 inhibition prevents weeks of the last dose of ipilimumab. Evaluation by irRC used physiologic downregulation of the immune response, the poten- two-dimensional measurements, required confirmation of dis- tial risks of an unchecked immune response following ease progression 4 to 6 weeks after first detection, and incorpo- vaccination or multiple exposures to other antigens in patients rated the measurements of new lesions into the overall tumor undergoing treatment with pembrolizumab were communicated burden (9). Patients with BRAF V600 mutation–positive mela- in the drug label. In addition, Merck was asked to conduct a noma were also required to have documented disease progression

Table 1. Trial P001 MK-3475 dose Interval between Patients Part Cohort Population (mg/kg) doses (weeks) (N) A A Refractory solid tumors 1, 3, and 10 2a 10 A1 Refractory solid tumors 10 2 7 A2 Refractory solid tumors 2 or 10b,c 313 B B1 Melanoma (IPI-na€ve or IPI-treated) 2 or 10 2 or 3 135 B2 Melanoma (IPI-refractory) 2 or 10b 3 173 B3 Melanoma (IPI-na€ve, IPI-treated, or IPI-refractory) 10b 2 or 3 248 C NSCLC 10 3 38 D Melanoma (IPI-na€ve) 2 or 10b 3103 F F1 NSCLC (no prior treatment) 10b 2or3 43d F2 NSCLC (previous systemic treatment) 10b 2 or 3 200d Abbreviations: IPI, ipilimumab; NSCLC, non–small cell lung cancer. aDosing interval of 28 days for cycle 1 for PK analysis and 14 days for cycle 2 and beyond. bRandomized. cThree cohorts with separate cycle 1 intrapatient dose titration followed by either 2 or 10 mg/kg every 3 weeks for cycle 2 and beyond. dEnrollment ongoing at the time of the BLA review.

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Table 2. ORR and DOR based on BICR per RECIST v1.1 for cohort B2 of trial P001 progressive disease were rescanned after 4 to 6 weeks and dis- Pembrolizumab Pembrolizumab continued treatment if progressive disease was confirmed. (2 mg/kg; (10 mg/kg; All The primary endpoint of cohort B2 was confirmed ORR as N ¼ 89) N ¼ 84) (N ¼ 173) assessed by blinded independent central review (BICR) using n (%) n (%) n (%) ORR (%) 21 (23.6) 20 (23.8) 41 (23.6) RECIST v1.1. With 160 patients, there was approximately 85% 95% CI (15.2–33.8) (15.2–34.3) (15.2–34.3) power to detect a 15% difference in ORR between doses at a CR 1 (1) 1 (1) 2 (1) 10% one-sided type I error rate, assuming that the ORR in the PR 20 (22) 19 (23) 39 (23) inferior arm was 10%. ORR by irRC was evaluated as a sec- DOR ondary endpoint. Median, months NR (1.4þ,8.5þ)NR(2þ,9þ)NR(1.5þ,9þ) (range of responses) NOTE: þ sign indicates response ongoing at time of data cutoff. Results Abbreviations: CI, confidence interval; CR, complete response; PR, partial Patient characteristics response; NR, not reached. The baseline demographic and tumor characteristics of the 173 patients treated in cohort B2 were as follows: median age 61 years after treatment with a BRAF and/or MEK inhibitor. Patients were (range, 18–88), 36% age 65; 60% male; 97% White; 66% and ineligible if they had any history of severe immune-related toxicity 34% with an ECOG Performance Status of 0 and 1, respectively; attributed to ipilimumab [defined as any NCI Common Termi- 17% BRAF V600 mutation; 39% elevated lactate dehydrogenase; nology Criteria for Adverse Events (CTCAE) grade 4 toxicity 82% M1c disease; 9% brain metastases; and 73% two or more requiring treatment with steroids or grade 3 toxicity requiring prior therapies for advanced or metastatic disease. steroid treatment (>10 mg/day prednisone or equivalent) for >12 weeks]; a medical condition that required systemic steroids or Efficacy other immune-suppressive medication; a history of pneumonitis The efficacy results for cohort B2 of trial P001 are summarized or interstitial lung disease; or an active infection requiring therapy, in Table 2. Pembrolizumab at the 2 mg/kg and 10 mg/kg doses including HIV or hepatitis B or C. Tumor response assessments demonstrated ORRs of 23.6% and 23.8%, respectively, according were conducted every 9 weeks. to RECIST v1.1. The median DOR was not reached, but responses Investigators used irRC to evaluate imaging during the course of ranged from 1.4þ to 8.5þ months (Table 2). Additional cohorts the trial, and patients were allowed to remain on treatment if they of trial P001 with longer duration of follow-up (at least 1 year and experienced progressive disease and met the following criteria: 9 months, respectively, for cohorts B1 and D) were analyzed to no symptoms and signs indicating clinically significant disease provide supportive evidence of the effect on ORR and on the progression, decline in Eastern Cooperative Oncology Group durability of response. (ECOG) Performance Status, or rapid progression of disease or Response rates were similar as assessed by the BICR per RECIST progressive tumor at critical anatomic sites requiring urgent v1.1 and by irRC (Table 3). Only one of the 89 patients receiving medical intervention. Patients who continued treatment after pembrolizumab 2 mg/kg every 3 weeks in cohort B2 was found to

Table 3. ORR in cohorts B1, B2, and D by BICR per RECIST v1.1 and irRC Pembrolizumab (2 mg/kg q3w) N (%) Pembrolizumab (10 mg/kg q3w) N (%) Pembrolizumab (10 mg/kg q2w) N (%) Response criteria RECIST irRC RECIST irRC RECIST irRC Cohort B1 N ¼ 22 N ¼ 22 N ¼ 56 N ¼ 56 N ¼ 57 N ¼ 57 ORR (%) 9 (41) 8 (36) 16 (29) 18 (32) 28 (49) 30 (53) 95% CI (21–64) (17–59) (17–42) (20–46) (36–63) (39–66) CR 2 2 3 3 11 12 PR 7 6 13 15 17 18 DOR (months) Median NR – NR – NR – Range 2.1þ to 13.8þ – 2.5þ to 16.6þ – 1.8þ to 17.5þ – Cohort B2 N ¼ 89 N ¼ 89 N ¼ 84 N ¼ 84 NA NA ORR (%) 21 (24) 17 (19) 20 (24) 20 (24) –– 95% CI (15–34) (12–29) (15–34) (15–34) –– CR 1 0 1 1 –– PR 20 17 19 19 –– DOR (months) Median NR – NR ––– Range 1.4þ,8.5þ – 2þ,9þ ––– Cohort D N ¼ 51 N ¼ 51 N ¼ 52 N ¼ 52 NA NA ORR (%) 17 (33) 18 (35) 19 (37) 19 (37) –– 95% CI (21–48) (22–50) (24–51) (24–51) –– CR 4 4 2 2 –– PR 13 14 17 17 –– DOR (months) Median NR – NR – NA NA Range 1.6þ to 8.3þ – 1.4þ to 9þ ––– Abbreviations: CI, conﬁdence interval; CR, complete response; PR, partial response; NA, not applicable. NR, not reached; q2w, every 2 weeks; q3w; every 3 weeks.

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have new lesions in the context of an overall decrease in tumor Table 4. Benefit–risk analysis for pembrolizumab in patients with advanced burden and was classified as having progressive disease by RECIST refractory melanoma but a partial response by irRC. Disease Patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Safety have a serious and life-threatening condition. The FDA's review concentrated on patients receiving 2 mg/kg in Unmet medical At the time of initial approval, FDA-approved therapies for cohort B2 for description of common adverse events (AE) in need this population included dacarbazine and aldesleukin product labeling, and on a pooled analysis of the 411 patients (IL2). Dacarbazine results in an ORR of 15% or less with with unresectable or metastatic melanoma treated on cohorts B1, short DORs, and aldesleukin has the potential for serious and fatal toxicity, such that it can be administered to a B2, and D to identify and characterize immune-related AEs (irAE). fi select group of exceptionally t patients. The most common ( 20%) adverse reactions with pembrolizu- Clinical benefit The ORR was 24% (95% CI, 15–34) according to BICR. These mab administered at 2 mg/kg every 3 weeks were fatigue (47%), responses appear durable, as with at least 6 months of cough (30%), pruritus (30%), nausea (30%), rash (29%), follow-up, 86% of patients had ongoing responses (range, decreased appetite (26%), constipation (21%), arthralgia 1.4þ to 8.5þ months). (20%), and diarrhea (20%). Risk The primary safety risks are immune-related adverse reactions, which were seen in 23% of patients in a pooled The pooled safety population consisted of patients who received N ¼ analysis. These were managed with steroid treatment and pembrolizumab at a dose of either 2 mg/kg every 3 weeks ( dose delays. Ten percent of patients discontinued 162), 10 mg/kg every 3 weeks (N ¼ 192), or 10 mg/kg every 2 weeks pembrolizumab, and 18% had treatment delays due to (N ¼ 57). The median duration of exposure was 6.2 months (range, any AEs. 1day–24.6 months), and patients received a median of 10 doses Uncertainties Although ORR is considered an endpoint that is reasonably fi (range, 1–51). The toxicity profile appeared similar across the three likely to predict clinical bene t in metastatic melanoma, no correlation with clinical benefit, including improved OS, dosages. Ten percent of patients discontinued pembrolizumab for has been established. Therefore, traditional approval for AEs, most commonly (0.7%) for pneumonitis. Eighteen percent of pembrolizumab requires confirmation of clinical benefit. patients had treatment delays due to AEs. Conclusions Pembrolizumab meets the criteria for accelerated approval The protocol defined irAEs as an AE of unknown etiology under the provisions of subpart E of 21 C.F.R. 601 (7). associated with drug exposure and consistent with an immune Pembrolizumab has a favorable benefit–risk profile for the phenomenon where efforts were made to exclude neoplastic, treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with infectious, metabolic, toxin, or other etiologic causes. In the ipilimumab and, if BRAF V600 mutation positive, a BRAF pooled analysis, 23% of patients experienced irAEs (any grade), inhibitor. Pembrolizumab results in an ORR of 24%, with including 5% with grade 3 to 4 irAEs. Serious irAEs included prolonged DORs in a patient population with a severe and hypothyroidism (8.3%), pneumonitis (2.9%), hyperthyroid- life-threatening condition with an unmet medical need. ism (1.2%), colitis (1%), nephritis (0.7%), hypophysitis The safety profile is acceptable given the life-threatening (0.5%), and hepatitis (0.5%). Other irAEs in >1% of patients nature of the condition being treated. were rash, vitiligo, pruritis, arthralgia, diarrhea, myalgia, cough, Abbreviation: CI, confidence interval. and pyrexia. Clinically significant irAEs in <1% of patients receiving 2 mg/kg in cohort B2 were exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, par- patients with refractory solid tumors in a "3 þ 3" dose-escalation tial seizures arising in a patient with inflammatory foci in brain cohort to determine a maximum tolerable dose, followed by 14 parenchyma, and adrenal insufficiency. patients with melanoma and renal cell cancer in disease-specific expansion cohorts. Over 2.5 years and eight amendments, Merck expanded the planned accrual to approximately 1,100 patients in Discussion nine disease-specific expansion cohorts that explored multiple The development program for pembrolizumab—the first FDA- doses and subpopulations. The evolution of trial P001 has been approved PD-1–blocking antibody—used three of the four FDA- previously described (11). This trial demonstrates that the expedited programs for development and review of drugs for nomenclature traditionally assigned to clinical trials at successive serious and life-threatening diseases (breakthrough therapy desig- stages of development (i.e., phase 1 for dose and toxicity evalu- nation, priority review, and accelerated approval; ref. 9). Pembro- ation, phase 2 for activity estimation, and phase 3 for determi- lizumab was the first oncology drug granted breakthrough therapy nation of clinical benefit) is not adequate to describe complex, designation, a program that facilitated frequent interactions with seamless-design clinical trials that, in select circumstances with the FDA during development. The BLA for pembrolizumab was highly effective drugs, may support regulatory approval. The designated priority review and received accelerated approval in advantage of this approach is an efficient development program September 2014 for the treatment of patients with advanced that has the potential to rapidly accrue patients and allow flex- refractory melanoma—less than 4 years from the date of initial ibility in exploration of activity. However, given the exposure of Investigational New Drug (IND) submission—based on a favor- large numbers of patients to an unapproved drug, the conduct of able benefit–risk profile, with demonstration of a clinically relevant these large trials requires considerable oversight, and consider- ORR with prolonged DORs and an acceptable toxicity profile in ation must be given to measures that ensure patient safety, this patient population with an unmet medical need (Table 4). appropriate patient selection, adequate informed consent, and This expedited development program consisted of data from adequate justification for sample sizes in expansion cohorts in one randomized cohort of a large "phase 1" trial that had multiple prespecified statistical designs (11–13). disease-specific, activity-estimating expansion cohorts. Trial Although a single trial was used to evaluate antitumor activity, P001, a first-in-human trial, was initially designed to enroll 18 there was an adequate sample size to assess the ORR with

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reasonable precision, the ability to make comparisons of the are insufficient data with use of irRC to determine whether it treatment effect with two different dosage regimens, and provides any advantages over RECIST for evaluating antitumor sufficient safety experience. The major issue was the short activity or predicting clinical benefit. The use of RECIST in this trial duration of follow-up in cohort B2 such that the DOR, which did not underestimate the clinical activity of pembrolizumab as was a major consideration in assessing antitumor activity, was assessed by ORR compared with irRC; therefore, the role of irRC in imperfectly characterized. assessing antitumor activity remains unclear. In addition to the use of a single trial to support regulatory Pembrolizumab was approved under the accelerated approval approval, several other important regulatory issues were pathway given the uncertainty of the relationship of the observed addressed during the BLA review and included evaluation of ORR and DOR to effects on PFS and OS. Clinical trials designed to a unique AE profile,doseselection,anduseofalternative verify clinical benefit were required and were ongoing at the time endpoints for immunotherapy drugs. IrAEs are a unique aspect of approval. of the safety profile of pembrolizumab. Serious irAEs observed in patients at the time of initial approval included pneumo- Disclosure of Potential Conflicts of Interest nitis, colitis, hepatitis, hypophysitis, nephritis, and hyper- and No potential conflicts of interest were disclosed. hypothyroidism. These events were managed with steroid Disclaimer treatment and dose delays, and were considered acceptable in The Deputy Editor handling the peer review and decision-making process for patients with a severe and life-threatening disease. A Risk this article has no relevant employment associations to disclose. Evaluation and Mitigation Strategy was not considered neces- sary given the experience of the medical community in man- Authors' Contributions aging similar irAEs from ipilimumab. Conception and design: M.K. Chuk, J.T. Chang, M.R. Theoret, E. Sampene, The doses of pembrolizumab chosen for evaluation in cohort R. Pazdur B2 were based upon a PK/pharmacodynamic (PD) approach Development of methodology: M.K. Chuk, J.T. Chang, E. Sampene, R. Pazdur using clinical biomarker (IL2 release) and a translational PK/PD Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.T. Chang, R. Pazdur projection of clinical response based on preclinical studies, as an Analysis and interpretation of data (e.g., statistical analysis, biostatistics, MTD was not reached in the initial dose-escalation cohorts. The computational analysis): M.K. Chuk, J.T. Chang, M.R. Theoret, E. Sampene, results of these analyses suggested that 1 to 2 mg/kg every 3 weeks K. He, R. Jin, L. Zhao, M. Paciga, D. Schmiel, P. Keegan, R. Pazdur was the lowest dose range with a high likelihood of providing Writing, review, and/or revision of the manuscript: M.K. Chuk, J.T. Chang, substantial clinical benefit. The exposure–response relationship M.R. Theoret, E. Sampene, K. He, S.L. Weis, W.S. Helms, R. Jin, H. Li, J. Yu, between 2 and 10 mg/kg every 3 weeks was flat for both efficacy H. Zhao, M. Paciga, D. Schmiel, P. Keegan Administrative, technical, or material support (i.e., reporting or organizing (ORR) and safety (immune-related and NCI CTCAE grade 3–5or data, constructing databases): J.T. Chang, R. Jin, P. Keegan, R. Pazdur serious AEs), supporting the approval of the lower dose (14). Study supervision: J.T. Chang, R. Pazdur Thus, the PK/PD approach toward dose selection was a good Other (I was the primary reviewer for pembrolizumab at time of clinical model for prediction of treatment effects. This finding underlies development, which included reviewing and granting the breakthrough the importance of verifying PK/PD modeling through clinical designation to pembrolizumab): J.T. Chang trials and the need to continue to assess and refine optimal dosage Other (I am one of the product quality reviewer who contributed to the product description in this manuscript and reviewed the manufacturing, regimens through dose-ranging clinical trials, preferably through chemistry, and control of pembrolizumab in the licensing application): randomization to doses, as occurred with cohort B2. R. Rawat The protocol for P001 initially specified that the primary endpoint of cohort B2 was ORR determined by the investigator Received October 12, 2016; revised December 8, 2016; accepted February 20, using irRC but was amended at the request of the FDA, as there 2017; published OnlineFirst February 24, 2017.

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FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

Meredith K. Chuk, Jennie T. Chang, Marc R. Theoret, et al.

Clin Cancer Res Published OnlineFirst February 24, 2017.

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