VOLUME 36 • NUMBER 17 • JUNE 10, 2018 JOURNAL OF CLINICAL ONCOLOGY R A P I D C O M M U N I C A T I O N Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, Jin Zhang, James Anderson, Scott J. Diede, Scot Ebbinghaus, and F. Stephen Hodi Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on December 28, 2017. Processed as a Rapid Communication manuscript. Clinical trial registration: NCT01295827. Corresponding author: Caroline Robert, MD, PhD, Institut Gustave Roussy,114 rue Edouard Vaillant, 94805, Villejuif Paris Sud, France; e-mail: caroline.robert@ gustaveroussy.fr. © 2017 by American Society of Clinical Oncology 0732-183X/18/3617w-1668w/$20.00 A B S T R A C T Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study (ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for $ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of $ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation. J Clin Oncol 36:1668-1674. © 2017 by American Society of Clinical Oncology INTRODUCTION ASSOCIATED CONTENT See accompanying Oncology Grand Rounds on page 1649 Data Supplement DOI: https://doi.org/10.1200/JCO. 2017.75.6270 DOI: https://doi.org/10.1200/JCO.2017. 75.6270 1668 Prognosis in patients with metastatic melanoma has historically been poor, with a median overall survival (OS) of , 1 year and a 10-year survival rate of approximately 10%.1,2 Melanoma treatment evolved with the introduction of targeted therapy for BRAF mutant disease and immune checkpoint inhibitors for patients with advanced disease regardless of BRAF mutation status. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), was the first checkpoint inhibitor to demonstrate activity in advanced melanoma, with an objective response rate of 6% to 11% and median OS of 9 months to 11 months.3-5 The anti–programmed death 1 (PD-1) monoclonal antibodies pembrolizumab and nivolumab, which block binding of PD-1 to its ligands PD-L1 and PD-L2, provided response rates of 30% to 40% and median OS of . 2 years in patients with metastatic melanoma.6-9 Pembrolizumab has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types, and is currently approved in . 60 countries for one or more advanced malignancies, including unresectable or metastatic melanoma. © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Complete Responses in Melanoma After Pembrolizumab In the multicohort, phase 1b KEYNOTE-001 study (ClinicalTrials.gov identifier: NCT01295827), pembrolizumab monotherapy provided an objective response rate of 33% per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) by independent central review in patients with advanced melanoma.6 The two main goals of the current analysis were to (1) characterize complete response (CR) in terms of time to response, duration of response, and outcomes for patients from the time of CR and from the time of discontinuation of treatment after CR; and (2) identify potential predictors of these optimal treatment outcomes with use of pembrolizumab in the KEYNOTE-001 study. METHODS Study Design and Patient Population KEYNOTE-001 was an open-label, phase 1b clinical trial that included multiple cohorts of patients with advanced solid tumors, including melanoma and non–small-cell lung cancer. Detailed eligibility criteria for the patients with ipilimumab-naive or ipilimumab-treated advanced melanoma were published previously by Ribas et al.6 Briefly, eligible patients were $ 18 years of age with confirmed metastatic melanoma, measurable disease per immune-related response criteria (irRC),10 Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, no history of chemotherapy within 4 weeks of first pembrolizumab dose, and no history of treatment targeting the PD-1/PD-L1 pathway. Patients were enrolled in nonrandomized and randomized cohorts. Treatment and Assessments Patients received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient or investigator decision to withdraw. After a protocol amendment, patients who experienced CR, confirmed by two imaging scans $ 4 weeks apart, and who received pembrolizumab treatment of $ 6 months could, at the discretion of the investigator and if the patient desired, discontinue treatment after receiving at least two pembrolizumab doses beyond the initial determination of CR. Patients were not considered to have achieved CR if they had undergone surgery or radiation for residual disease. Tumor response was assessed every 12 weeks by independent central review using RECIST v1.1 (for determining efficacy) and by investigator review using irRC (for patient management). For the purpose of this analysis, CR was defined using investigator response per irRC. Disease-free survival (DFS) was defined as the time from declaration of CR to documented disease progression or death from any cause; for patients who did not experience an event, CR duration was censored at the time of their last disease evaluation. Duration of CR from time of discontinuation of pembrolizumab was calculated similarly. Statistical Analysis All analyses were performed in the treated population, which was defined as all patients who received at least one dose of pembrolizumab. CR rates and associated 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method. DFS was estimated using the Kaplan-Meier method. SAS software, version 9.4 (SAS Institute, Cary, NC), was used for all analyses. Several potential prognostic baseline factors (Supplemental Data) were studied in relation to response. PD-L1 expression was assessed using a clinical trial immunohistochemistry assay (PD-L1 IHC 22C3 pharmDx; Agilent Technologies, Santa Clara, CA) and the 22C3 antibody (Merck, Kenilworth, NJ), as previously described by Daud et al11; PD-L1 positivity was defined as $ 1% staining in tumor cells and mononuclear inflammatory cells. Factors identified using a univariate analysis were further examined in a multivariate analysis using a step-wise regression for jco.org variable selection. Analyses were performed using a data cutoff date of September 1, 2016. RESULTS Patients Of the 655 patients with advanced melanoma who received at least one dose of pembrolizumab, 104 (15.9%) were still receiving treatment as of the data cutoff date; median follow-up was 43 months (range, 36 to 57 months). The most common reasons for treatment discontinuation were progressive disease (41.7%) and adverse events (AEs; 25.0%). Median duration of pembrolizumab exposure was 6 months (range, 1 day to 55 months). Clinical Status Median OS in all 655 treated patients was 23.8 months (95% CI, 20.2-30.4), with 3-year and 4-year survival estimates of 42% and 37%, respectively. In the 152 treatment-naive patients, the 3-year and 4-year survival estimates were 51% and 48%, respectively. In the 561 treated patients with an evaluable first clinical response assessment, CR was the first radiologic response assessment in only nine patients (1.6%) per irRC, as evaluated by investigator review. In the 655 overall treated patients, across all assessments, 105 patients had a best confirmed overall response of CR, as evaluated by investigator review, for a CR rate of 16.0% (95% CI, 13.3% to 19.1%; Fig 1). Median time to first objective response was 3 months (range, 0.5 to 11 months); median time to CR was 12 months (range, 3 to 36 months). Notably, 84 of 105 patients (80.0%) with CR as their best confirmed overall response had partial response (PR) or CR at their first radiologic response assessment. Of the 105 patients with confirmed CR as best overall response, 92 (87.6%) remained in CR after a median follow-up of 30 months from first declaration of CR; median time receiving treatment was 24 months (range, 1 to 53 months). At the time of data cutoff, 14 patients (13.3%) were still electively receiving pembrolizumab, with a median time on treatment of $ 40 months (range, $ 36 to $ 53 months; Fig 1). Pembrolizumab was discontinued by the other 91 patients (86.7%) who experienced CR, which included 67 patients (63.8%) who elected to stop treatment after CR and proceeded to observation without further anticancer therapy (Fig 1). Among these 67 patients, median time to overall response was 3 months (range, 0.5 to 11 months), median time to CR was 13 months (range, 3 to 36 months), and median time receiving pembrolizumab was 23 months (range, 8 to 44 months; Fig 2). Median time receiving treatment after achieving CR (CR to last pembrolizumab dose) was 7 months (range, 0.5 to 41 months). Of the 67 patients who proceeded to observation without additional anticancer therapy, two (3.0%) died (of cardiac failure and aspiration, considered unrelated to study treatment or progressive disease), and four (6.0%) had progressive disease 5.6, 8.5, 22.8, and 37.3 months, respectively, after discontinuing pembrolizumab. Three of these four patients subsequently started a second course of pembrolizumab treatment. Of these patients, one remained on pembrolizumab for 4 months before a second occurrence of progressive disease and that patient is still alive; one is still receiving pembrolizumab therapy and has been for approximately © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. 1669 Robert et al Treated with pembrolizumab (N = 655) Had a best confirmed overall response of CR per irRC by investigator review* (n = 105; 16%) Remained on pembrolizumab (n = 14; 13%) Discontinued pembrolizumab (n = 91; 87%) Eligible for a second course of pembrolizumab, proceeded to observation without further anticancer therapy (n = 67) Died (n = 2) Not eligible for a second course of pembrolizumab, discontinued pembrolizumab (n = 24) Remained in CR (n = 61) Had PD (n = 4) AEs (n = 12) Physician decision (n = 7) PD (n = 2) Remained in CR (n = 9) Died (n = 3) Died (n = 1) Withdrew consent (n = 3) Remained in CR (n = 6) Fig 1. Patient disposition. (*) 92 patients (87.6%) remained in CR as of the data cutoff date. Of the 13 patients (12.4%) not in CR, seven experienced PD and six died. AE, adverse event; CR, complete response; irRC, immune-related response criteria; PD, progressive disease. 15 months; and one was receiving pembrolizumab therapy for approximately 9 months and subsequently died as a result of malignant neoplasm progression. Most patients (n = 61; 91.0%) maintained CR after a median time off pembrolizumab of 22 months (range, 4 to 46 months). For the remaining 24 patients (22.9%) who experienced CR but were Time to PD or last assessment Last dose Fig 2. Time to response and durability of response from the start of therapy in complete responders who discontinued pembrolizumab and proceeded to observation (n = 67). Bar length is equivalent to the time to the last imaging assessment by investigator review. CR, complete response; PD, progressive disease; PR, partial response. CR PR PD Time to death 0 6 12 18 24 30 36 42 48 54 60 Time Since the Start of Therapy (months) 1670 © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Complete Responses in Melanoma After Pembrolizumab not eligible for a second course of pembrolizumab and who discontinued pembrolizumab because of AEs (n = 12), progressive disease (n = 2), physician decision to withdraw (n = 7), or patient withdrawal of consent (n = 3; Fig 1), median time receiving treatment was 21 months (range, 1 to 44 months). Among the 12 patients who discontinued pembrolizumab because of an AE, three (25.0%) deaths occurred, one each from respiratory failure, ventricular fibrillation, and cardiorespiratory arrest; all were considered unrelated to study treatment. The remaining nine (75.0%) patients remained in CR at data cutoff. Of the seven patients who discontinued per investigator decision to withdraw because of CR, one (14.3%) died (of lymphoma) and six (85.7%) remained in CR. Disease-Free Survival As of the data cutoff date, only seven of 105 patients with CR experienced confirmed progressive disease, two while receiving initial pembrolizumab treatment, four after stopping pembrolizumab and proceeding to observation, and one still reported as receiving pembrolizumab treatment. As of the cutoff date, all seven patients with progressive disease were alive. For all 105 patients who experienced CR, the estimated 24-month DFS rate from declaration of CR was 90.9% (95% CI, 82.5% to 95.4%; Fig 3A). Four of 22 patients who discontinued pembrolizumab treatment for reasons other than progressive disease (AEs [n = 3], protocol violation [n = 1]) and who did not proceed to observation had died as of the data cutoff date. For the 67 patients who discontinued pembrolizumab after CR for observation, the estimated 24-month DFS rate from treatment discontinuation was 89.9%. For all 89 patients who discontinued pembrolizumab after CR for reasons other than progressive disease (regardless of whether they proceeded to observation), the estimated 24-month DFS rate from treatment discontinuation was 85.8% (Fig 3B). Potential Predictors of Complete Response Among the potential prognostic baseline factors explored and per univariate analysis, age, ipilimumab status, lactate dehydrogenase (LDH) level, ECOG PS, BRAF mutation status, prior BRAF inhibitor therapy, prior lines of therapy, tumor PD-L1 status, site of metastasis, tumor size, and albumin level were statistically significantly associated with CR (Table 1). Among the 655 patients treated, tumor PD-L1 status was unknown in 146 patients because of missing samples or insufficient tissue, and target lesion size per central review was unknown in 72 patients; tumor PD-L1 status and baseline tumor size both were unknown in 22 patients. Among the 459 patients with assessment data for baseline tumor PD-L1 status and tumor size, the highest rates of CR (42.7%) occurred in patients with smaller (1 to 5 cm) PD-L1–positive tumors at baseline (Table 2). Patients with larger baseline tumors (5 to 90 cm) had a lower CR rate (, 10%), except for those with baseline tumors 5 to 10 cm and with positive PD-L1 expression who had a CR rate of 20.5%, which was similar to the CR rate of those patients with smaller tumors (1 to 5 cm) and negative PD-L1 expression (20.7%). After adjusting for the association of baseline tumor PD-L1 status and tumor size with CR in a multivariate analysis, only age (P = .020) was associated with experiencing CR. CR rates were higher in treatment-naive patients and in those $ 65 years of age (Supplemental Data). Because LDH level was a highly significant predictor of CR rate in univariate analysis, is a known prognostic factor in melanoma associated with baseline tumor size, and is easier to measure than baseline tumor size, CR rates were also examined in subsets of patients defined by LDH level (less than one times the upper level of normal [ULN]; more than one times the ULN to no more than twice the ULN; and more than twice the ULN) and tumor PD-L1 status. A total of 155 patients could not be classified because of unknown LDH level or unknown tumor PD-L1 status. Only one CR was observed in a patient whose baseline LDH level was more than twice the ULN. In patients with baseline LDH level no more than twice the ULN, CR rates were lower in those with LDH level more than one times the ULN to no more than twice the ULN than in those with normal baseline LDH levels (no more than one times the ULN; Supplemental Data). In patients with normal baseline LDH levels, CR rates were higher in those with PD-L1–positive tumors (26.0%) than in those with PD-L1–negative tumors (16.9%). However, after adjusting for baseline tumor PD-L1 status and tumor size, the LDH level was no B 100 Disease-Free Survival (%) Disease-Free Survival (%) A 90 80 70 60 50 40 30 20 10 0 6 12 18 24 30 36 42 48 100 90 80 70 60 50 40 30 20 10 54 0 Time Since Achieving CR (months) No. at risk: All patients 105 6 12 18 24 30 36 42 48 Time Since Stopping Therapy (months) No. at risk: 97 90 70 63 38 18 9 3 0 All patients 89 75 56 42 26 12 5 1 0 Fig 3. Disease-free survival (A) from time of experiencing complete response (CR) in all patients who achieved CR (n = 105) and (B) from time of discontinuation of pembrolizumab in patients who discontinued after CR for reasons other than progression (n = 89). The hash marks designate patients who were censored at that time point. jco.org © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. 1671 Robert et al Table 1. Statistically Significant (P , .05) Univariate Comparisons of CR Rates by Baseline Patient and Disease Characteristics Characteristic No. of Patients With CR/Total No. of Patients Per Group CR Rate (95% CI), % 50/397 55/258 12.6 (9.5 to 16.3) 21.3 (16.5 to 26.8) 62/313 43/342 19.8 (15.5 to 24.7) 12.6 (9.3 to 16.6) 20/249 85/394 8.0 (5.0 to 12.1) 21.6 (17.6 to 26.0) 3/8 12/50 28/89 62/508 37.5 24.0 31.5 12.2 Age group, years # 64 $ 65 Ipilimumab status Naive Exposed LDH level . ULN # ULN M stage M0 M1a M1b M1c ECOG PS 0 1 BRAF mutation status Wild type Mutant Prior BRAF inhibitor therapy Yes No Lines of prior therapy 0 1 2 3+ Tumor PD-L1 status Negative Positive Unknown* Site of metastasis Lung only Liver, with or without other sites Other sites No baseline metastasis per central review Tumor burden† $ 1 to , 5 cm $ 5 to , 10 cm $ 10 to , 20 cm $ 20 to # 90 cm Unknown* Albumin level‡, quartile (g/dL) 1 ($ 2.3 to , 3.7) 2 ($ 3.7 to , 4.1) 3 ($ 4.1 to , 4.4) 4 ($ 4.4 to # 5.6) Unknown* P .003 .012 , .001 , .001 (8.5 to 75.5) (13.1 to 38.2) (22.0 to 42.2) (9.5 to 15.4) .002 85/444 20/210 19.1 (15.6 to 23.1) 9.5% (5.9 to 14.3) 87/493 17/156 17.6 (14.4 to 21.3) 10.3 (6.0 to 16.1) 7/111 98/544 6.3 (2.6 to 12.6) 18.0 (14.9 to 21.5) 36/157 40/207 16/178 13/113 22.9 19.3 9.0 11.5 13/123 75/386 17/146 10.6 (5.7 to 17.4) 19.4 (15.6 to 23.7) 11.6 (6.9 to 18.0) 29/84 16/201 46/298 14/72 34.5 8.0 15.4 19.4 (24.5 to 45.7) (4.6 to 12.6) (11.5 to 20.0) (11.1 to 30.5) 57/161 21/128 13/155 0/139 14/72 35.4 16.4 8.4 0 19.4 (28.0 to 43.3) (10.5 to 24.0) (4.5 to 13.9) (0 to 2.6) (11.1 to 30.5) .028 .002 .001 (16.6 to 30.3) (14.2 to 25.4) (5.2 to 14.2) (6.3 to 18.9) .024 , .001 , .001 .012 14/136 23/190 34/162 34/165 0/2 10.3 12.1 21.0 20.6 0 (5.7 to 16.7) (7.8 to 17.6) (15.0 to 28.1) (14.7 to 27.6) (0 to 84.2) Abbreviations: CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; PD-L1, programmed death ligand 1; ULN, upper limit of normal. *Patients with unknown baseline characteristics were excluded from P value calculation. †Defined as the sum of the longest dimension of all measurable target lesions assessed by Response Evaluation Criteria in Solid Tumor v1.1. ‡The difference in the number of patients per quartile is a result of many patients having an albumin value of exactly 3.7 g/dL. longer significantly associated with CR, largely because tumor size and LDH level were highly related. DISCUSSION Although data on antitumor activity and safety of immune checkpoint inhibitors in oncology are abundant, to our knowledge, 1672 this report is the first in-depth analysis of CR in a large cohort of patients with metastatic melanoma treated with a PD-1 inhibitor. Similar results were recently published in a smaller retrospective study in patients with melanoma.12 Among patients with advanced melanoma enrolled in KEYNOTE-001, pembrolizumab provided a confirmed best overall response based on investigator assessment per irRC of CR in 16.2% of patients. Risk for disease progression or death in patients who experienced CR was low; the 24-month DFS © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Complete Responses in Melanoma After Pembrolizumab Table 2. Response Rates by Baseline Tumor Size and Tumor PD-L1 Status for the Patients With Available Data (n = 459) Tumor Size, cm Tumor PD-L1 Status No. PR, % CR, % ORR, % $ 1 to , 5 Positive Negative Positive Negative Positive Negative 96 29 78 23 179 54 24.0 6.9 37.2 8.7 24.0 16.7 42.7 20.7 20.5 8.7 5.6 1.9 66.7 27.6 57.7 17.4 29.6 18.5 $ 5 to , 10 $ 10 to # 90* Abbreviations: CR, complete response; ORR, overall response rate; PD-L1, programmed death ligand 1; PR, partial response. *Patients with tumors measuring 10 to 20 cm or 20 to 90 cm at baseline were pooled because these groups were not statistically different in univariate analysis. was estimated to be 90.9% after a median follow-up of 43 months and a median follow-up of 30 months from the time of first declaration of CR. The risk for disease progression or death after CR and discontinuation of pembrolizumab was similarly low; 24month DFS was estimated to be 85.8% for all patients who stopped treatment of any reason other than progressive disease and was 89.9% for those who discontinued treatment after CR for observation. In patients whose best confirmed overall response was CR, the majority had PR at first evaluation several months before occurrence of CR (median duration of 11 months between PR and CR), which is indicative of the delayed responses often seen with immunotherapy.13 In line with results of previous analyses of the large, randomized, phase 3 KEYNOTE-006 study (ClinicalTrials.gov identifier: NCT01866319), which showed that pembrolizumab has clinical activity in patients with advanced melanoma regardless of tumor PD-L1 status, CR was achieved even in patients with PDL1–negative tumors as similarly observed for 10.6% of the patients in this study.14,15 Analysis of baseline parameters potentially associated with objective response and CR showed that several baseline factors were associated with CR, many of which are also well-known prognostic factors like tumor burden, LDH level, and ECOG PS. When combining tumor burden and PD-L1 expression, we identified groups of patients with dramatically different objective response and CR rates (Fig 4). Indeed, patients (n = 96) with target tumor size between 1 and 5 cm and PD-L1–positive tumors had a CR rate of 42.7% versus 1.9% in patients (n = 54) with large tumor size and PD-L1–negative tumors. Between these two extremes, CR rates progressively decreased. In multivariate analysis, there was a similar, although less impressive, variation in CR rate when combining LDH level and PD-L1 expression status. Difference in CR rates resulting from baseline LDH level, albumin level, and ECOG PS probably reflect the relationship of these variables with tumor size. As of the data cutoff date in the current analysis, 61 of 67 patients (91.0%) who went on to observation after experiencing CR maintained CR after a median of approximately 2 years after pembrolizumab discontinuation. This prolongation of CR after pembrolizumab discontinuation has not been observed with targeted agents for which treatment is typically continued indefinitely.2 Treatment discontinuation for CR was not initially written into the protocol design for immune checkpoint inhibitors. On the basis of the results observed during clinical studies, which include the data presented herein from KEYNOTE-001, achievement of CR is now considered a possible reason for treatment discontinuation of this class of drugs; however, there is no standard recommendation for when to stop treatment after CR. Continued remission after a median of approximately 2 years after discontinuing pembrolizumab treatment is a promising advance in the field. However, as with any new paradigm, many questions emerge. The goal now is to understand the mechanisms underlying such optimal responses to therapy and the reasons for primary or secondary resistance in patients who do not experience CR. Additional studies are needed to evaluate the optimum duration of treatment to achieve prolonged CR, determine when to stop treatment after CR, and assess the interplay of the various factors potentially associated with CR. Indeed, KEYNOTE-006 systematically addresses the optimal duration of pembrolizumab treatment by limiting patients to 2 years of treatment. After approximately 10 months of median follow-up, more than 90% of patients who had discontinued pembrolizumab after 2 years were still experiencing CR or continued to have stable disease.16 In the current study, the prolonged CRs experienced with pembrolizumab provide hope for a cure for advanced melanoma without the need for additional treatment, a goal that seemed previously unachievable. Patients with known tumor size and PD-L1 expression status CR rate: 76 of 459 patients (16.6%) Small tumors 1-4.9 cm CR rate: 47 of 125 patients (37.6%) PD-L1+ CR rate: 41 of 96 patients (42.7%) jco.org PD-L1− CR rate: 6 of 29 patients (20.7%) Medium tumors 5-9.9 cm CR rate: 18 of 101 patients (17.8%) PD-L1+ CR rate: 16 of 78 patients (20.5%) PD-L1− CR rate: 2 of 23 patients (8.7%) Large tumors 10-90 cm CR rate: 11 of 233 patients (4.7%) PD-L1+ CR rate: 10 of 179 patients (5.6%) Fig 4. Regression tree for baseline factors associated with objective response and CR. CR, complete response; PD-L1, programmed death ligand 1. PD-L1− CR rate: 1 of 54 patients (1.9%) © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. 1673 Robert et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. AUTHOR CONTRIBUTIONS Conception and design: Caroline Robert, Adil Daud, Jedd D. Wolchok, Wen-Jen Hwu, Jin Zhang, Scot Ebbinghaus, F. Stephen Hodi Provision of study materials or patients: Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S.Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana REFERENCES 1. Balch CM, Gershenwald JE, Soong SJ, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199-6206, 2009 2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology, NCCN Evidence Blocks: Melanoma Version 1.2018 3. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010 4. O’Day SJ, Maio M, Chiarion-Sileni V, et al: Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: A multicenter single-arm phase II study. Ann Oncol 21: 1712-1717, 2010 5. Wolchok JD, Neyns B, Linette G, et al: Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155-164, 2010 Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, F. Stephen Hodi Collection and assembly of data: Caroline Robert, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, Jin Zhang, Scott J. Diede, F. Stephen Hodi Data analysis and interpretation: Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Jin Zhang, James Anderson, Scott J. Diede, Scot Ebbinghaus, F. Stephen Hodi Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors 6. Ribas A, Hamid O, Daud A, et al: Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315:1600-1609, 2016 7. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015 8. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015 9. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015 10. Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin Cancer Res 15:7412-7420, 2009 11. Daud AI, Wolchok JD, Robert C, et al: Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34:4102-4109, 2016 12. Ladwa R, Atkinson V: The cessation of antiPD-1 antibodies of complete responders in metastatic melanoma. Melanoma Res 27:168-170, 2017 13. Hodi FS, Hwu WJ, Kefford R, et al: Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 34:1510-1517, 2016 14. Carlino MS, Ribas A, Gonzalez R, et al: KEYNOTE-006: PD-L1 expression and efficacy in patients (Pts) treated with pembrolizumab (pembro) vs ipilimumab (IPI) for advanced melanoma. Proc Am Assoc Cancer Res. 76, 2016 (abstr CT004) 15. Daud A, Blank CU, Robert C, et al: KEYNOTE006 study of pembrolizumab (pembro) versus ipilimumab (ipi) for advanced melanoma: Efficacy by PDL1 expression and line of therapy. J Clin Oncol 34: 9513, 2016 (15_suppl) 16. Robert C, Long GV, Schachter J, et al: Longterm outcomes in patients (pts) with ipilimumab (ipi)naive advanced melanoma in the phase 3 KEYNOTE006 study who completed pembrolizumab (pembro) treatment. J Clin Oncol 35:9504, 2017 (15_suppl) Affiliations Caroline Robert, Gustave Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France; Antoni Ribas, University of California, Los Angeles; Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles; Adil Daud, University of California, San Francisco, San Francisco, CA; Jedd D. Wolchok, Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY; Anthony M. Joshua, The Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Wen-Jen Hwu, The University of Texas MD Anderson Cancer Center, Houston; Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Jeffrey S. Weber, H Lee Moffitt Cancer Center, Tampa; Richard W. Joseph, Mayo Clinic Cancer Center–Florida, Jacksonville, FL; Tara C. Gangadhar, Abramson Cancer Center at the University of Pennsylvania, Philadelphia; Hassane Zarour, UPMC Hillman Cancer Center, Pittsburgh, PA; Roxana Dronca, Mayo Clinic, Rochester, MN; Richard Kefford, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead; Melanoma Institute Australia, Wollstonecraft; and Macquarie University, MQ Health, Health Sciences Centre; Peter Hersey, University of Sydney, Sydney, New South Wales, Australia; Jin Zhang, James Anderson, Scott J. Diede, and Scot Ebbinghaus, Merck & Co., Inc., Kenilworth, NJ; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA. Support Supported by Merck & Co. Prior Presentation Presented in part at the 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016. The current data were presented in part at the 7th European Association of Dermato Oncology Post-Chicago Melanoma/Skin Cancer Meeting, Munich, Germany, June 29-30, 2017. nnn 1674 © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Complete Responses in Melanoma After Pembrolizumab AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Caroline Robert Consulting or Advisory Role: Amgen, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, Merck Antoni Ribas Stock or Other Ownership: Kite Pharma, Compugen, FLX Bio, CytomX Therapeutics, Five Prime Therapeutics, Arcus Ventures Consulting or Advisory Role: Merck, Amgen, Roche, Novartis Omid Hamid Consulting or Advisory Role: Amgen, Novartis, Roche, Bristol-Myers Squibb, Merck Speakers’ Bureau: Bristol-Myers Squibb, Genentech, Novartis, Amgen Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Celldex (Inst), Genentech (Inst), Immunocore (Inst), Incyte (Inst), Merck (Inst), Merck Serono (Inst), MedImmune (Inst), Novartis (Inst), Pfizer (Inst), Rinat (Inst), Roche (Inst) Adil Daud Stock or Other Ownership: Oncosec Honoraria: EMD Serono, Inovio Pharmaceuticals Consulting or Advisory Role: Oncosec, Merck, GlaxoSmithKline, Genoptix Research Funding: Merck (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Roche (Inst), Oncosec (Inst) Patents, Royalties, Other Intellectual Property: Patent relating to test for immunotherapy Jedd D. Wolchok Stock or Other Ownership: Potenza Therapeutics, Tizona Therapeutics, Serametrix, Adaptive Biotechnologies, Trieza Therapeutics, Imvaq Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, MedImmune, Polynoma, Polaris, Genentech, FStar, Beigene, Sellas Life Sciences, Lilly, Potenza Therapeutics, Tizona Therapeutics, Amgen, Chugai Pharma, Adaptive Biotechnologies, Janssen Pharmaceuticals Research Funding: Bristol-Myers Squibb (Inst), Merck, Roche, MedImmune Patents, Royalties, Other Intellectual Property: Co-inventor on an issued patent for DNA vaccines for treatment of cancer in companion animals, and on a patent for use of oncolytic Newcastle Disease virus Travel, Accommodations, Expenses: Bristol-Myers Squibb, Chugai Pharma, Roche, Janssen, Kadmon, Regeneron Anthony M. Joshua No relationship to disclose Wen-Jen Hwu Consulting or Advisory Role: Merck Research Funding: Merck, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune Jeffrey S. Weber Stock or Other Ownership: Altor BioScience, Celldex, CytomX Therapeutics Honoraria: Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Lion Biotechnologies, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris , CytomX Therapeutics Pharmaceuticals, Nektar, Novartis, Medivation, Sellas Life Sciences, WindMIL Consulting or Advisory Role: Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai, GlaxoSmithKline CytomX Therapeutics, Nektar, Novartis, Medivation, Sellas Life Sciences, WindMIL Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), GlaxoSmithKline (Inst), Genentech (Inst), Astellas Pharma (Inst), Incyte (Inst), Roche (Inst), Novartis (Inst) Patents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker and on a patent from Biodesix for an anti-programmed death 1 antibody biomarker Travel, Accommodations, Expenses: Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis Tara C. Gangadhar Honoraria: Medscape, Novartis, Merck, Bristol-Myers Squibb, Incyte Research Funding: Merck (Inst), Incyte (Inst), Bristol-Myers Squibb (Inst), Roche (Inst) Richard W. Joseph Consulting or Advisory Role: Bristol-Myers Squibb, Nektar, Genoptix, Eisai, Incyte, Novartis, Merck (Inst), Exelixis Research Funding: Merck (Inst), Bristol-Myers Squibb (Inst), Roche (Inst), X4P (Inst), Amgen (Inst) Roxana Dronca Research Funding: Merck (Inst) Other Relationship: advisory board member for Elsevier’s Practice Update Website Amita Patnaik Research Funding: Merck (Inst), Pfizer (Inst), AVEO (Inst), Lilly (Inst), Plexxikon (Inst), Jiangsu Hengrui Medicine (Inst), Symphogen (Inst), Corvus Pharmaceuticals (Inst), Tesaro (Inst), Bayer (Inst), Abbvie, Aeglea Biotherapeutics, Alexion Pharmaceuticals, Amgen, Asana Biosciences, Ascentage Pharma Group, Astex Pharmaceuticals, Calithera Biosciences, Celgene (Inst), Daiichi Sankyo (Inst), Eisai (Inst), EMD Serono (Inst), Endocyte (Inst), Forty Seven, Five Prime Therapeutics (Inst), Formation Biologics (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Merck, Plexxikon, Upsher-Smith, Novartis, Bayer, OncoMed, Teva (Inst), Zymeworks (Inst), Tesaro (Inst), TaiRx (Inst), Cerulean Pharma (Inst), Regeneron (Inst), Jiangsu Hengrui Medicine, Macrogenics (Inst) Hassane Zarour Research Funding: Merck (Inst), Bristol-Myers Squibb (Inst), Tesaro (Inst) jco.org © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. Robert et al Richard Kefford Consulting or Advisory Role: Novartis, Merck, Bristol-Myers Squibb, Teva, Amgen Speakers’ Bureau: Merck Travel, Accommodations, Expenses: Bristol-Myers Squibb Peter Hersey No relationship to disclose Jin Zhang Employment: Merck Stock or Other Ownership: Merck James Anderson Employment: Merck Scot Ebbinghaus Employment: Merck Stock or Other Ownership: Merck F. Stephen Hodi Consulting or Advisory Role: Merck, Novartis, Roche, Amgen, EMD Serono, Bristol-Myers Squibb, Celldex Research Funding: Bristol-Myers Squibb (Inst), Merck (Inst), Roche (Inst), Novartis (Inst) Patents, Royalties, Other Intellectual Property: Patent pending as per institutional policy, and patent pending royalties received on MHC class I chain-related gene A-related disorders application to institution per institutional intellectual property policy Scott J. Diede Employment: Merck Stock or Other Ownership: Merck © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved. JOURNAL OF CLINICAL ONCOLOGY Complete Responses in Melanoma After Pembrolizumab Acknowledgment We thank the patients and their families and all investigators and site personnel. We also thank Maxine Giannotti for data acquisition and Roger Dansey for critical review of the manuscript, both from Merck. Medical writing and/or editorial assistance was provided by Tricia Brown and Payal Gandhi of the ApotheCom pembrolizumab team (Yardley, PA). This assistance was funded by Merck. Academic advisers, in conjunction with representatives of the company, designed the study. Data were collected by investigators and site personnel and analyzed in collaboration with senior academic authors and representatives of the study sponsor. jco.org © 2017 by American Society of Clinical Oncology Downloaded from ascopubs.org by 90.44.238.100 on March 3, 2021 from 090.044.238.100 Copyright © 2021 American Society of Clinical Oncology. All rights reserved.