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U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of Patients with Melanoma

U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of... Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 The Regulatory Issues: FDA Oncologist U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of Patients with Melanoma a a b b a THOMAS M. HERNDON, SUZANNE G. DEMKO, XIAOPING JIANG, KUN HE, JOSEPH E. GOOTENBERG, a a a MARTIN H. COHEN, PATRICIA KEEGAN, RICHARD PAZDUR a b Office of Oncology Drug Products, Office of New Drugs, and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA  Melanoma Key Words. FDA  PEG-IFN  Interferon- Disclosures: The authors indicated no financial relationships. Section Editors: Keith Flaherty: Roche/Genentech, GlaxoSmithKline, Eisai, Metamark, Otsuka, Novartis (C/A); Walter Urba: Bristol- Myers Squibb (C/A), (H) Reviewer “A”: Novartis, Merck, Bristol-Myers Squibb, Prometheus (C/A); Prometheus (H) Reviewer “B”: Merck (C/A), (H) (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the setting in which the use of peginterferon-alfa-2b is appropriate for melanoma patients. 2. Define the expectations with regard to survival and side effect profile in patients with melanoma receiving peginterferon-alfa-2b. CME CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT On March 29, 2011, the U.S. Food and Drug Administration thickness, ulceration, sex, and study center. Patients were approved peginterferon alfa-2b (PEG-IFN) (Sylatron™; assessed for recurrence by the investigators based on phys- Schering Corporation, Kenilworth, NJ) for the adjuvant ical examination every 3 months for 2 years and every 6 treatment of melanoma patients with microscopic or gross months thereafter. nodal involvement following definitive surgical resection in- The relapse-free survival (RFS) interval, the primary cluding complete lymphadenectomy. efficacy endpoint, was significantly longer in PEG-IFN– The approval was based on a single, open-label, multi- treated patients. The median RFS times were 34.8 center trial enrolling 1,256 patients. After surgical resec- months and 25.5 months, respectively. There was no sta- tion, patients were randomized (1:1) to either PEG-IFN or tistically significant difference in the overall survival observation for 5 years. PEG-IFN, 6 g/kg per week, was time. administered s.c. for eight doses, followed by 3 g/kg per The most common (>60%) grade 1–4 adverse reac- week for up to 252 weeks. tions were fatigue, increased alanine aminotransferase Stratification factors included microscopic or gross (ALT) and aspartate aminotransferase (AST), pyrexia, nodal involvement, number of positive nodes, Breslow headache, anorexia, myalgia, nausea, chills, and injec- Correspondence: Thomas M. Herndon, M.D., Division of Biological Oncology Products, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 5222, Silver Spring, Maryland 20993, USA. Telephone: 301-796-2320; Fax: 301-796-9849; e-mail: [email protected] Received March 19, 2012; accepted for publication August 20, 2012; first published online in The Oncologist Express on September 21, 2012. ©AlphaMed Press 1083-7159/2012/$20.00/0 http://dx.doi.org/10.1634/theoncologist. 2012-0123 The Oncologist 2012;17:1323–1328 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1324 PEG-IFN for Melanoma tion site reactions. The most common serious adverse re- tions. Five deaths were reported within 30 days of the actions were fatigue, increased ALT and AST, and last treatment dose, two resulting from cardiovascular pyrexia. Thirty-three percent of patients receiving PEG- disease considered as possibly related to treatment. The IFN discontinued treatment as a result of adverse reac- Oncologist 2012;17:1323–1328 INTRODUCTION including regional lymphadenectomy within 70 days of study Interferon has a long history in the adjuvant treatment of pa- entry, and had acceptable hematologic, hepatic, and renal func- tients with malignant melanoma. It was first approved in tion. Patients with ocular or mucous membrane melanoma December, 1995 for patients who were rendered disease were excluded as were patients with in-transit metastasis. free by surgery and who were at high risk for recurrence. In Other exclusions were for serious concomitant disease and for the trial that supported the approval, interferon treatment prior systemic melanoma therapy. led to a significantly longer overall survival duration, al- Randomization was performed using a minimization pro- though the survival advantage diminished after a longer fol- cedure to balance the following stratification factors: type of low-up time [1, 2]. Since the first adjuvant interferon trial, nodal involvement (N1, microscopic, nonpalpable node in- 12 additional surgical adjuvant randomized trials have been volvement usually discovered by sentinel node biopsy; N2, conducted using various dosing schedules of interferon (in- palpable node involvement), number of positive nodes (one, terferon-alfa-2a, interferon-alfa-2b, interferon , peginter- two to four, five or more, or not assessed), Breslow primary feron alfa-2b [PEG-IFN]) and various comparator regimens thickness (1.5 mm, 1.5 mm to 4 mm, 4 mm), ulceration [3, 4]. Six of the 12 trials demonstrated a relapse-free sur- of the primary tumor (present, absent, or unknown), gender, vival (RFS) benefit and one showed a survival benefit. A and institution. literature-based meta-analysis of 12 interferon trials dem- Patients were randomized 1:1 to the following arms: arm onstrated a 17% lower relapse risk than in untreated con- A, in which PEG-IFN was administered at 6 g/kg s.c. weekly trols, without a survival advantage [5]. Since the approval of for eight doses, then at 3 g/kg s.c. weekly for up to 5 years or PEG-IFN for melanoma, a meta-analysis of 14 interferon until disease progression, unacceptable toxicity, or death, and trials reported a modest, but statistically significant, sur- arm B, with observation for 5 years beginning at randomiza- vival advantage in patients with high-risk cutaneous mela- tion. noma treated with interferon- [6]. Dose modifications for PEG-IFN toxicity were included in PEG-IFN is a covalent conjugate of recombinant interferon the protocol. During the first 8 weeks of treatment, the starting alfa-2b with monomethoxy-polyethylene glycol. The biologi- dose of 6 g/kg per week could be first decreased to 3 g/kg cal activity derives from the interferon alfa-2b moiety. The per week, then to 2 g/kg per week, and finally to 1 g/kg per PEG (polyethylene glycol) protects the molecule from pro- week. PEG-IFN was permanently discontinued if the patient teolytic breakdown and increases the biological half-life of was unable to tolerate 1 g/kg per week. When the PEG-IFN the interferon protein. Peg-Intron is a longer-acting formu- dose was 3 g/kg per week, the dose could be decreased to 2 lation of Schering-Plough’s Intron A, which is a recombi- g/kg per week and then to 1 g/kg per week. PEG-IFN was nant version of a naturally occurring interferon-.In permanently discontinued if the patient was unable to tolerate contrast to Intron A, which is administered as an i.v. infu- 1 g/kg per week. sion daily for 5 days, weekly for 4 weeks, followed by a s.c. The primary FDA regulatory endpoint was the relapse-free injection three times weekly, Peg-Intron is administered s.c. survival (RFS) interval as determined by an independent re- once a week. [7–9]. view committee (IRC) whose members were masked to treat- On March 29, 2011, the U.S. Food and Drug Administra- ment assignment. The IRC conducted an audit of patient-level tion (FDA) granted approval of PEG-IFN (Sylatron™; Scher- data from case report forms (radiology and pathology reports ing Corporation, Kenilworth, NJ) for the adjuvant treatment of were available upon request) and assigned the following dates patients with American Joint Committee on Cancer (AJCC) for each patient: earliest date of recurrence, last date the patient stage III melanoma as evidenced by microscopic or gross was free from recurrence, earliest date of distant metastasis, nodal involvement. In this report, we describe the FDA review and last date the patient was free from distant metastasis. Sec- process and results that led to this approval. ondary endpoints were the distant metastasis-free survival (DMFS) time (the applicant’s primary endpoint), the overall survival time, the recurrence-free interval, and quality of life. MATERIALS AND METHODS The RFS time was defined as the time to the earliest of the fol- A single, phase III, open-label, randomized, multicenter trial was submitted, which included 101 participating sites, primar- lowing events: local-regional relapse, distant metastasis, or death. Investigators were instructed to obtain pathologic evi- ily European. The trial was conducted by The European Or- ganisation for Research and Treatment of Cancer (EORTC) dence of melanoma recurrence unless the recurrence occurred in the brain. The presence of multiple lesions during an imag- [10]. Study patients had melanoma of any tumor stage with ei- ing examination of the chest or liver was considered as accept- able evidence of distant recurrence. ther microscopic or palpable nodal involvement and no distant metastases. They had undergone definitive surgical resection, Tumor assessments during the lower-dose treatment phase Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 Herndon, Demko, Jiang et al. 1325 were made by physical examination every 3 months (months was 0.036, based on the number of DMFS events in the interim 3–24) and then every 6 months (years 2–5). Patients with N1 analysis. disease required a chest x-ray and liver ultrasound, and patients The RFS outcome is a composite endpoint that may be de- fined by death or relapse. In the PEG-IFN arm there were 328 with N2 disease required imaging with a chest c-ray or com- puted tomography (CT) scan of the chest, CT scan of the ab- RFS events (52%), and death was the first RFS event in 1% of domen, and CT or magnetic resonance imaging scan of the patients, distant metastasis was the first event in 30% of pa- tients, and local-regional recurrence was the first event in 22% brain at study entry. All patients were to undergo a chest x-ray of patients. Eighty-two percent of patients with local-regional every 6 months, and additional imaging modalities were per- formed in accordance with medical practice and physician dis- recurrence subsequently developed distant metastasis. In the observation arm, there were 368 RFS events (59%), and death cretion. was the first RFS event in 1% of patients, distant metastasis The original analysis plan required a sample size of 879 pa- was the first event in 33% of patients, and local-regional recur- tients. The final analysis was to be performed after 571 DMFS rence was the first event in 25% of patients. Seventy-three per- events, in order to provide 90% power at a two-sided signifi- cent of patients with local-regional recurrence subsequently cance level of 0.05 to detect a 10% greater 4-year DMFS rate, developed distant metastasis. assuming that the true DMFS rate at 4 years in the observation Sensitivity analyses were performed by the FDA to verify arm was 30%. The analysis plan included a proposal for an in- the reliability and robustness of the RFS effect. A “worst-case” terim analysis of the DMFS rate after 450 events and used the scenario analysis of the RFS outcome was conducted to inves- O’Brien Fleming boundaries for significance determination tigate the potential impact of missing data on the RFS effect and adjustment for controlling the type I error rate with a two- size. In this “worst-case” scenario analysis, RFS dates were re- sided p-value of .05. The study also was planned to have 85% assigned to the previous office visit date if the event date for power to detect a 10% absolute difference (35% versus 45%; patients in the PEG-IFN arm was outside the planned assess- hazard ratio [HR], 0.76) in the 5-year survival rates after 486 ment window, and it was reassigned to the next visit date for deaths. patients in the observation arm if the event date occurred In June 2002, the protocol was amended based on revised within 3 months of the previous visit (6 months if after 2 years assumptions for the 4-year DMFS-free rate among patients from randomization). The “worst-case” scenario analysis re- with N1 disease in the observation arm of a second EORTC sults using these reassigned dates demonstrated median RFS study, which indicated that the DMFS rate for control patients times of 33.9 months (95% CI, 25.3–47.4 months) for the in the study could approach 40% at 4 years. Thus, based on PEG-IFN group and 28.5 months (95% CI, 20.0–32.9 months) these revised assumptions, the sample size was increased to for the observation group and an estimated HR of 0.86 (95% 1,200 patients in order to observe the required 576 events to CI, 0.74–0.99), which was consistent with the primary RFS detect a 9.75% greater 4-year DMFS rate (control vs. PEG- analysis. IFN, 40% vs, 49.75%) with 90% power. There was no significant survival difference between PEG- The analysis plan was also revised following the FDA’s IFN–treated patients and patients randomized to observation. meeting with Schering on September 5, 2006. The revised There were 525 deaths (PEG-IFN, 262; observation, 263). The analysis plan stated that the primary efficacy analysis of the estimated HR was 0.98 (95% CI, 0.82–1.16; p-value  .781). RFS rate would be an unadjusted log-rank test to be conducted The safety database was derived from the experiences of after 576 DMFS events. 608 patients who received treatment with PEG-IFN from study EORTC 18991 and 628 patients who were observed. Nineteen RESULTS patients in the intent-to-treat population randomized to the In total, 1,256 patients were registered and randomized at 101 PEG-IFN arm received no treatment and were not included in clinical sites from July 18, 2000 to August 15, 2003. The ma- the review of safety. jority of the patients were enrolled from Europe (96%), with There was differential ascertainment for safety information the remainder accrued in Australia (3%) and Israel (1%). The between the two arms. For patients receiving PEG-IFN, ad- countries with the highest accruals were the U.K. (26%) and verse event data were collected from the date of randomization Italy (18%). Patient demographics for baseline entry variables until 30 days after the final dose of PEG-IFN. For patients in and tumor characteristics are summarized in Table 1. the observation arm, adverse event data were collected for the Based on 696 RFS events determined by the IRC at the data total time on study. This leads to a longer duration of follow-up cutoff date of March 31, 2006, the primary analysis of the RFS for patients in the observation arm and a possible overestima- probability was performed using the intent-to-treat population, tion of adverse events for these patients. of whom 696 patients experienced RFS events PEG-IFN, 328; Approximately 33% of patients receiving PEG-IFN dis- observation, 368). The median RFS interval was 34.8 months continued treatment because of adverse reactions. The most (95% confidence interval [CI], 26.1–47.4 months) for PEG- common adverse reactions present at the time of treatment dis- IFN and 25.5 months (95% CI, 19.6–30.8 months) for ob- continuation were fatigue (27%), depression (17%), anorexia served patients (Table 2, Fig. 1). In order to maintain a two- (15%), increased alanine aminotransferase (ALT) (14%), in- sided type I error rate of 0.05, the nominal two-sided creased aspartate aminotransferase (AST) (14%), myalgia significance level for the final analysis of the RFS outcome (13%), nausea (13%), headache (13%), and pyrexia (11%). www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1326 PEG-IFN for Melanoma Table 1. Patient demographics and tumor characteristics PEG-IFN Observation Total Characteristic (n  627), n (%) (n  629), n (%) (n  1,256), n (%) Demographics Sex Female 262 (42) 263 (42) 525 (42) Male 365 (58) 366 (58) 731 (58) Age, yrs 65 64 (10) 80 (13) 144 (11) Mean (SD) 48.8 (11.9) 48.8 (12.8) 48.8 (12.4) Median 50.0 50.0 50.0 Performance status score 0 529 (84) 531 (84) 1060 (84) 1 98 (16) 98 (16) 196 (16) Tumor characteristics Tumor stage TxN1 250 (40) 258 (41) 508 (40) TxN2 375 (60) 368 (59) 743 (59) Unspecified 2 (1) 3 (1) 5 (1) n of pathologically positive lymph nodes 02(1) 3 (1) 5 (1) 1 332 (53) 341 (54) 673 (54) 2–4 216 (34) 207 (33) 423 (34) 5 73 (12) 74 (12) 147 (12) Not evaluable 4 (1) 4 (1) 8 (1) Presence of a synchronous primary No 517 (82) 527 (84) 1044 (83) Yes 93 (15) 83 (13) 176 (14) Missing 17 (3) 19 (3) 36 (3) Site of the primary Head 39 (6) 35 (6) 74 (6) Neck 13 (2) 10 (2) 23 (2) Trunk 267 (43) 277 (44) 544 (43) Arm 67 (11) 71 (11) 138 (11) Leg 201 (32) 197 (31) 398 (32) Missing/unknown 40 (6) 39 (6) 79 (6) Breslow thickness of the primary, mm 1.5 136 (22) 136 (22) 272 (22) 1.5–3.99 276 (44) 284 (45) 560 (45) 4.0 147 (23) 148 (24) 295 (24) Missing/unknown 68 (11) 61 (10) 129 (10) Ulceration of the primary No 315 (50) 338 (54) 653 (52) Yes 192 (31) 181 (29) 373 (30) Missing/unknown 120 (19) 110 (18) 230 (18) Abbreviations: N, node; PEG-IFN, peginterferon-alfa-2b; SD, standard deviation; T, tumor. Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 Herndon, Demko, Jiang et al. 1327 Table 2. Independent review committee–determined RFS results in the intent-to-treat population RFS result PEG-IFN (n  627) Observation (n  629) n (%) of patients with RFS event 328 (52.3) 368 (58.5) n (%) of patients without RFS event 299 (47.7) 261 (41.5) Median duration of RFS (95% CI), mos 34.8 (26.1–47.4) 25.5 (19.6–30.8) Hazard ratio (95% CI) 0.82 (0.71–0.96) Nominal p-value (unadjusted log-rank test) .011 Data cutoff date was March 31, 2006. The hazard ratio was estimated using a Cox proportional hazards regression model with treatment arm as the only covariate. A hazard ratio 1 indicates that treatment with PEG-IFN is associated with a lower risk for recurrence or death than observation. Abbreviations: CI, confidence interval; PEG-IFN, peginterferon-alfa-2b; RFS, relapse-free survival. Figure 1. Kaplan–Meier curves of the recurrence-free survival (RFS) probability. The log-rank p-value was .011 based on 696 RFS events determined by the independent review committee at the data cutoff date of March 31, 2006. The incidence of serious adverse reactions was approxi- tients, compared with 1% of patients in the observation mately twofold higher (33% vs. 15%) in PEG-IFN–treated pa- arm. Cardiac adverse reactions, including myocardial in- tients than in those in the observation arm. Five deaths were farction, bundle-branch block, ventricular tachycardia, and reported within 30 days of the last treatment dose, two from supraventricular arrhythmia, occurred in 4% of PEG-IFN– cardiovascular disease that were considered possibly related to treated patients, compared with 2% of patients in the obser- treatment and three from unrelated causes. vation group. As with interferon alfa-2b, the most serious adverse reac- tions were severe depression, cardiac adverse events, and ret- DISCUSSION inopathy or other visual changes. The most common severe or The approval of PEG-IFN for the adjuvant treatment of pa- life-threatening (National Cancer Institute grade 3–4) adverse tients with AJCC stage III melanoma with microscopic or reactions were fatigue (16%), depression (7%), increased ALT gross nodal involvement was based on a sustained and clini- (11%), increased AST (11%), pyrexia (4%), increased -glu- cally meaningful longer RFS time (median, 34.8 months for tamyltransferase (4%), myalgia (4%), and headache (4%) in patients randomized to receive PEG-IFN compared with 25.5 the PEG-IFN–treated group, compared with 1% in the ob- months for those receiving no additional therapy). The result is servation group for these reactions. internally consistent across relevant subgroups defined by Depression occurred in 59% of PEG-IFN–treated patients baseline demographics and prognostic variables. Additional and 24% of patients in the observation group. Depression was evidence supporting the validity of the observed PEG-IFN severe or life threatening in 7% of PEG-IFN–treated pa- treatment effect on the RFS time is provided by the extensive www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1328 PEG-IFN for Melanoma prior experience with the predecessor drug, interferon alfa-2b, were limited by their retrospective approach and are more con- which has been demonstrated to have a similar effect on RFS sistent with “responder“ analyses in which the optimal treat- outcomes [1–6]. ment duration is based on who lives longest prior to recurrence. Although the toxicities associated with PEG-IFN treatment In this setting, patients who relapse early do not contribute to are considerable and have a negative impact on global health re- the analysis of appropriate dosing at later time points. In the absence of better information, product labeling both describes lated-quality of life [11], they are often reversible with treatment interruption or discontinuation. As such, they can be outweighed the planned treatment and provides information characterizing the dropout rate for toxicity and average treatment durations. in a risk:benefit assessment by a robust benefit outcome. This issue will be addressed as a postmarketing requirement. The FDA has stated that the RFS time is direct evidence of Given the clinically meaningful prolongation in time with- clinical benefit when the adjuvant treatment has minimal tox- out disease observed in study EORTC 18991, which is evi- icity [12], as in the case of hormonal agents for the adjuvant dence of direct clinical benefit given its magnitude, the scarcity treatment of breast cancer. However, the FDA recently ap- of alternative, noninterferon-based adjuvant treatments, and proved three drugs for the adjuvant treatment of solid tumors, the absence of curative salvage treatments for patients with re- either alone (imatinib) [13] or in combination with cytotoxic current melanoma, the risks for toxicity during treatment with chemotherapy (oxaliplatin, trastuzumab) [14, 15]. In those in- PEG-IFN do not outweigh the benefit of the 18% lower risk for stances, evidence of a disease-free survival benefit alone was disease recurrence. sufficient to support regular approval, despite the demonstra- tion of a greater risk for severe toxicities involving the neuro- AUTHOR CONTRIBUTIONS logic, cardiac, gastrointestinal, and vascular (edema) systems. Conception/Design: Martin H. Cohen, Thomas M. Herndon, Suzanne G. Similarly, in 2002, the FDA Oncologic Drugs Advisory Commit- Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, tee agreed that approval of interferon alfa-2b for the adjuvant Richard Pazdur Provision of study material or patients: Thomas M. Herndon, Suzanne G. treatment of melanoma was appropriate even though subsequent Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, studies did not provide evidence of an effect on the overall sur- Richard Pazdur vival time. The toxicity profile of PEG-IFN is similar to, if not Collection and/or assembly of data: Thomas M. Herndon, Suzanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, more favorable than, that observed for the interferon alfa-2b reg- Richard Pazdur imen indicated for the adjuvant treatment of melanoma. Data analysis and interpretation: Thomas M. Herndon, Suzanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, Richard The ideal dose of PEG-IFN as well as the ideal duration of Pazdur PEG-IFN therapy are unknown at this time. Describing a rec- Manuscript writing: Martin H. Cohen, Thomas M. Herndon, Suzanne G. ommended dose, when many patients were unable to tolerate Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, Richard Pazdur therapy as planned, was problematic. The FDA conducted Final approval of manuscript: Martin H. Cohen, Thomas M. Herndon, Su- multiple exploratory analyses to investigate relationships be- zanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia tween the extent of therapy and outcomes. All these analyses Keegan, Richard Pazdur alpha adjuvant therapy in patients with high-risk mela- vation in resected stage III melanoma: A phase III ran- REFERENCES noma: A systematic review and meta-analysis. J Natl domized controlled trial of health-related quality of life 1. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Cancer Inst 2010;102:493–501. and symptoms by the European Organisation for Re- Interferon alfa-2b adjuvant therapy of high-risk resected search and Treatment of Cancer Melanoma Group. 7. Bukowski RM, Tendler C, Cutler D et al. Treating cutaneous melanoma: The Eastern Cooperative Oncol- J Clin Oncol 2009;27:2916–2923. cancer with PEG Intron: Pharmacokinetic profile and ogy Group Trial EST 1684, J Clin Oncol 1996;14:7–17. dosing guidelines for an improved interferon-alpha-2b 12. 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U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of Patients with Melanoma

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Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 The Regulatory Issues: FDA Oncologist U.S. Food and Drug Administration Approval: Peginterferon-alfa-2b for the Adjuvant Treatment of Patients with Melanoma a a b b a THOMAS M. HERNDON, SUZANNE G. DEMKO, XIAOPING JIANG, KUN HE, JOSEPH E. GOOTENBERG, a a a MARTIN H. COHEN, PATRICIA KEEGAN, RICHARD PAZDUR a b Office of Oncology Drug Products, Office of New Drugs, and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA  Melanoma Key Words. FDA  PEG-IFN  Interferon- Disclosures: The authors indicated no financial relationships. Section Editors: Keith Flaherty: Roche/Genentech, GlaxoSmithKline, Eisai, Metamark, Otsuka, Novartis (C/A); Walter Urba: Bristol- Myers Squibb (C/A), (H) Reviewer “A”: Novartis, Merck, Bristol-Myers Squibb, Prometheus (C/A); Prometheus (H) Reviewer “B”: Merck (C/A), (H) (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the setting in which the use of peginterferon-alfa-2b is appropriate for melanoma patients. 2. Define the expectations with regard to survival and side effect profile in patients with melanoma receiving peginterferon-alfa-2b. CME CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT On March 29, 2011, the U.S. Food and Drug Administration thickness, ulceration, sex, and study center. Patients were approved peginterferon alfa-2b (PEG-IFN) (Sylatron™; assessed for recurrence by the investigators based on phys- Schering Corporation, Kenilworth, NJ) for the adjuvant ical examination every 3 months for 2 years and every 6 treatment of melanoma patients with microscopic or gross months thereafter. nodal involvement following definitive surgical resection in- The relapse-free survival (RFS) interval, the primary cluding complete lymphadenectomy. efficacy endpoint, was significantly longer in PEG-IFN– The approval was based on a single, open-label, multi- treated patients. The median RFS times were 34.8 center trial enrolling 1,256 patients. After surgical resec- months and 25.5 months, respectively. There was no sta- tion, patients were randomized (1:1) to either PEG-IFN or tistically significant difference in the overall survival observation for 5 years. PEG-IFN, 6 g/kg per week, was time. administered s.c. for eight doses, followed by 3 g/kg per The most common (>60%) grade 1–4 adverse reac- week for up to 252 weeks. tions were fatigue, increased alanine aminotransferase Stratification factors included microscopic or gross (ALT) and aspartate aminotransferase (AST), pyrexia, nodal involvement, number of positive nodes, Breslow headache, anorexia, myalgia, nausea, chills, and injec- Correspondence: Thomas M. Herndon, M.D., Division of Biological Oncology Products, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 5222, Silver Spring, Maryland 20993, USA. Telephone: 301-796-2320; Fax: 301-796-9849; e-mail: [email protected] Received March 19, 2012; accepted for publication August 20, 2012; first published online in The Oncologist Express on September 21, 2012. ©AlphaMed Press 1083-7159/2012/$20.00/0 http://dx.doi.org/10.1634/theoncologist. 2012-0123 The Oncologist 2012;17:1323–1328 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1324 PEG-IFN for Melanoma tion site reactions. The most common serious adverse re- tions. Five deaths were reported within 30 days of the actions were fatigue, increased ALT and AST, and last treatment dose, two resulting from cardiovascular pyrexia. Thirty-three percent of patients receiving PEG- disease considered as possibly related to treatment. The IFN discontinued treatment as a result of adverse reac- Oncologist 2012;17:1323–1328 INTRODUCTION including regional lymphadenectomy within 70 days of study Interferon has a long history in the adjuvant treatment of pa- entry, and had acceptable hematologic, hepatic, and renal func- tients with malignant melanoma. It was first approved in tion. Patients with ocular or mucous membrane melanoma December, 1995 for patients who were rendered disease were excluded as were patients with in-transit metastasis. free by surgery and who were at high risk for recurrence. In Other exclusions were for serious concomitant disease and for the trial that supported the approval, interferon treatment prior systemic melanoma therapy. led to a significantly longer overall survival duration, al- Randomization was performed using a minimization pro- though the survival advantage diminished after a longer fol- cedure to balance the following stratification factors: type of low-up time [1, 2]. Since the first adjuvant interferon trial, nodal involvement (N1, microscopic, nonpalpable node in- 12 additional surgical adjuvant randomized trials have been volvement usually discovered by sentinel node biopsy; N2, conducted using various dosing schedules of interferon (in- palpable node involvement), number of positive nodes (one, terferon-alfa-2a, interferon-alfa-2b, interferon , peginter- two to four, five or more, or not assessed), Breslow primary feron alfa-2b [PEG-IFN]) and various comparator regimens thickness (1.5 mm, 1.5 mm to 4 mm, 4 mm), ulceration [3, 4]. Six of the 12 trials demonstrated a relapse-free sur- of the primary tumor (present, absent, or unknown), gender, vival (RFS) benefit and one showed a survival benefit. A and institution. literature-based meta-analysis of 12 interferon trials dem- Patients were randomized 1:1 to the following arms: arm onstrated a 17% lower relapse risk than in untreated con- A, in which PEG-IFN was administered at 6 g/kg s.c. weekly trols, without a survival advantage [5]. Since the approval of for eight doses, then at 3 g/kg s.c. weekly for up to 5 years or PEG-IFN for melanoma, a meta-analysis of 14 interferon until disease progression, unacceptable toxicity, or death, and trials reported a modest, but statistically significant, sur- arm B, with observation for 5 years beginning at randomiza- vival advantage in patients with high-risk cutaneous mela- tion. noma treated with interferon- [6]. Dose modifications for PEG-IFN toxicity were included in PEG-IFN is a covalent conjugate of recombinant interferon the protocol. During the first 8 weeks of treatment, the starting alfa-2b with monomethoxy-polyethylene glycol. The biologi- dose of 6 g/kg per week could be first decreased to 3 g/kg cal activity derives from the interferon alfa-2b moiety. The per week, then to 2 g/kg per week, and finally to 1 g/kg per PEG (polyethylene glycol) protects the molecule from pro- week. PEG-IFN was permanently discontinued if the patient teolytic breakdown and increases the biological half-life of was unable to tolerate 1 g/kg per week. When the PEG-IFN the interferon protein. Peg-Intron is a longer-acting formu- dose was 3 g/kg per week, the dose could be decreased to 2 lation of Schering-Plough’s Intron A, which is a recombi- g/kg per week and then to 1 g/kg per week. PEG-IFN was nant version of a naturally occurring interferon-.In permanently discontinued if the patient was unable to tolerate contrast to Intron A, which is administered as an i.v. infu- 1 g/kg per week. sion daily for 5 days, weekly for 4 weeks, followed by a s.c. The primary FDA regulatory endpoint was the relapse-free injection three times weekly, Peg-Intron is administered s.c. survival (RFS) interval as determined by an independent re- once a week. [7–9]. view committee (IRC) whose members were masked to treat- On March 29, 2011, the U.S. Food and Drug Administra- ment assignment. The IRC conducted an audit of patient-level tion (FDA) granted approval of PEG-IFN (Sylatron™; Scher- data from case report forms (radiology and pathology reports ing Corporation, Kenilworth, NJ) for the adjuvant treatment of were available upon request) and assigned the following dates patients with American Joint Committee on Cancer (AJCC) for each patient: earliest date of recurrence, last date the patient stage III melanoma as evidenced by microscopic or gross was free from recurrence, earliest date of distant metastasis, nodal involvement. In this report, we describe the FDA review and last date the patient was free from distant metastasis. Sec- process and results that led to this approval. ondary endpoints were the distant metastasis-free survival (DMFS) time (the applicant’s primary endpoint), the overall survival time, the recurrence-free interval, and quality of life. MATERIALS AND METHODS The RFS time was defined as the time to the earliest of the fol- A single, phase III, open-label, randomized, multicenter trial was submitted, which included 101 participating sites, primar- lowing events: local-regional relapse, distant metastasis, or death. Investigators were instructed to obtain pathologic evi- ily European. The trial was conducted by The European Or- ganisation for Research and Treatment of Cancer (EORTC) dence of melanoma recurrence unless the recurrence occurred in the brain. The presence of multiple lesions during an imag- [10]. Study patients had melanoma of any tumor stage with ei- ing examination of the chest or liver was considered as accept- able evidence of distant recurrence. ther microscopic or palpable nodal involvement and no distant metastases. They had undergone definitive surgical resection, Tumor assessments during the lower-dose treatment phase Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 Herndon, Demko, Jiang et al. 1325 were made by physical examination every 3 months (months was 0.036, based on the number of DMFS events in the interim 3–24) and then every 6 months (years 2–5). Patients with N1 analysis. disease required a chest x-ray and liver ultrasound, and patients The RFS outcome is a composite endpoint that may be de- fined by death or relapse. In the PEG-IFN arm there were 328 with N2 disease required imaging with a chest c-ray or com- puted tomography (CT) scan of the chest, CT scan of the ab- RFS events (52%), and death was the first RFS event in 1% of domen, and CT or magnetic resonance imaging scan of the patients, distant metastasis was the first event in 30% of pa- tients, and local-regional recurrence was the first event in 22% brain at study entry. All patients were to undergo a chest x-ray of patients. Eighty-two percent of patients with local-regional every 6 months, and additional imaging modalities were per- formed in accordance with medical practice and physician dis- recurrence subsequently developed distant metastasis. In the observation arm, there were 368 RFS events (59%), and death cretion. was the first RFS event in 1% of patients, distant metastasis The original analysis plan required a sample size of 879 pa- was the first event in 33% of patients, and local-regional recur- tients. The final analysis was to be performed after 571 DMFS rence was the first event in 25% of patients. Seventy-three per- events, in order to provide 90% power at a two-sided signifi- cent of patients with local-regional recurrence subsequently cance level of 0.05 to detect a 10% greater 4-year DMFS rate, developed distant metastasis. assuming that the true DMFS rate at 4 years in the observation Sensitivity analyses were performed by the FDA to verify arm was 30%. The analysis plan included a proposal for an in- the reliability and robustness of the RFS effect. A “worst-case” terim analysis of the DMFS rate after 450 events and used the scenario analysis of the RFS outcome was conducted to inves- O’Brien Fleming boundaries for significance determination tigate the potential impact of missing data on the RFS effect and adjustment for controlling the type I error rate with a two- size. In this “worst-case” scenario analysis, RFS dates were re- sided p-value of .05. The study also was planned to have 85% assigned to the previous office visit date if the event date for power to detect a 10% absolute difference (35% versus 45%; patients in the PEG-IFN arm was outside the planned assess- hazard ratio [HR], 0.76) in the 5-year survival rates after 486 ment window, and it was reassigned to the next visit date for deaths. patients in the observation arm if the event date occurred In June 2002, the protocol was amended based on revised within 3 months of the previous visit (6 months if after 2 years assumptions for the 4-year DMFS-free rate among patients from randomization). The “worst-case” scenario analysis re- with N1 disease in the observation arm of a second EORTC sults using these reassigned dates demonstrated median RFS study, which indicated that the DMFS rate for control patients times of 33.9 months (95% CI, 25.3–47.4 months) for the in the study could approach 40% at 4 years. Thus, based on PEG-IFN group and 28.5 months (95% CI, 20.0–32.9 months) these revised assumptions, the sample size was increased to for the observation group and an estimated HR of 0.86 (95% 1,200 patients in order to observe the required 576 events to CI, 0.74–0.99), which was consistent with the primary RFS detect a 9.75% greater 4-year DMFS rate (control vs. PEG- analysis. IFN, 40% vs, 49.75%) with 90% power. There was no significant survival difference between PEG- The analysis plan was also revised following the FDA’s IFN–treated patients and patients randomized to observation. meeting with Schering on September 5, 2006. The revised There were 525 deaths (PEG-IFN, 262; observation, 263). The analysis plan stated that the primary efficacy analysis of the estimated HR was 0.98 (95% CI, 0.82–1.16; p-value  .781). RFS rate would be an unadjusted log-rank test to be conducted The safety database was derived from the experiences of after 576 DMFS events. 608 patients who received treatment with PEG-IFN from study EORTC 18991 and 628 patients who were observed. Nineteen RESULTS patients in the intent-to-treat population randomized to the In total, 1,256 patients were registered and randomized at 101 PEG-IFN arm received no treatment and were not included in clinical sites from July 18, 2000 to August 15, 2003. The ma- the review of safety. jority of the patients were enrolled from Europe (96%), with There was differential ascertainment for safety information the remainder accrued in Australia (3%) and Israel (1%). The between the two arms. For patients receiving PEG-IFN, ad- countries with the highest accruals were the U.K. (26%) and verse event data were collected from the date of randomization Italy (18%). Patient demographics for baseline entry variables until 30 days after the final dose of PEG-IFN. For patients in and tumor characteristics are summarized in Table 1. the observation arm, adverse event data were collected for the Based on 696 RFS events determined by the IRC at the data total time on study. This leads to a longer duration of follow-up cutoff date of March 31, 2006, the primary analysis of the RFS for patients in the observation arm and a possible overestima- probability was performed using the intent-to-treat population, tion of adverse events for these patients. of whom 696 patients experienced RFS events PEG-IFN, 328; Approximately 33% of patients receiving PEG-IFN dis- observation, 368). The median RFS interval was 34.8 months continued treatment because of adverse reactions. The most (95% confidence interval [CI], 26.1–47.4 months) for PEG- common adverse reactions present at the time of treatment dis- IFN and 25.5 months (95% CI, 19.6–30.8 months) for ob- continuation were fatigue (27%), depression (17%), anorexia served patients (Table 2, Fig. 1). In order to maintain a two- (15%), increased alanine aminotransferase (ALT) (14%), in- sided type I error rate of 0.05, the nominal two-sided creased aspartate aminotransferase (AST) (14%), myalgia significance level for the final analysis of the RFS outcome (13%), nausea (13%), headache (13%), and pyrexia (11%). www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1326 PEG-IFN for Melanoma Table 1. Patient demographics and tumor characteristics PEG-IFN Observation Total Characteristic (n  627), n (%) (n  629), n (%) (n  1,256), n (%) Demographics Sex Female 262 (42) 263 (42) 525 (42) Male 365 (58) 366 (58) 731 (58) Age, yrs 65 64 (10) 80 (13) 144 (11) Mean (SD) 48.8 (11.9) 48.8 (12.8) 48.8 (12.4) Median 50.0 50.0 50.0 Performance status score 0 529 (84) 531 (84) 1060 (84) 1 98 (16) 98 (16) 196 (16) Tumor characteristics Tumor stage TxN1 250 (40) 258 (41) 508 (40) TxN2 375 (60) 368 (59) 743 (59) Unspecified 2 (1) 3 (1) 5 (1) n of pathologically positive lymph nodes 02(1) 3 (1) 5 (1) 1 332 (53) 341 (54) 673 (54) 2–4 216 (34) 207 (33) 423 (34) 5 73 (12) 74 (12) 147 (12) Not evaluable 4 (1) 4 (1) 8 (1) Presence of a synchronous primary No 517 (82) 527 (84) 1044 (83) Yes 93 (15) 83 (13) 176 (14) Missing 17 (3) 19 (3) 36 (3) Site of the primary Head 39 (6) 35 (6) 74 (6) Neck 13 (2) 10 (2) 23 (2) Trunk 267 (43) 277 (44) 544 (43) Arm 67 (11) 71 (11) 138 (11) Leg 201 (32) 197 (31) 398 (32) Missing/unknown 40 (6) 39 (6) 79 (6) Breslow thickness of the primary, mm 1.5 136 (22) 136 (22) 272 (22) 1.5–3.99 276 (44) 284 (45) 560 (45) 4.0 147 (23) 148 (24) 295 (24) Missing/unknown 68 (11) 61 (10) 129 (10) Ulceration of the primary No 315 (50) 338 (54) 653 (52) Yes 192 (31) 181 (29) 373 (30) Missing/unknown 120 (19) 110 (18) 230 (18) Abbreviations: N, node; PEG-IFN, peginterferon-alfa-2b; SD, standard deviation; T, tumor. Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 Herndon, Demko, Jiang et al. 1327 Table 2. Independent review committee–determined RFS results in the intent-to-treat population RFS result PEG-IFN (n  627) Observation (n  629) n (%) of patients with RFS event 328 (52.3) 368 (58.5) n (%) of patients without RFS event 299 (47.7) 261 (41.5) Median duration of RFS (95% CI), mos 34.8 (26.1–47.4) 25.5 (19.6–30.8) Hazard ratio (95% CI) 0.82 (0.71–0.96) Nominal p-value (unadjusted log-rank test) .011 Data cutoff date was March 31, 2006. The hazard ratio was estimated using a Cox proportional hazards regression model with treatment arm as the only covariate. A hazard ratio 1 indicates that treatment with PEG-IFN is associated with a lower risk for recurrence or death than observation. Abbreviations: CI, confidence interval; PEG-IFN, peginterferon-alfa-2b; RFS, relapse-free survival. Figure 1. Kaplan–Meier curves of the recurrence-free survival (RFS) probability. The log-rank p-value was .011 based on 696 RFS events determined by the independent review committee at the data cutoff date of March 31, 2006. The incidence of serious adverse reactions was approxi- tients, compared with 1% of patients in the observation mately twofold higher (33% vs. 15%) in PEG-IFN–treated pa- arm. Cardiac adverse reactions, including myocardial in- tients than in those in the observation arm. Five deaths were farction, bundle-branch block, ventricular tachycardia, and reported within 30 days of the last treatment dose, two from supraventricular arrhythmia, occurred in 4% of PEG-IFN– cardiovascular disease that were considered possibly related to treated patients, compared with 2% of patients in the obser- treatment and three from unrelated causes. vation group. As with interferon alfa-2b, the most serious adverse reac- tions were severe depression, cardiac adverse events, and ret- DISCUSSION inopathy or other visual changes. The most common severe or The approval of PEG-IFN for the adjuvant treatment of pa- life-threatening (National Cancer Institute grade 3–4) adverse tients with AJCC stage III melanoma with microscopic or reactions were fatigue (16%), depression (7%), increased ALT gross nodal involvement was based on a sustained and clini- (11%), increased AST (11%), pyrexia (4%), increased -glu- cally meaningful longer RFS time (median, 34.8 months for tamyltransferase (4%), myalgia (4%), and headache (4%) in patients randomized to receive PEG-IFN compared with 25.5 the PEG-IFN–treated group, compared with 1% in the ob- months for those receiving no additional therapy). The result is servation group for these reactions. internally consistent across relevant subgroups defined by Depression occurred in 59% of PEG-IFN–treated patients baseline demographics and prognostic variables. Additional and 24% of patients in the observation group. Depression was evidence supporting the validity of the observed PEG-IFN severe or life threatening in 7% of PEG-IFN–treated pa- treatment effect on the RFS time is provided by the extensive www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/17/10/1323/6400884 by DeepDyve user on 01 February 2022 1328 PEG-IFN for Melanoma prior experience with the predecessor drug, interferon alfa-2b, were limited by their retrospective approach and are more con- which has been demonstrated to have a similar effect on RFS sistent with “responder“ analyses in which the optimal treat- outcomes [1–6]. ment duration is based on who lives longest prior to recurrence. Although the toxicities associated with PEG-IFN treatment In this setting, patients who relapse early do not contribute to are considerable and have a negative impact on global health re- the analysis of appropriate dosing at later time points. In the absence of better information, product labeling both describes lated-quality of life [11], they are often reversible with treatment interruption or discontinuation. As such, they can be outweighed the planned treatment and provides information characterizing the dropout rate for toxicity and average treatment durations. in a risk:benefit assessment by a robust benefit outcome. This issue will be addressed as a postmarketing requirement. The FDA has stated that the RFS time is direct evidence of Given the clinically meaningful prolongation in time with- clinical benefit when the adjuvant treatment has minimal tox- out disease observed in study EORTC 18991, which is evi- icity [12], as in the case of hormonal agents for the adjuvant dence of direct clinical benefit given its magnitude, the scarcity treatment of breast cancer. However, the FDA recently ap- of alternative, noninterferon-based adjuvant treatments, and proved three drugs for the adjuvant treatment of solid tumors, the absence of curative salvage treatments for patients with re- either alone (imatinib) [13] or in combination with cytotoxic current melanoma, the risks for toxicity during treatment with chemotherapy (oxaliplatin, trastuzumab) [14, 15]. In those in- PEG-IFN do not outweigh the benefit of the 18% lower risk for stances, evidence of a disease-free survival benefit alone was disease recurrence. sufficient to support regular approval, despite the demonstra- tion of a greater risk for severe toxicities involving the neuro- AUTHOR CONTRIBUTIONS logic, cardiac, gastrointestinal, and vascular (edema) systems. Conception/Design: Martin H. Cohen, Thomas M. Herndon, Suzanne G. Similarly, in 2002, the FDA Oncologic Drugs Advisory Commit- Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, tee agreed that approval of interferon alfa-2b for the adjuvant Richard Pazdur Provision of study material or patients: Thomas M. Herndon, Suzanne G. treatment of melanoma was appropriate even though subsequent Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, studies did not provide evidence of an effect on the overall sur- Richard Pazdur vival time. The toxicity profile of PEG-IFN is similar to, if not Collection and/or assembly of data: Thomas M. Herndon, Suzanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, more favorable than, that observed for the interferon alfa-2b reg- Richard Pazdur imen indicated for the adjuvant treatment of melanoma. Data analysis and interpretation: Thomas M. Herndon, Suzanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, Richard The ideal dose of PEG-IFN as well as the ideal duration of Pazdur PEG-IFN therapy are unknown at this time. Describing a rec- Manuscript writing: Martin H. Cohen, Thomas M. Herndon, Suzanne G. ommended dose, when many patients were unable to tolerate Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia Keegan, Richard Pazdur therapy as planned, was problematic. The FDA conducted Final approval of manuscript: Martin H. Cohen, Thomas M. Herndon, Su- multiple exploratory analyses to investigate relationships be- zanne G. Demko, Xiaoping Jiang, Kun He, Joseph E. Gootenberg, Patricia tween the extent of therapy and outcomes. All these analyses Keegan, Richard Pazdur alpha adjuvant therapy in patients with high-risk mela- vation in resected stage III melanoma: A phase III ran- REFERENCES noma: A systematic review and meta-analysis. J Natl domized controlled trial of health-related quality of life 1. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Cancer Inst 2010;102:493–501. and symptoms by the European Organisation for Re- Interferon alfa-2b adjuvant therapy of high-risk resected search and Treatment of Cancer Melanoma Group. 7. Bukowski RM, Tendler C, Cutler D et al. Treating cutaneous melanoma: The Eastern Cooperative Oncol- J Clin Oncol 2009;27:2916–2923. cancer with PEG Intron: Pharmacokinetic profile and ogy Group Trial EST 1684, J Clin Oncol 1996;14:7–17. dosing guidelines for an improved interferon-alpha-2b 12. 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Published: Oct 1, 2012

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