Results of an International Randomized Phase III Trial ...

VOLUME

31

䡠

NUMBER

19

䡠

JULY

1

2013

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy George D. Demetri, Sant P. Chawla, Isabelle Ray-Coquard, Axel Le Cesne, Arthur P. Staddon, Mohammed M. Milhem, Nicolas Penel, Richard F. Riedel, Binh Bui-Nguyen, Lee D. Cranmer, Peter Reichardt, Emmanuelle Bompas, Thierry Alcindor, Daniel Rushing, Yang Song, Ruey-min Lee, Scot Ebbinghaus, Joseph E. Eid, John W. Loewy, Frank G. Haluska, Pierre F. Dodion, and Jean-Yves Blay Listen to the podcast by Dr Desai at www.jco.org/podcasts Author affiliations appear at the end of this article. Published online ahead of print at www.jco.org on May 28, 2013. Written on behalf of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) investigators. Supported by Merck Sharp and Dohme, a subsidiary of Merck, which provided editorial nonwriting assistance. Presented in part at the 47th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2011. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00538239. Corresponding author: George D. Demetri, MD, Ludwig Center, DanaFarber Cancer Institute, Dana 1212, 450 Brookline Ave, Boston, MA 02215; e-mail: [email protected]. © 2013 by American Society of Clinical Oncology 0732-183X/13/3119w-2485w/$20.00 DOI: 10.1200/JCO.2012.45.5766

A

B

S

T

R

A

C

T

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P ⫽ .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P ⬍ .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P ⫽ .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ⱖ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas. J Clin Oncol 31:2485-2492. © 2013 by American Society of Clinical Oncology

INTRODUCTION

Sarcomas account for approximately 1% of adult solid malignancies and approximately 15% of pediatric cancers.1 Incidence of soft tissue and bone sarcomas is between four and five patient cases per 100,000 persons in the United States and Europe.2-5 Some sarcomas, such as GI stromal tumors, are defined by molecular aberrations or histopathologic

characteristics into well-characterized subsets with uniquely effective therapies. However, a vast majority of patients with metastatic soft tissue and bone sarcomas have rapid disease progression and poor overall survival (OS) rates, despite administration of any currently available palliative chemotherapy.2,6 Although patients achieving clinical benefit with initial therapy may continue to receive chemotherapy until disease progression or unacceptable toxicity, © 2013 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on November 3, 2015. For personal use only. No other uses without permission. Copyright © 2013 American Society of Clinical Oncology. All rights reserved.

2485

Demetri et al

chemotherapy can also be stopped after maximal benefit has been obtained, with ongoing surveillance of metastatic disease until eventual disease progression. The benefits of continuing chemotherapy have never been proven to be greater than those of stopping therapy once benefit has been obtained, and there are known risks from cumulative drug-associated toxicities, such as cardiac toxicity associated with doxorubicin.1,4,7 An effective and convenient therapy that could be used to maintain benefits from prior cytotoxic chemotherapy, such as prolonged disease stability, might offer a useful addition to the pharmacologic management of patients with sarcomas with metastatic disease. Intracellular signaling through the mammalian target of rapamycin (mTOR) and associated upstream signaling pathways are dysregulated in most sarcoma subtypes, including leiomyosarcoma, rhabdomyosarcoma, and perivascular epithelioid cell tumors.8-10 Ridaforolimus, an mTOR inhibitor, prevents cell growth and proliferation in multiple sarcoma cell lines and exhibits antitumor activity in sarcoma xenograft models.11,12 In phase I and II trials, ridaforolimus demonstrated clinical activity in various solid tumors, including sarcomas.13-15 In a nonrandomized phase II trial in patients with advanced sarcomas, ridaforolimus administered intravenously was associated with durable stable disease (SD) and a favorable OS rate.13 A subsequent trial established similar findings in patients with sarcomas receiving oral ridaforolimus.16 No biomarker to predict benefit in these patients was identified, and treatment benefit seemed to be

consistent across different histopathologic subsets. The phase III SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) trial was designed to assess the efficacy and safety of oral ridaforolimus in patients with advanced sarcomas who achieved clinical benefit with prior standard cytotoxic therapy, using impact of treatment on progression-free survival (PFS) as the primary end point. PATIENTS AND METHODS Study Design and Treatment This was a phase III randomized double-blinded placebo-controlled multicenter international trial (Appendix). Eligible patients were randomly assigned at a ratio of one to one to receive a 40-mg dose of ridaforolimus (four 10-mg tablets) or matching placebo administered orally once per day for 5 days every week. Patients were stratified by geographic region, histologic category, and lines of prior chemotherapy. Dose interruption or reduction was allowed, according to protocol-specified guidelines, in the event of adverse events (AEs) judged to be related to the study drug. The study was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with International Conference on Harmonisation, Good Clinical Practice, and all applicable regulatory guidelines. The protocol, its amendments, and the patient informed consent form were reviewed and approved by an independent ethics committee or institutional review board at each site before patients were allowed to enroll at that site. All patients provided written informed consent before participating in this study.

Screened patients (N = 851)

Excluded Ineligible radiology review Ineligible laboratory results Patient withdrew consent Other Unknown

(n = 140) (n = 38) (n = 22) (n = 18) (n = 51) (n = 11)

Randomly assigned (n = 711)

Assigned to receive ridaforolimus (n = 347) Received allocated intervention (n = 343) Did not receive allocated intervention (n = 4)

Assigned to receive placebo (n = 364) Received allocated intervention (n = 359) Did not receive allocated intervention (n = 5)

Lost to follow-up (n = 0) Follow-up ongoing (n = 25) Discontinued intervention (n = 318) Nontreatment-related adverse events (n = 13) Treatment-related adverse events (n = 37) PD/clinical PD (n = 231) Death (n = 6 ) Intercurrent illness (n = 1) Physician decision (n = 5 ) Protocol violation (n = 0 ) Withdrew consent (n = 13) Other (n = 12)

Lost to follow-up (n = 0) Follow-up ongoing (n = 28) Discontinued intervention (n = 331) Nontreatment-related adverse events (n = 7) Treatment-related adverse events (n = 2) PD/clinical PD (n = 309) Death (n = 2) Intercurrent illness (n = 0) Physician decision (n = 0) Protocol violation (n = 2) Withdrew consent (n = 4) Other (n = 5)

Efficacy analysis set Safety set

Efficacy analysis set Safety set

2486

(n = 347) (n = 343)

© 2013 by American Society of Clinical Oncology

Fig 1. CONSORT diagram. PD, progressive disease.

(n = 364) (n = 359)

JOURNAL OF CLINICAL ONCOLOGY


Ridaforolimus for Patients With Metastatic Sarcomas

Patients Patients age ⱖ 13 years with metastatic sarcomas of either soft tissue or bone origin were eligible for the trial. Certain histopathologic subtypes of sarcomas considered to derive no benefit from conventional chemotherapies (such as alveolar soft part sarcoma) or with uniquely different natural histories (such as GI stromal tumors) were excluded (Appendix Table A1, online only), and patients with bone sarcomas were required to have measurable soft tissue (lung or liver) metastases. To be eligible, patients must have exhibited current SD or ongoing complete or partial response (PR), as defined by RECIST (version 1.0) guidelines,17 after a minimum of four cycles and maximum of 12 months of immediately preceding cytotoxic chemotherapy (administered either as first-, second-, or third-line therapy for advanced disease). Disease status at study entry was required to be confirmed by blinded central review of the two most recent consecutive radiologic evaluations, obtained a minimum of 5 weeks and maximum of 13 weeks apart. Patients with PR or SD at study entry were required to have at least one measurable or evaluable tumor. Patients had to have received their last dose of chemotherapy at least 3 weeks before random assignment and started study treatment within 13 weeks after previous treatment. Other eligibility criteria included an Eastern Cooperative Oncology Group performance score of 0 or 1, adequate organ and marrow function, serum cholesterol ⱕ 350 mg/dL, and triglycerides ⱕ 400 mg/dL. Major exclusion criteria included uncontrolled brain or CNS metastases, prior therapy with mTOR inhibitors, ongoing toxicity associated with prior anticancer therapy of grade ⱖ 2 (excluding alopecia), concomitant treatment with inhibitors or inducers of cytochrome P4503A, significant uncontrolled cardiovascular disease, active infection requiring systemic therapy, or known HIV infection. Efficacy Assessments The primary end point of the trial was PFS, defined as the time from date of random assignment to date of documented progressive disease or death, whichever occurred first. OS (defined as the time from date of random assignment to date of death resulting from any cause) was a key secondary end point. Other secondary end points included best response in target lesions (defined as the smallest postbaseline sum of the longest diameter of all target lesions after random assignment until disease progression), safety, and tolerability. Baseline disease status was determined at screening (ⱕ 28 days) before random assignment (day 1). Disease progression was assessed by a blinded (to treatment arm, patient identification, and scan sequence) independent review committee (primary end point) and site investigators (secondary end point) every 8 weeks using standard imaging (computed tomography [CT] scans and/or magnetic resonance imaging) according to modified RECIST guidelines. Patients were to be observed for survival every 3 months for at least 24 months and up to 60 months after random assignment. At the time of data cutoff for OS analysis (January 21, 2012), all patients had been observed for at least 24 months. Safety Assessments All patients who received at least one dose of study drug were eligible for safety analysis. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) and assessed for their relationship to study medication by the investigator. Safety was assessed by physical examination, interim history, and laboratory assessment; safety evaluations were repeated when patients discontinued study treatment and at the 1-month follow-up visit. The data monitoring committee performed quarterly safety reviews during the conduct of the trial, and an interim analysis for safety was performed after approximately 100 patients were treated. Statistical Analyses For the trial primary end point, approximately 650 patients were projected to be randomly assigned, and it was projected that 516 events would need to be observed to provide approximately 90% power to detect a 25% effect size based on a 0.75 hazard ratio (HR). There were two preplanned interim analyses for efficacy and safety after approximately 172 and 344 progression events had occurred. The power projection for both interim and final analyses was based on a one-sided log-rank test at a significance level of ␣ ⫽ 0.025, assuming proportional hazard rates. The proportion of patients lost to www.jco.org

follow-up was assumed to be ⬍ 10%, and the median time to progression was projected to be in the range of 6 to 9 months from study entry. PFS and OS were analyzed using a stratified log-rank test, with stratification by histology and line of therapy. Best target lesion response was analyzed using a Wilcoxon rank sum test based on the independent review committee– blinded assessment. Two-sided P values are reported for differences between ridaforolimus and placebo treatment groups. For safety analyses, AEs were coded according to body system and preferred term using the Medical Dictionary for Regulatory Activities and analyzed using descriptive statistics.

Table 1. Baseline Patient Demographic and Clinical Characteristics Ridaforolimus (n ⫽ 347) Characteristic Age, yearsⴱ Mean SD Sexⴱ Male Female ECOG performance scoreⴱ 0 1 Histologic categoryⴱ Soft tissue Bone No. of prior cytotoxic chemotherapy regimensⴱ 1 2 3 ⱖ4 Missing No. of cycles of most recent cytotoxic chemotherapy regimen Mean SD Median Range Best response to most recent cytotoxic chemotherapy regimenⴱ† Complete response‡ Partial response Stable disease Unknown Not applicable Missing Independent pathologist tumor gradeⴱ High Low Could not be assessed Not applicable Missing Metastatic site Lungⴱ Liver§ Boneⴱ

No.

% 52.0 16.0

Placebo (n ⫽ 364) No.

% 50.6 15.0

158 189

45.5 54.5

156 208

42.9 57.1

174 172

50.1 49.6

184 180

50.5 49.5

310 37

89.3 10.7

332 32

91.2 8.8

214 91 40 1 1

61.7 26.2 11.5 ⬍ 1.0 ⬍ 1.0

233 95 34 1 1

64.0 26.1 9.3 ⬍ 1.0 ⬍ 1.0

5.9 2.2 6.0 1-17

6.1 2.1 6.0 2-22

19 64 258 3 1 2

5.5 18.4 74.4 0.9 ⬍ 1.0 0.6

18 70 273 2 0 1

4.9 19.2 75.0 0.5 0.0 ⬍ 1.0

256 13 30 8 40

73.8 3.7 8.6 2.3 11.5

266 20 28 9 41

73.1 5.5 7.7 2.5 11.3

231 50 40

66.6 14.4 11.5

234 70 39

64.3 19.2 10.7

Abbreviations: ECOG, Eastern Cooperative Oncology Group; SD, standard deviation. ⴱ P ⬎ .1 for difference between ridaforolimus and placebo groups. †Assessed by individual treating physicians before enrollment; disease stability confirmed by two additional scans reviewed by independent review committee. ‡For these patients, any disease recurrence observed in trial was considered progressive disease for purpose of statistical analysis. §P ⬎ .05 for difference between ridaforolimus and placebo groups.

© 2013 by American Society of Clinical Oncology


2487

Demetri et al

A

Median PFS PFS Rate (%) 3 month 6 month (weeks) 95% CI Ridaforolimus 17.7 15.4 to 23.0 70 34 Placebo 14.6 13.9 to 15.6 54 23

Progression-Free Survival by IRC Assessment (%)

100

80

HR = 0.72 (95% CI, 0.61 to 0.85); P < .001

60

40

20

0

10

20

30

40

50

B

221 185

88 62

42 35

32 23

80

Region North America European Union Rest of world

0.75 0.68 0.55

4 11

No. of cycles of most recent chemotherapy