PMID- 36001000 OWN - NLM STAT- MEDLINE DCOM- 20221221 LR - 20240102 IS - 1528-1132 (Electronic) IS - 0009-921X (Print) IS - 0009-921X (Linking) VI - 481 IP - 1 DP - 2023 Jan 1 TI - Pexidartinib Provides Modest Pain Relief in Patients With Tenosynovial Giant Cell Tumor: Results From ENLIVEN. PG - 107-116 LID - 10.1097/CORR.0000000000002335 [doi] AB - BACKGROUND: The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described. QUESTIONS/PURPOSES: (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief? METHODS: The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 +/- 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups. RESULTS: A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 +/- 2.2 after 25 weeks and -3.3 +/- 1.7 after 50 weeks of receiving pexidartinib). CONCLUSION: Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief. LEVEL OF EVIDENCE: Level II, therapeutic study. CI - Copyright (c) 2022 by the Association of Bone and Joint Surgeons. FAU - Healey, John H AU - Healey JH AD - Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. FAU - Tap, William D AU - Tap WD AD - Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. FAU - Gelhorn, Heather L AU - Gelhorn HL AD - Evidera, Bethesda, MD, USA. FAU - Ye, Xin AU - Ye X AD - Daiichi Sankyo Inc, Basking Ridge, NJ, USA. FAU - Speck, Rebecca M AU - Speck RM AD - Evidera, Bethesda, MD, USA. FAU - Palmerini, Emanuela AU - Palmerini E AD - IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. FAU - Stacchiotti, Silvia AU - Stacchiotti S AD - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. FAU - Desai, Jayesh AU - Desai J AD - Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. FAU - Wagner, Andrew J AU - Wagner AJ AD - Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Alcindor, Thierry AU - Alcindor T AD - McGill University, Montreal, Quebec, Canada. FAU - Ganjoo, Kristen AU - Ganjoo K AD - Stanford Cancer Institute, Stanford, CA, USA. FAU - Martin-Broto, Javier AU - Martin-Broto J AD - University Hospital Virgen del Rocio and Institute of Biomedicine of Sevilla (IBIS) (HUVR, CSIC, University of Sevilla), Sevilla, Spain. FAU - Wang, Qiang AU - Wang Q AD - Daiichi Sankyo Inc, Basking Ridge, NJ, USA. FAU - Shuster, Dale AU - Shuster D AD - Daiichi Sankyo Inc, Basking Ridge, NJ, USA. FAU - Gelderblom, Hans AU - Gelderblom H AD - Leiden University Medical Center, Leiden, the Netherlands. FAU - van de Sande, Michiel AU - van de Sande M AD - Leiden University Medical Center, Leiden, the Netherlands. LA - eng SI - ClinicalTrials.gov/NCT02371369 GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20220824 PL - United States TA - Clin Orthop Relat Res JT - Clinical orthopaedics and related research JID - 0075674 RN - 6783M2LV5X (pexidartinib) RN - 0 (Aminopyridines) SB - IM CIN - Clin Orthop Relat Res. 2023 Jan 1;481(1):117-119. PMID: 36227323 MH - Adult MH - Humans MH - Female MH - Middle Aged MH - Treatment Outcome MH - *Giant Cell Tumor of Tendon Sheath MH - Aminopyridines MH - Pain MH - Double-Blind Method PMC - PMC9750631 COIS- All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research(R) editors and board members are on file with the publication and can be viewed on request. EDAT- 2022/08/25 06:00 MHDA- 2022/12/22 06:00 PMCR- 2024/01/01 CRDT- 2022/08/24 10:05 PHST- 2021/06/24 00:00 [received] PHST- 2022/07/01 00:00 [accepted] PHST- 2022/08/25 06:00 [pubmed] PHST- 2022/12/22 06:00 [medline] PHST- 2022/08/24 10:05 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - 00003086-202301000-00019 [pii] AID - CORR-D-21-01015 [pii] AID - 10.1097/CORR.0000000000002335 [doi] PST - ppublish SO - Clin Orthop Relat Res. 2023 Jan 1;481(1):107-116. doi: 10.1097/CORR.0000000000002335. Epub 2022 Aug 24.