Deciphera Pharmaceuticals Presents New Clinical Study Results Across Pipeline at the European
Society for Medical Oncology (ESMO) Congress 2021
Rebastinib in Combination with Paclitaxel Demonstrated Progression Free Survival of 9.1 months in
Heavily Pretreated Patients with Platinum-Resistant Ovarian Cancer (PROC)
Pivotal Phase 3 Study of Rebastinib plus Paclitaxel in PROC Planned to Initiate in 2022 Subject to
Updated Results for Vimseltinib Showed Objective Response Rate of 47% in Patients with Tenosynovial
Giant Cell Tumor (TGCT)
Pivotal Phase 3 Study of Vimseltinib in TGCT Expected to Initiate in the Fourth Quarter of
Company to Host Virtual Investor Event to Discuss Rebastinib and Vimseltinib Results Today
at 10 AM ET
Waltham, MA September 17, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, today announced four e-poster presentations at the ESMO Congress 2021. The presentations include updated preliminary results from the ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in patients with PROC and updated preliminary results from the ongoing Phase 1/2 study of vimseltinib in patients with TGCT. A long-term update on the Phase 3 INVICTUS study of QINLOCK® (ripretinib) in patients with advanced gastrointestinal stromal tumors (GIST), and results from the expansion phase of the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma will also be presented.
All e-poster presentations are now available on-demand via the ESMO website and on the Companys website at www.deciphera.com/presentations-publications. Deciphera will also host an investor event featuring key opinion leaders to discuss the rebastinib and vimseltinib data today, September 17, 2021, at 10 AM ET. A live webcast of the event may be accessed through the Investors section of Decipheras website at www.deciphera.com. A replay of the webcast will be available following the event.
We are excited to present strong results at this years ESMO Congress, which support both our plans to initiate a Phase 3 pivotal study for rebastinib pending regulatory feedback, and our plans to initiate a Phase 3 pivotal study for vimseltinib. The updated safety and efficacy results for rebastinib in combination with paclitaxel show highly encouraging results, including a median progression free survival of 9.1 months, in heavily pretreated patients with PROC where additional treatment is heterogeneous and single agent paclitaxel retreatment has historically shown only 3-4 months of PFS. Based on these impressive results in patients with a significant unmet medical need, we have begun planning for a pivotal Phase 3 study that we plan to initiate in 2022 following regulatory feedback, said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera. We are equally encouraged by the tolerability and efficacy data presented today from the Phase 1/2 study of vimseltinib in TGCT. The data presented today with vimseltinib in TGCT reinforce its potential to be a best-in-class treatment for this disease. We are rapidly moving forward with this program and we expect to initiate our Phase 3 study, MOTION, in the fourth quarter of this year.
Dr. Sherman continued, In addition to rebastinib and vimseltinib, we presented positive results from the Phase 1 study of ripretinib in patients with KIT-altered metastatic melanoma, and a long-term update from the Phase 3 INVICTUS study of QINLOCK, which shows further prolonged clinically meaningful median overall survival among patients receiving QINLOCK. Finally, we look forward to our Phase 3 INTRIGUE readout later this year in patients with second-line GIST.
Updated Preliminary Data from the Ongoing Phase 1b/2 Study of Rebastinib in Combination with Paclitaxel in PROC
The Phase 1b/2 study of rebastinib in combination with paclitaxel is a two-part, open-label, multicenter study assessing the safety, tolerability, anti-tumor activity, and pharmacokinetics of rebastinib in patients with advanced or metastatic solid tumors. The data presented today is from the second stage of Part 2 of the Simon two-stage design in PROC.
As of the June 22, 2021 cutoff date, 38 patients with PROC initiated treatment with rebastinib and paclitaxel and are included in the safety population and 34 patients that met the criteria for the modified intent-to-treat population (mITT) are included in the efficacy analysis.
The median progression-free survival (PFS) was 9.1 months.
There were 13 patients with objective responses (10 confirmed) for an objective response rate (ORR) of 38% (confirmed and unconfirmed) and 29% (confirmed only) with a median duration response of 5.5 months.
The clinical benefit rate at 16 weeks was 76%.
A CA-125 response occurred in 19 of 26 patients (73%).
Rebastinib in combination with paclitaxel was generally well tolerated at 50 mg BID, and most common (³15%) treatment-emergent adverse events (TEAEs) were Grade 1 or 2.
Four patients experienced serious adverse events (SAEs) at least possibly related to rebastinib including reversible muscular weakness (n=2), constipation (n=1), fatigue (n=1), and urinary tract infection (n=1).
Based on the strength of these findings, the Company has begun planning for a pivotal study in PROC that is anticipated to start in 2022, subject to feedback from regulators.
Updated Preliminary Data from the Ongoing Phase 1/2 Study of Vimseltinib in TGCT
The Phase 1/2 study of vimseltinib is an open-label, multicenter study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of vimseltinib in patients with solid tumors and TGCT. The data today is from patients with TGCT in both the Phase 1 dose escalation portion of the study and from cohort A in the Phase 2 expansion portion of the study. Cohort A includes TGCT patients with no prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib is allowed) and cohort B includes patients with prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib are not eligible).
As of the June 7, 2021 cutoff date, 68 TGCT patients were treated with vimseltinib and included in the safety population, including 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 36 TGCT patients enrolled in cohort A in the Phase 2 portion of the study. Efficacy data presented today is from 51 TGCT patients, including all 32 TGCT patients enrolled in the Phase 1 dose escalation portion of the study and 19 TGCT patients enrolled in cohort A in the Phase 2 portion of the study that were evaluable for efficacy as of the cutoff date.
Dose Cohorts and Demographics:
32 patients enrolled in Phase 1 (dose escalation) and 36 patients enrolled in Phase 2 cohort A (expansion):
Phase 1 cohort 5 (n=8): 30 mg loading dose daily for five days followed by a maintenance dose of 30 mg twice a week.
Phase 1 cohort 8 (n=12): 30 mg loading dose daily for three days followed by a maintenance dose of 10 mg daily.
Phase 1 cohort 9 (n=12): 20 mg loading dose daily for three days followed by a maintenance dose of 6 mg daily.
Phase 2 cohort A (n=36): 30 mg twice weekly (no loading dose).
12 out of 32 patients (38%) in Phase 1 and 32 out of 36 patients (89%) in Phase 2 cohort A had at least one prior surgery; five patients (16%) in Phase 1 and two patients (6%) in Phase 2 cohort A had received at least one prior systematic therapy.
51 patients were evaluable for efficacy by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 at the data cutoff in Phase 1 across all dose cohorts and in Phase 2 cohort A; response data is based on independent central radiologic review with the exception of one patient who had a local assessment, and for whom no central assessment was performed.
Updated Preliminary Efficacy and Duration of Treatment:
Of the 51 efficacy-evaluable patients in Phase 1 across all dose cohorts and in the Phase 2 cohort A, 24 patients had a response resulting in an ORR of 47%.
Of the 32 patients in Phase 1, 16 patients achieved an objective response for an ORR of 50% with durable responses observed across all dose cohorts, including one complete response in cohort 5. The median duration of treatment for all patients was 10.1 months. 72% of patients remain active in the study as of the data cutoff date.
Of the 36 patients enrolled in Phase 2 cohort A, 19 patients were evaluable for efficacy, of which there were eight patients with an objective response for an ORR of 42%. Of the 19 patients, 10 had more than one follow-up imaging assessment and two responses occurred at later scans. The median duration of treatment for all patients was 1.9 months. The study is ongoing and follow-up evaluation is continuing with 83% of patients remaining active as of the data cutoff date.
Safety and Tolerability:
In both Phase 1 and Phase 2 cohort A, treatment with vimseltinib was generally well tolerated in patients with TGCT. Two patients (6%) discontinued treatment due to a TEAE in Phase 1 and one patient (3%) discontinued treatment due to an TEAE in Phase 2 cohort A.
Two patients experienced SAEs at least possibly related to vimseltinib, including metabolic encephalopathy and vaginal hemorrhage in Phase 1; no treatment-related SAEs were reported in Phase 2 cohort A.
The majority of the common (³15%) TEAEs were Grade 2 or lower.
Observed transaminase, pancreatic, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors.
No abnormalities in bilirubin levels were reported.
Phase 3 MOTION Study
Based on the positive results of the ongoing Phase 1/2 study, the Company plans to advance vimseltinib into a pivotal Phase 3 study in patients with TGCT. The MOTION study is two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery. In Part 1 of the study, eligible study participants will be assigned to receive either vimseltinib or matching placebo for 24 weeks. Participants assigned to placebo in Part 1 will have the option to receive vimseltinib for Part 2 of the study. Part 2 is a long-term treatment phase in which all participants receive open-label vimseltinib. The primary endpoint of the study is ORR at 25 weeks as measured by RECIST v1.1 by blinded independent central review. The Company expects to initiate the MOTION study in the fourth quarter of this year.
Long-term Update from Phase 3 INVICTUS Study of QINLOCK in Patients with Advanced GIST
The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of QINLOCK compared to placebo in patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The Company previously reported primary results from the randomized portion of the INVICTUS study, in which QINLOCK significantly improved PFS and showed a clinically meaningful overall survival (OS) benefit.
An exploratory evaluation of primary and secondary endpoints in the Phase 3 INVICTUS study, with a cutoff date of January 15, 2021, an additional 19 months after the primary analysis, demonstrates consistent PFS with no change since the primary data cut off, and improved median OS among patients receiving ripretinib.
Median PFS was 6.3 months with QINLOCK compared to 1.0 month with placebo.
Median OS was 18.2 months with QINLOCK compared to 6.3 months with placebo.
Median OS was 10 months in placebo patients who crossed over to QINLOCK.
Median ORR was 11.8% with QINLOCK compared to 0% with placebo.
Median duration of response with QINLOCK was 14.5 months.
Safety findings were consistent with the primary analysis results and most TEAEs were Grade 1 or 2. Increases in TEAEs and TEAEs leading to dose modifications in the additional 19 months of follow up were minimal.
These more mature results continue to support the clinically meaningful benefit in PFS and OS for QINLOCK with an acceptable safety profile in patients with advanced GIST treated with three or more prior lines of therapy.
Phase 1 Study of Ripretinib in Patients with KIT-altered Metastatic Melanoma
As part of the expansion phase of the Phase 1 study, 26 patients with KIT-altered metastatic melanoma were treated with ripretinib at the recommended Phase 2 dose of 150 mg daily in repeated 28-day cycles. Tumor progression was assessed by the investigator using computed tomography/magnetic resonance imaging according to RECIST v1.1 on day 1 of cycles 3, 5, 7, and every three cycles thereafter, and a final study visit. ORR was confirmed with follow-up imaging approximately 28 days later. Patients who had disease progression at ripretinib 150 mg daily were allowed to dose escalate to 150 mg twice daily.
Ripretinib demonstrated encouraging efficacy in patients with KIT-altered metastatic melanoma with a confirmed ORR of 23%, median duration of response of 9.1 months, and median PFS of 7.3 months. In addition, there were two unconfirmed partial responses resulting in an ORR of 31% (confirmed and unconfirmed).
Tyrosine kinase inhibitor (TKI)-naïve patients had a greater response (confirmed ORR of 29% and median PFS of 10.2 months) to ripretinib than those with prior TKI treatment (confirmed ORR of 11% and median PFS of 2.9 months).
Ripretinib had an acceptable safety profile in KIT-altered metastatic melanoma consistent with the approved indication in GIST.
About Deciphera Pharmaceuticals
Deciphera is a biopharmaceutical company focused on discovering, developing and commercializing important new medicines to improve the lives of people with cancer. We are leveraging our proprietary switch-control kinase inhibitor platform and deep expertise in kinase biology to develop a broad portfolio of innovative medicines. In addition to advancing multiple product candidates from our platform in clinical studies, QINLOCK® is Decipheras FDA-approved switch-control kinase inhibitor for the treatment of fourth-line gastrointestinal stromal tumor (GIST). QINLOCK is also approved for fourth-line GIST in Australia, Canada, China, Hong Kong, and Taiwan. For more information, visit www.deciphera.com and follow us on LinkedIn and Twitter (@Deciphera).
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, our expectations and timing regarding top-line data from our Phase 3 INTRIGUE study in second-line GIST, pivotal study plans and timing of study initiation for vimseltinib in TGCT patients and for the rebastinib/paclitaxel combination in platinum-resistant ovarian cancer patients, subject to feedback from regulators, and the potential for vimseltinib to be a best-in-class treatment for TGCT. The words may, will, could, would, should, expect, plan, anticipate, intend, believe, estimate, predict, project, potential, continue, seek, target and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on managements current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to the severity and duration of the impact of COVID-19 on our business and operations, our ability to successfully demonstrate the efficacy and safety of our drug candidates and in additional indications for our existing drug, the preclinical or clinical results for our product candidates, which may not support further development of such product candidates, our ability to manage our reliance on sole-source third parties such as our third party drug substance and drug product contract manufacturers, comments, feedback and actions of regulatory agencies, our ability to commercialize QINLOCK and execute on our marketing plans for any drugs or indications that may be approved in the future, our ability to build and scale our operations to support growth in additional geographies, the inherent uncertainty in estimates of patient populations, competition from other products, our ability to obtain and maintain reimbursement for any approved product and the extent to which patient assistance programs are utilized, our ability to comply with healthcare regulations and laws, our ability to obtain, maintain and enforce our intellectual property rights, any or all of which may affect the initiation, timing and progress of clinical studies and the timing of and our ability to obtain additional regulatory approvals, and other risks identified in our Securities and Exchange Commission (SEC) filings, including our Quarterly Report on Form 10-Q for the quarter ended June 30, 2021, and subsequent filings with the SEC. We caution you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. We disclaim any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent our views only as of the date hereof and should not be relied upon as representing our views as of any subsequent date. We explicitly disclaim any obligation to update any forward-looking statements.
QINLOCK and the QINLOCK logo are registered trademarks, and Deciphera and the Deciphera logo are trademarks, of Deciphera Pharmaceuticals, LLC.
Deciphera Pharmaceuticals, Inc.
A phase 1b/2 study of rebastinib and paclitaxel in advanced/metastatic platinum-resistant ovarian cancer Erika P Hamilton1, Sanjay Goel2, Rebecca Arend3, Christina Chu4, Debra L Richardson5, Bradley Corr6, Veena John7, Filip Janku8, John L Hays9, Mary Michenzie10, William Reichmann10, Haroun Achour10, Matthew L Sherman10, Rodrigo Ruiz-Soto10, Cara Mathews11 1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 2Medical Oncology, Montefiore Medical Center, Bronx, NY, USA; 3Comprehensive Cancer Center, Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA; 4Division of Gynecologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA; 5Gynecologic Oncology Department, Stephenson Cancer Center/University of Oklahoma/Sarah Cannon Research Institute, Oklahoma City, OK, USA; 6Division of Gynecologic Oncology, University of Colorado Denver, Denver, CO, USA; 7GYN Medical Oncology, Monter Cancer Center, New Hyde Park, NY, USA; 8Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; 9Wexner Medical Center, The Ohio State University, Columbus, OH, USA; 10Deciphera Pharmaceuticals, LLC, Waltham, MA, USA; 11Womens Oncology, Women and Infants Hospital of Rhode Island, Providence, RI, USA 728P Figure 2. Overall study design Figure 3. Patient disposition in PROC cohort Table 3. Best overall response from PROC cohort (mITT) Figure 5. PFS Kaplan-Meier curve for patients in the PROC cohort (mITT) Table 5. Summary of treatment-emergent AEs INTRODUCTION 100 ³15% regardless of relatedness (N = 38) Starting dose rebastinib 100 mg BID PROC cohort (N = 34) Part 1 Part 2 (n = 10) Objective response rate 13 (38) 90 Median PFS Preferred term Any grade Grade 3 Rebastinib is a first-in-class investigational, orally administered, potent, and Confirmed objective response rate 10 (29) Simon 2-stage design 9.1 months (90% CI 6.5, NE) selective inhibitor of the tunica interna endothelial cell kinase 2 (TIE2) kinase1 Decision to dose reduce rebastiniba 80 Best overall response Fatigue 22 (58) 3 (8) TIE2 is the receptor for angiopoietins (ANG) 1 and 2, an important family of CR 1 (3) (%) Cohort 1: 70 Alopaecia 16 (42) 1 (3)a vascular growth factors, and are expressed on endothelial cells and Triple-negative Starting dose rebastinib 50 mg BID PR 12 (35) ival angiogenic macrophages, promoting the survival, maturation, and functional breast cancer (n = 28) SD 18 (53) 60 Oedema peripheral 15 (39) 2 (5) integrity of the vasculature; they play an important role in regulating tumour Rebastinib N = 24 PD 1 (3) surv 50 mg BID + If ³5 responses are angiogenesis, invasiveness, and metastasis (Figure 1)2,3 No follow-up radiological assessment 2 (6) Dry mouth 14 (37) 0 2 a Cohort 2: observed from 18 ee 80 mg/m weekly paclitaxel a 50 Inflammatory patients, 15 Duration of response, months fr Rebastinib binds potently into the switch pocket of TIE2, stabilising the RP2D breast cancer - Nausea 14 (37) 1 (3) 1 additional patients Safety population (n = 38) Median 5.5 n inhibitory switch and displacing the activation switch to block TIE2 signaling will be enrolled for 40 Rebastinib 100 mg BID (n = 3) 90% CI 2.6, 7.4 each cohort ssio Peripheral sensory There is a high unmet need for an effective therapy for heavily pretreated Rebastinib dose reduced from 100 to 50 mg BID (n = 7) b 14 (37) 0 Enrolling in parallel Cohort 3: Rebastinib 50 mg BID (n = 28) Clinical benefit rate (8 weeks) 30 (88) neuropathy 30 patients with advanced or metastatic platinum-resistant ovarian cancer competitive enrollment determination Platinum-resistant Clinical benefit rateb (16 weeks) 26 (76) If <5 responses, (PROC); in this setting, single-agent weekly paclitaxel provides a median ovarian cancer One patient had a best response of SD at day 42 (6 weeks) and is not counted as having clinical benefit at 8 weeks. rogre Constipation 12 (32) 0 discontinue P 4,5 aEstimated using Kaplan-Meier methods among 13 patients with objective response. Among 10 patients with confirmed objective responses, 20 progression-free survival (PFS) of approximately 34 months enrollment RP2D the median duration of response was 5.6 months (90% CI: 5.4NE). Discontinued due to unrelated AE (n = 1)b bClinical benefit rate at 8 and 16 weeks was defined as overall response of CR, PR, or SD according to RECIST v1.1 at the 8- and 16-week Diarrhoea 12 (32) 2 (5) This study is a 2-part open-label, phase 1b/2, multicentre study of rebastinib Cohort 4: response assessments, respectively. 10 Rebastinib N = 19 Withdrew consent (n = 1)b orally administered in combination with paclitaxel Endometrial cancer Data shown as n (%) unless indicated otherwise. Hypertension 12 (32) 100 mg BID + Did not meet eligibility criteria (n = 2)c CI, confidence interval; CR, complete response, mITT, modified intent-to-treat; PD, progressive disease; PR, partial response; PROC, platinum 3 (8) 80 mg/m2 weekly paclitaxela resistant ovarian cancer; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. 0 In Part 1, we observed encouraging antitumour activity of rebastinib in Abdominal pain 11 (29) 2 (5) combination with paclitaxel with 5 partial responses (PR) in 24 patients at Figure 4. (A) Best percent change from baseline in tumour size (mITT) 0 2 4 6 8 10 12 Cohort 5: rebastinib 50 mg twice daily (BID) and 3 PRs in 19 patients at rebastinib 100 Gynecological and (B) time on treatment for patients in the PROC cohort (safety) Number at risk: Months Muscular weakness 10 (26) 3 (8)b mITT population (n = 34) carcinosarcoma mg BID from a heavily pretreated heterogeneous patient population6 34 29 22 20 13 4 0 Stomatitis 10 (26) a 0 Decision to dose reduce to 50 mg BID due to observed reversible muscular weakness. b Number of events (%): 15 (44%) Here, we summarise preliminary results of rebastinib in combination with Patients who discontinued due to withdrawal of consent or an unrelated AE were excluded because they did not have a postbaseline CI, confidence interval; mITT, modified intent-to-treat; NE, non-estimable; PFS, progression-free survival; PROC, platinum resistant ovarian cancer. assessment. Dyspnoea 9 (24) 1 (3) paclitaxel in patients with PROC from Part 2 of the study ClinicalTrials.gov: NCT03601897 cOf the 2 patients who did not meet eligibility criteria, 1 had non-measurable disease at baseline and the other did not have ovarian cancer. aPaclitaxel was administered weekly for 3 weeks followed by 1 week off treatment AE, adverse event; BID, twice daily; mITT, modified intent-to-treat; PROC, platinum resistant ovarian cancer. Safety BID, twice daily; RP2D, recommended phase 2 dose. Dizziness 8 (21) 0 Figure 1. Rebastinib mechanism of action Table 2. Baseline demographics and characteristics for patients in the Most AEs reported were Grade £2 (Table 5) Table 1. Key inclusion and exclusion criteria for PROC cohort Hypomagnesaemia 8 (21) 0 PROC cohort Four patients (11%) experienced 5 serious AEs at least possibly related to rebastinib: Grade 3 reversible muscular weakness (n = 2 [5%], occurred at 50 mg and 75 mg BID), Grade 2 Urinary tract infection 8 (21) 1 (3) Inclusion criteria PROC cohort (N = 38) constipation (n = 1; 3%), Grade 3 fatigue (n = 1; 3%), Grade 3 urinary tract infection (n = 1; Abdominal distension 7 (18) 0 ³18 years old 3%) Histologically confirmed, recurrent epithelial ovarian, peritoneal or fallopian tube Age, years, median (min, max) 59.5 (36, 76) Anaemia 7 (18) 1 (3) carcinoma Table 4. Treatment duration and dose modifications in the PROC cohort Histology Decreased appetite 7 (18) 0 Progressed or relapsed within 6 months after the completion of a platinum-containing PROC cohort High-grade serous 34 (89)a Hypokalaemia 7 (18) 1 (3) chemotherapy regimen (N = 38) Patients who progressed during treatment or £1 month after the completion of the Mixed 2 (5) Vomiting 7 (18) 1 (3) Treatment duration (months), median (min, max) 6.5 (0.5, 15.4) first platinum-containing chemotherapy regimen (primary platinum refractory) are Endometrioid 1 (3) Interruption due to AE excluded Rebastinib 28 (74) Arthralgia 6 (16) 0 Seromucinous 1 (3) £5 prior lines of systemic anticancer therapy Rebastinib (related) 16 (42) Cough 6 (16) 0 If BRCA 1 or 2 alteration (germline or somatic), must have received prior PARP inhibitor BRCA+ 8 (21) Paclitaxel 23 (61) Dry eye 6 (16) 0 Measurable disease per RECIST v1.1 Median number of prior regimens (min, max) 4 (2, 7) Dose reduction due to AE Rebastinib 8 (21) Headache 6 (16) 0 ECOG Performance Status of £2 23 regimens 15 (39) Rebastinib (related) 8 (21) Adequate organ function, bone marrow reserve, and cardiac function Nail discolouration 6 (16) 0 ³4 regimens 23 (61) Paclitaxel 3 (8) Exclusion criteria Discontinuation of rebastinib due to AE 9 (24) Pain in extremity 6 (16) 1 (3) Prior therapy ANG-1, angiopoietin 1; ANG-2, angiopoietin 2; TIE2, tunica interna endothelial cell kinase 2. Discontinuation of rebastinib due to AE (related)a 7 (18) aGrade 3 alopecia is not in CTCAE, site queried and updated to Grade 2. Prior anticancer therapy or other investigational therapy £28 days or 5x half-life prior to Paclitaxel 38 (100) aRebastinib-related AEs leading to discontinuation, at least possibly related to rebastinib: Grade 3 muscular weakness and Grade 3 fatigue (n = 1), Grade 1 bOne patient had Grade 3 muscular weakness that was considered related to rebastinib muscular weakness (n=1), Grade 2 vulvitis and Grade 2 priapism (n = 1), Grade 1 oedema peripheral (n = 2), Grade 2 oedema peripheral (n = 1), and retinal vein but was not entered as an SAE. This event occurred at 100 mg BID. the first dose of study drug, whichever is shorter Bevacizumab 33 (87) occlusion (n=1). AE, adverse event; BID, twice daily; CTCAE, common terminology criteria for adverse Data shown as n (%) unless indicated otherwise. events; SAE, serious AE. METHODS Not recovered from toxicities from prior therapy to Grade 1 (or baseline) AE, adverse event; max, maximum; min, minimum; PROC, platinum resistant ovarian cancer. Anti-PARP 26 (68) Grade >1 peripheral neuropathy (any etiology) Part 1 enrolled adults with locally advanced/metastatic solid tumours into Other 8 (21) 1 of 2 rebastinib dose cohorts (50 or 100 mg BID) in combination with Known active CNS metastases CONCLUSIONS History or presence of clinically relevant cardiovascular abnormalities Prior surgery 37 (97) paclitaxel using a parallel cohort design to determine recommended dose Known retinal neovascularisation, macular oedema, or macular degeneration for part 2 (Figure 2) Prior radiation 1 (3) Part 2 of this study has 5 disease-specific cohorts (triple-negative breast BRCA, breast cancer gene, CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; PARP, poly adenosine diphosphate- a Rebastinib demonstrated encouraging preliminary antitumour activity in combination with paclitaxel in heavily pretreated patients with Includes one patient whose histology was classified as Other, high-grade serous. ribose polymerase; PROC, platinum resistant ovarian cancer; RECIST, Response Evaluation Criteria in Solid Tumors. cancer, inflammatory breast cancer, PROC, endometrial cancer, and Data shown as n (%) unless indicated otherwise. advanced/metastatic PROC (all receiving platinum/taxane, 61% ³4 prior anticancer regimens, 87% prior bevacizumab): BRCA, breast cancer gene; PARP, poly adenosine diphosphate-ribose polymerase; PROC, platinum resistant ovarian cancer. gynecological carcinosarcoma) (Figure 2) The median PFS was 9.1 months According to the Simon 2-stage design, if ³5 responses are observed RESULTS The ORR was 38% (confirmed + unconfirmed) and 29% (confirmed); the median duration of response was 5.5 months from 18 patients, the cohort will be expanded with 15 additional patients In this analysis, 100% of patients received ³2 lines of therapy; 61% of patients received ³4 lines of therapy (Table 2) The clinical benefit rate at 16 weeks (confirmed + unconfirmed) was 76% Patients were treated with rebastinib (50 or 100 mg BID) in combination 2 Patient demographics and disposition All patients received prior platinum/taxane chemotherapy and 87% of patients A CA-125 response occurred in 19 of 26 patients (73%) with 80 mg/m intravenous weekly paclitaxel (day 1, day 8, and day 15 of repeated 28-day cycles) In this analysis, 38 patients with PROC have initiated treatment with rebastinib and are received bevacizumab (Table 2) The safety profile of rebastinib 50 mg BID in combination with paclitaxel was generally well tolerated In this pr esentation, results are reported for patients with PROC with a in the safety population; 4 patients did not meet the criteria to be in the modified intent- Antitumour activity The median PFS was promising when considering previously reported data for weekly paclitaxel monotherapy in the PROC setting data cut-off of June 22, 2021 to-treat population (mITT), resulting in 34 patients in the mITT population (Figure 3) (median PFS 34 months)4,5 The ORR (confirmed + unconfirmed) was 38%; the clinical benefit rate (CBR) at 16 Patients were evaluated for safety according to CTCAE v5.0, tumour Of 38 patients, 10 patients were treated with rebastinib starting dose of 100 mg a weeks was 76% (Table 3) Patients with ³1 postbaseline radiological assessment are shown (N = 32); plot includes confirmed and unconfirmed responses. response according to RECIST v1.1, and cancer antigen-125 (CA-125) BID (7 patients reduced to 50 mg BID) and 28 patients with rebastinib starting bDotted lines denote 30% decrease and 20% increase in tumour size cutoffs for PR and PD, respectively. This updated safety and efficacy analysis supports further development of rebastinib 50 mg BID in combination with paclitaxel in 2 cOverall, 13 patients (34%) discontinued due to radiological PD, 9 patients (24%) discontinued due to an AE, 7 patients (18%) discontinued due previously treated patients with PROC response (at least 50% reduction of CA-125 levels confirmed and dose of 50 mg BID in combination with weekly paclitaxel 80 mg/m CA-125 was evaluated in 26 patients; 19 (73%) had a CA-125 response to clinical PD, 2 patients (5%) chose to withdraw, and 1 patient (3%) died due to causes unrelated to rebastinib. AE, adverse event; CR, complete response; mITT, modified intent-to-treat; PD, progressive disease; PR, partial response; PROC, platinum maintained for at least 28 days) according to Gynecological Cancer As of June 22, 2021, there were 6 patients on active treatment (Figure 4B) The median PFS was 9.1 months (90% confidence interval, 6.5NE; Figure 5) resistant ovarian cancer; SD, stable disease. Intergroup criteria Presented at the ESMO 2021 Congress Corresponding Author/Disclosure Acknowledgements References Corresponding Author: Erika P Hamilton (email@example.com). This study was sponsored by Deciphera Pharmaceuticals, LLC (Waltham, MA). Medical writing and editorial 1) Harney AS, et al. Mol Cancer Ther. 2017;16:2486501. 2) Thurston G, et al. Cold Spring Harb Perspect Med. 2012;2:a006550. 3) Mazzieri R, et al. Cancer Cell. 2011;19:51226. 4) Poveda AM, et al. J Clin Dr. Hamilton is employed by Sarah Cannon Research Institute, Tennessee Oncology, LLC; acts in an advisory/consultancy role fo r AstraZeneca, Black Diamond, Boehringer Ingelheim, Daiichi Sankyo, Genentech/Roche, Lilly, Mersana, Novartis, Pfizer, Puma Biot echnology, and Silverback; receives accommodations from AstraZeneca, Clovis Oncology, Eisai, September 1621, 2021 EMD Serono, Genentech/Roche, Lilly, Novartis, Pfizer, Tesaro, Amgen, Bayer, Bristol-Myers Squibb, Foundation Medicine, Genzyme, Guardant Health, Helsinn Therapeutics, HERON, Lexicon, Medivation, Merck, and Sysmex. Dr. Hamiltons institution receives fun ding from AstraZeneca, Black Diamond, Boehringer Ingelheim, AbbVie, Acerta Pharma, Aravive, support were provided by Lauren Hanlon, PhD, of AlphaBioCom, LLC (King of Prussia, PA). Oncol. 2015;33:383638. 5) Pignata S, et al. Lancet Oncol. 2015;16:56168. 6) Janku F, et al. Mol Cancer Ther. 2019;18(12_suppl):B055. ArQule, Arvinas, BerGenBio, Clovis Oncology, Compugen, Curis, CytomX Therapeutics, Daiichi Sankyo, Deciphera, eFFECTOR Therap eutics, Eisai, EMD Serono, Fochon, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon, Hutchison MediPharma, Im munomedics, InventisBio, Karyopharm Therapeutics, Leap Therapeutics, Lilly, Lycera, Macrogenics, MedImmune, Medivation, Mersana, Merus, Millennium, Molecular Templates, Novartis, Nucana, OncoMed, Orinove, Pfiz er, Puma Biotechnology, Radius Health, Regeneron, Rgenix, Seattle Genetics, Sermonix Pharmaceuticals, Silverback, Stem CentRx, Sy ros Pharmaceuticals, Taiho Pharmaceutical, Takeda, TapImmune Inc., Tesaro, Torque, Unum Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks.
Safety and preliminary efficacy of vimseltinib in tenosynovial giant cell tumor (TGCT) Gelderblom H1, Abdul Razak AR2, Sánchez-Gastaldo A3, Rutkowski P4, Wilky BA5, Wagner AJ6, van de Sande M7, Michenzie M8, Vallee M8, Sharma M8, Sherman ML8, Ruiz-Soto R8, Tap WD9 1Medical Oncology, Leiden University Medical Center, Leiden, Netherlands; 2Toronto Sarcoma Program, Princess Margaret Cancer Center, Toronto, ON, Canada; 3Phase I Unit, Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain; 4Maria Sklodowska-Curie National Research Institute of Oncology, Abstract: Warsaw, Poland; 5Medicine, University of Colorado Cancer Center, Aurora, CO, United States; 6Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; 7Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands; 8Deciphera Pharmaceuticals, LLC, Waltham, MA, United States; 1821P 9Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States ePoster INTRODUCTION Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm, where overexpression of colony-stimulating factor 1 (CSF1) drives recruitment of macrophages leading to local inflammation and joint destruction1,2 Patients with TGCT experience debilitating symptoms and significant disease burden. There remains an unmet need for treatment options for patients with TGCT not amenable to surgery Vimseltinib (DCC-3014) is an investigational, oral, highly selective, switch-control kinase inhibitor of CSF1 receptor (CSF1R)3 We report the safety and preliminary efficacy of patients with TGCT not amenable to surgery receiving vimseltinib in the Phase 1/2 study (NCT03069469) METHODS NCT03069469, an ongoing, multicenter, open-label study of vimseltinib in patients with advanced solid tumors and TGCT consists of 2 phases: - Phase 1 (dose escalation) study, a pharmacologically guided 3 + 3 design, to determine the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD) - Phase 2 (expansion) study to evaluate the safety, tolerability, and preliminary efficacy in 2 TGCT expansion cohorts Cohort A: TGCT patients with no prior anti-CSF1/CSF1R therapy (previous therapy with imatinib or nilotinib is allowed) Cohort B: TGCT patients with prior anti-CSF1/CSF1R therapy (previous therapy with imatinib or nilotinib alone would not be eligible) RESULTS Figure 1. TGCT enrollment and disposition in Phase 1/2 Study RP2D Phase 2 TGCT Phase 1 TGCT enrollment (30 mg twice weekly) enrollment (n = 32) (n = 45) Cohort 5, n = 8 Cohort A, n = 37 Cohort 8, n = 12 Cohort 9, n = 12 Cohort B, n = 8 Pending entry of dosing data in EDC (n = 1) Phase 1 TGCT Cohort A n = 32 n = 36 (Safety population) (Safety population) Patient withdrew prior to assessment (n = 1) Phase 1 TGCT Pending first imaging assessment n = 32 (n = 16) (Efficacy-evaluable populationa) Cohort A n = 19 Loading dose Dose (Efficacy-evaluable populationa) Cohort 5 30 mg QD x 5 days 30 mg twice weekly Cohort 8 30 mg QD x 3 days 10 mg QD Data cutoff Cohort 9 20 mg QD x 3 days 6 mg QD 7 June 2021 Phase 2 NA 30 mg twice weekly ClinicalTrials.gov: NCT03069469 a At least one post-baseline efficacy assessment. EDC, electronic data capture; QD, once daily; RP2D, recommended phase 2 dose; TGCT, tenosynovial giant cell tumor. Enrollment in phase 1 with dose escalation is complete (n = 32) The target enrollment of 40 patients in phase 2 cohort A has been reached as of 13 July 2021 The results of patients with TGCT in phase 1 (n = 32) and phase 2 Cohort A (n = 36) receiving vimseltinib as of 7 June 2021 are presented Table 1. Baseline characteristics of patients with TGCT receiving vimseltinib Phase 1 TGCT patients Phase 2 Cohort A patients n = 32 n = 36 Age, median (range), years 51 (2373) 44 (2171) Sex Female 17 (53) 26 (72) Male 15 (47) 10 (28) Race White 31 (97) 28 (78) Asian 1 (3) 2 (6) Not Reported or Missing 0 6 (17) Disease location Knee 20 (63) 20 (56) Ankle 5 (16) 5 (14) Hip 4 (13) 2 (6) Foot 1 (3) 6 (17) Othera 2 (6) 3 (8) Patients with at least one prior surgery 12 (38) 32 (89) Patients with at least one prior systemic therapy 5 (16) 2 (6) Imatinib or nilotinib 4 (13) 2 (6) Lacnotuzumab (MCS-110) 1 (3) 0 Data are presented as n (%) unless otherwise noted. Percentages might not add up to 100% due to rounding. a Other locations include wrist, shoulder, and jaw. TGCT, tenosynovial giant cell tumor. Table 2. TEAEs in ³15% of patients with TGCT receiving vimseltinib Phase 1 Phase 2 Cohort 5 All Patientsa Cohort Aa Preferred term, No. (%) (n = 8) (n = 32) (n = 36) All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 Blood CPK increased 7 (88) 4 (50) 20 (63) 10 (31) 19 (53) 9 (25) Periorbital oedema 3 (38) 0 17 (53) 0 8 (22) 0 Fatigue 3 (38) 0 15 (47) 0 6 (17) 0 AST increased 5 (63) 1 (13) 14 (44) 4 (13) 12 (33) 0 ALT increased 2 (25) 0 10 (31) 1 (3) 4 (11) 0 Myalgia 0 0 9 (28) 1 (3) 5 (14) 0 Arthralgia 2 (25) 0 8 (25) 1 (3) 2 (6) 0 Face oedema 0 0 8 (25) 0 0 0 Headache 3 (38) 0 8 (25) 0 10 (28) 0 Lipase increased 1 (13) 0 8 (25) 3 (9) 4 (11) 0 Oedema peripheral 1 (13) 0 8 (25) 0 5 (14) 0 Pruritus 1 (13) 0 8 (25) 0 3 (8) 0 Amylase increased 1 (13) 1 (13) 7 (22) 2 (6) 5 (14) 0 Diarrhoea 1 (13) 1 (13) 6 (19) 1 (3) 2 (6) 0 Generalised oedema 2 (25) 0 6 (19) 0 0 0 Hypertension 0 0 6 (19) 2 (6) 1 (3) 0 Nausea 2 (25) 0 6 (19) 0 8 (22) 0 Constipation 1 (13) 0 5 (16) 0 2 (6) 0 Parasthesia 0 0 5 (16) 0 1 (3) 0 Rash macular 0 0 5 (16) 0 0 0 Rash maculopapular 0 0 5 (16) 0 5 (14) 0 Asthenia 1 (13) 0 3 (9) 0 6 (17) 0 a TEAEs cutoff of >15% based on all grades for total phase 1 and phase 2 cohort A. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; TEAE, treatment-emergent adverse event. Table 3. Dose modifications due to any TEAEs Phase 1 Phase 2 Cohort 5 All patients Cohort A (n = 8) (n = 32) (n = 36) Any TEAEs leading to dose 5 (63) 19 (59) 10 (28) modification, n (%) Dose interruption 5 (63) 18 (56) 9 (25) Dose reduction 4 (50) 13 (41)a 3 (8)b Treatment discontinuation 1 (13) 2 (6)c 1 (3)d a Cohort 5: Gr3 urticaria (n = 1), Gr3 diarrheoa (n = 1), Gr2 AST increase (n = 1), Gr3 amylase, Gr3 CPK, and Gr3 LDH increased (n = 1); Cohort 8: Gr2 fatigue, Gr2 edema peripheral, and Gr2 rash maculopapular (n = 1), Gr2 rash macular (n = 1), Gr2 joint swelling and Gr1 pyrexia (n = 1), Gr3 CPK increased (n = 1), Gr3 CPK increased and Gr2 myalgia (n = 1), Gr3 pruritic rash (n = 1); Cohort 9: Gr1 generalized oedema and Gr1 periorbital oedema (n = 1), Gr1 rash maculopapular (n = 1), Gr3 AST increased (n = 1). b Cohort A: Gr1 periorbital oedema and Gr1 rash maculopapular (n = 1); Gr1 headache (n = 1), Gr2 headache, Gr2 nausea, and Gr2 vomiting (n = 1). c Cohort 5: Gr3 metabolic encephalopathy (n = 1); Cohort 8: Gr3 AST increase (DLT, n = 1); d Gr1 periorbital oedema and Gr1 rash maculopapular (n = 1). AST, aspartate aminotransferase; CPK, creatine phosphokinase; DLT, dose-limiting toxicity; Gr, Grade; LDH, lactate dehydrogenase; TEAE, treatment-emergent adverse event. Table 4. Best overall response in patients with TGCT Cohort 5 All patients Cohort A (n = 8b) (n = 32b) (n = 19) Best overall response, n (%) Complete response 1 (13) 1 (3) 0 Partial response 3 (38) 15 (47) 8 (42) Stable disease 4 (50) 16 (50) 11 (58) ORR, % 4 (50) 16 (50) 8 (42) a Of the 51 efficacy-evaluable patients in phase 1 across all dose cohorts and phase 2 cohort A, 24 patients had a response resulting in an ORR of 47%. b 1 patient had a local assessment for efficacy, but no central assessment was performed. ORR, objective response rate; QD, once daily. SAFETY Majority of the common (³15%) TEAEs were £Grade 2 (Table 2) Observed transaminase, pancreatic, and CPK enzyme elevations were mostly low grade and not associated with symptoms; are consistent with the mechanism of action of CSF1R inhibitors No abnormalities in bilirubin levels reported In phase 1, 2 patients had TEAEs leading to treatment discontinuation (Table 3) and 2 patients had treatment-related grade 3 serious AEs (SAE): metabolic encephalopathy (possibly related) and vaginal hemorrhage (probably related) In phase 2 Cohort A, 1 patient had a TEAE leading to treatment discontinuation (Table 3) and no treatment-related SAEs were reported EFFICACY Phase 1: ORR of 50%; responses observed across all dose cohorts (Table 4, Figure 2, Figure 3) Phase 2 Cohort A: ORR of 42% (all partial responses; Table 4, Figure 2, Figure 3) Figure 2. Duration of treatment and response in patients with TGCT receiving vimseltinib Phase 1a Phase 2 Cohort Ab 5 Cohort # 8 Cohort SD PR 9 NE SD Cohort CR PR Ongoing Ongoing # From Local Data 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 1 2 3 4 5 6 7 8 9 10 11 12 Months on Study Months on Study # 1 patient had a local assessment for efficacy, but no central assessment was performed. a Median duration of treatment of 10.1 months across all phase 1 dose cohorts. b Median duration of treatment of 1.9 months in phase 2 cohort A. CR, complete response; NE, not evaluable; PR, partial response; SD, stable disease; TGCT, tenosynovial giant cell tumor. Figure 3. Best percentage change in target lesions in patients with TGCT receiving vimseltinib Phase 1 Phase 2 Cohort A 100 Cohort 5 100 Expansion A from Cohort 8 80 80 Cohort 9 Lesions 60 60 Target Baseline 40 40 - in Post 20 20 of SD 0 0 SD SD SD SD SD SD Diameters Nadir SD SD SD SD SD SD of SD SD the -20 SD SD SD SD -20 SD SD to Local SD SD Sum SD SD SD SD PR PR in -40 -40 PR PR PR PR PR PR PR PR PR PR Baseline PR PR Change -60 PR PR -60 PR PR PR PR PR -80 -80 Percent PR PR -100 -100 CR CR, complete response; NE, not evaluable; ORR, objective response rate; PR, partial response; SD, stable disease; TGCT, tenos ynovial giant cell tumor. CONCLUSIONS In patients with TGCT not amenable to surgical resection, - Vimseltinib was well tolerated in both phase 1 and phase 2 Cohort A. The safety profile remains manageable with longer-term follow-up across all phase 1 dose cohorts - Vimseltinib demonstrated encouraging preliminary efficacy Of the 32 patients in phase 1, ORR of 50% with durable responses observed across all dose cohorts, including 1 complete response in Cohort 5 Of the 36 patients enrolled in phase 2 Cohort A, 19 patients were evaluable for efficacy and had an ORR of 42%. Of the 19 patients, 10 had >1 follow-up imaging assessment and 2 responses occurred at later scans. The study is ongoing and follow-up evaluation is continuing These results support further evaluation of vimseltinib in the MOTION study, a randomized, placebo-controlled, phase 3 trial in patients with TGCT not amenable to surgical resection To be presented at the 2021 ESMO Congress, Acknowledgments Corresponding Author References The study was sponsored by Deciphera Pharmaceuticals, LLC, Waltham, MA, USA Dr. H. Gelderblom (firstname.lastname@example.org) 1) Staals EL, et al. Eur J Cancer. 2016;63:34-40; 2) West RB, et al. Proc Natl Acad Sci USA. 2006;103:690-695; 3) Smith BD, et al. Mol Cancer 16-21 Sep 2021 (Virtual) No financial disclosures Medical writing was provided by Uma Chandrasekaran, PhD (Deciphera Pharmaceuticals, LLC); editorial support was provided by Ashfield Ther. 2021 Aug 25. doi:10.1158/1535-7163.MCT-21-0361. Health and was funded by Deciphera Pharmaceuticals, LLC