In an interview with PharmaShots, Matthew L. Sherman, M.D., Executive Vice President and Chief Medical Officer of Deciphera shed light on encouraging preliminary results from the ongoing P-I/II study of DCC-3014 in TGCT patients and also presented the data of QINLOCK at CTOS 2020
- Deciphera presented encouraging preliminary results from the ongoing Phase 1/2 study of DCC-3014 in tenosynovial giant cell tumor patients at the Connective Tissue Oncology Society 2020 Virtual Annual Meeting
- The company also announced data presentations from clinical studies of QINLOCK, a switch-control tyrosine kinase inhibitor approved in the US for 4L GIST
- Deciphera also presented results from an exploratory analysis of the P-III INVICTUS study in 4L GIST that demonstrates the broad clinical activity of QINLOCK across mutation sub-groups
Tuba: Please provide details about both studies presented at the CTOS 2020 Virtual Annual Meeting.
Matthew: At the CTOS 2020 Virtual Annual Meeting, Deciphera presented data from its ongoing Phase 1/2 study of DCC-3014 in patients with tenosynovial giant cell tumors (TGCT) and from clinical studies of QINLOCK (ripretinib), the Company’s switch-control tyrosine kinase inhibitor approved in the U.S. for fourth-line gastrointestinal stromal tumor (GIST).
Phase 1 Dose-Escalation Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DCC-3014 in Advanced Solid Tumors and Tenosynovial Giant Cell Tumor (TGCT)
The Company’s international, multicenter, open-label Phase 1/2 study of DCC-3014, a highly selective, oral, investigational switch-control kinase inhibitor of CSF1R, was designed to evaluate its safety, efficacy, pharmacokinetics, and pharmacodynamics in patients with malignant solid tumors and tenosynovial giant cell tumor (TGCT). TGCT is a rare disease caused by a translocation in colony-stimulating factor 1 (CSF1) gene resulting in overexpression of CSF1 and recruitment of colony-stimulating factor 1 receptor (CSF1R)-positive inflammatory cells into the lesion. TGCT is also known as a giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS), a diffuse-type of TGCT. Although benign, these tumors can grow and cause damage to surrounding tissues and structures inducing pain, swelling, and limitation of movement of the joint. Surgery is the main treatment option; however, these tumors tend to recur, particularly in diffuse-type TGCT. If untreated or if the tumor continually recurs, damage and degeneration may occur in the affected joint and surrounding tissues, which may cause significant disability.
Data presented at the CTOS 2020 Virtual Annual Meeting are from 25 TGCT patients enrolled in the dose-escalation portion of the Phase 1/2 study. The cutoff date for the safety data was September 23, 2020, and the cutoff date for the efficacy data was October 5, 2020, which included 22 evaluable patients.
Encouraging Preliminary Anti-Tumor Activity:
- 9 patients (41%) across all TGCT cohorts achieved an objective response (1 CR, 8 PR) o
- 7 of the 9 responders (78%) had a partial response at their first restaging scan evaluation (week 9)
Preliminary Safety Data Shows DCC-3014 as Well Tolerated in TGCT Patients:
- Treatment with DCC-3014 was generally well-tolerated in patients with TGCT not amenable to surgery. One patient (4%) discontinued treatment due to an adverse event (asymptomatic Grade 3 AST elevation, from Grade 1 at baseline)
- Treatment-emergent adverse events (TEAEs) occurring in ≥25% of patients regardless of relatedness were blood CPK increased (52%), AST increased (44%), periorbital edema (44%), fatigue (40%), lipase increased (32%), and ALT increased (28%). No SAEs related to DCC-3014 were reported.
- All bilirubin levels were within the normal limit and observed transaminase and pancreatic enzyme elevations were asymptomatic and not clinically significant
Characterization of the extensive heterogeneity of KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: Genomic analysis of the phase 3 INVICTUS study
At CTOS we presented the first and largest baseline genomic analysis by tumor and liquid biopsy in fourth-line patients with 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. Baseline tumor and plasma samples were collected to investigate the genomic heterogeneity of resistance in the INVICTUS study.
- This is the first and largest baseline genomic analysis by tumor and liquid biopsy in fourth-line patients with GIST that failed prior treatment with at least imatinib, sunitinib, and regorafenib.
- In patients with fourth-line and fourth-line plus GIST, data demonstrated a complex and heterogenous mutational landscape. o
- The most frequent primary mutations found were in KIT exon 11 and KIT exon 9.
- By tumor biopsy, secondary mutations were more diverse in KIT exons 17/18 (15 unique mutations) compared to KIT exons 13/14 (5 unique mutations).
- More mutations were detected by liquid biopsy compared with tumor biopsy, increasing the detection rate of secondary mutations from 15 to 26 unique mutations (73% increase) in KIT exons 17/18 and from 5 to 12 unique mutations (140% increase) in KIT exons 13/14.
- The heterogeneity of the KIT mutations highlights the need for therapies that are effective against a broad spectrum of mutations.
Ripretinib demonstrated activity across all KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: Analysis from the phase 3 INVICTUS study
Results from an exploratory analysis from the Phase 3 INVICTUS study showed that QINLOCK demonstrated clinically meaningful activity in patients with a broad spectrum of KIT and PDGFRA mutations. The data cutoff for this analysis was March 9, 2020.
In INVICTUS, QINLOCK demonstrated clinically meaningful activity in patients with fourth-line and fourth-line plus GIST (n=129) with multiple, heterogeneous genetic subsets of KIT/PDGFRA mutations. QINLOCK showed a median progression-free survival (PFS) benefit of 6.3 months versus a placebo of 1 month in all patients (hazard ratio = 0.16).
The HRs of PFS within different mutation subgroups all favored treatment with QINLOCK, which is in line with the primary outcome of the INVICTUS study. These results support the proposed broad mechanism of action of QINLOCK with its specific receptor-binding properties.
Tuba: Is Deciphera planning to assess QINLOCK in other than the 4th and 2nd lines in GIST?
Matthew: We are focused on exploring the full potential of QINLOCK to benefit people with GIST. Our near-term focus for further clinical development remains in the second-line treatment setting. We recently completed target enrollment in the Phase 3 INTRIGUE study, in which we are comparing QINLOCK to sunitinib in the 2nd line, and expect to provide top-line data for this study in the second half of 2021. We believe QINLOCK has the potential to play an even broader role in the treatment of GIST.
Tuba: Are you planning to expand the potential of QINLOCK in other indications?
Matthew: Deciphera is focusing its resources on first exploring the full potential of QINLOCK in GIST including earlier lines of treatment and expanding access to QINLOCK for people with GIST outside the United States.
Tuba: Does Deciphera plan to assess DCC-3014 in indications other than TGCT?
Matthew: We do see a potential path forward to evaluate DCC-3014 in other indications, both as monotherapy and in combination, but it’s too early to discuss specific studies and for now our near-term focus is on developing DCC-3014 for patients with TGCT.
Tuba: What are the novel mechanism of actions of QINLOCK and DCC-3014?
QINLOCK Mechanism of Action:
QINLOCK is a novel switch-control tyrosine kinase inhibitor (TKI) specifically designed to broadly inhibit KIT and PDGFRA kinase signaling through a dual mechanism of action that secures the kinase into an inactive conformation, resulting in inhibition of downstream signaling and cell proliferation. QINLOCK precisely and durably binds to both the switch pocket region and the activation loop to lock the kinase in the inactive “off” state. Portions of QINLOCK mimic the inhibitory loop and occupy the switch pocket, thereby preventing the activation loop’s entry. Other residues on QINLOCK bind to the activation loop, stabilizing it out of the switch pocket and covering the adenosine triphosphate (ATP) binding site, so kinase activation cannot occur. This dual mechanism of action secures KIT and PDGFRA kinases in their inactive conformations providing broad in vitro inhibition of KIT and PDGFRA kinase activity, including wild type and multiple primary and secondary mutations.
DCC-3014 Mechanism of Action:
DCC-3014 is an investigational, orally-administered, potent, and highly selective switch-control kinase inhibitor of CSF1R. DCC-3014 was designed to selectively bind to the CSF1R switch pocket. It has greater than 100-fold selectivity for CSF1R over the closely related kinases FLT3, KIT, PDGFRA, PDGFRß, and VEGFR2 and has even greater selectivity for CSF1R over approximately 300 other human kinases that we tested. DCC-3014 inhibits CSF1R signaling in cellular assays, as well as blocks macrophage-mediated tumor cell migration, osteoclast differentiation, and proliferation of a CSF1R-dependent cell line.
Tuba: Please provide any relevant information about the rest of the company’s pipeline programs and their targeted indications?
Matthew: Enabled by Deciphera’s proprietary switch-control kinase inhibitor, the company has developed a diverse pipeline of wholly-owned drug candidates. The company has used its platform to develop its approved drug, QINLOCK, and two clinical programs DCC-3014 and rebastinib, and one preclinical program, DCC-3116, that we expect to enter clinical development in 2021.
Overview of the Rebastinib Program:
Rebastinib is a potent and selective TIE2 inhibitor, which is currently being studied in combination with chemotherapy. TIE2 is a target primarily expressed in endothelial cells and TIE2-expressing macrophages, or TEMs, and plays an important role in angiogenesis as part of the angiopoietin/TIE2 signaling axis.
We presented positive initial data from the endometrial cohort at the ASCO 2020 Virtual program showing promising preliminary anti-tumor activity and favorable tolerability:
• An objective response rate of 39%, confirmed and unconfirmed.
• A clinical benefit rate of 72% at eight weeks in heavily pre-treated patients.
In addition, data presented at the ESMO Virtual Congress 2020 in platinum-resistant ovarian cancer demonstrated encouraging initial activity:
• An objective response rate of 38%, confirmed and unconfirmed.
• A clinical benefit rate of 88% at eight weeks in heavily pre-treated patients.
Deciphera is currently studying rebastinib in a Phase 1b/2 clinical study in combination with paclitaxel (NCT03601897) and in a Phase 1b/2 clinical study in combination with carboplatin (NCT03717415).
Overview of the DCC-3116 Program:
DCC-3116 is a small molecule and potential first-in-class ULK kinase inhibitor discovered using our novel switch-control kinase inhibitor platform. DCC-3116 is designed to inhibit autophagy, a key tumor survival mechanism in cancer cells, by inhibiting the ULK kinase, which has been shown to be the initiating factor that activates autophagy. In the near-term, we expect to file an IND for DCC-3116 for the potential treatment of RAS mutant cancers in combination with inhibitors of downstream RAS effector targets including RAF, MEK, or ERK inhibitors as well as with direct inhibitors of mutant RAS.
Tuba: Are you looking for collaborations to develop and commercialize any of your therapies?
Matthew: Our current focus is on moving our clinical development efforts forward in each of our programs to achieve our mission to discover, develop and deliver important new medicines to patients for the treatment of cancer. We continue to evaluate the most efficient path forward for our programs, whether that be in partnership or on our own.
Image Source: Fortis Bangalore
Matthew L. Sherman, M.D. is Executive Vice President and Chief Medical Officer of Deciphera Pharmaceuticals. He brings over 25 years of experience as a physician-scientist in clinical drug development in oncology and hematology at leading biotechnology and pharmaceutical companies.