Background Colony-stimulating factor 1 receptor (CSF1R) signaling is a key pathway involved in the expansion and infiltration of donor-derived macrophages that mediate chronic graft-versus-host disease (cGVHD). Vimseltinib, an oral, selective small molecule inhibitor of CSF1R, has recently received US Food and Drug Administration (FDA) approval for the treatment of adult patients with tenosynovial giant cell tumor (TGCT), and is currently being investigated for treatment of cGVHD. As an oral agent targeting this key inflammatory and fibrotic pathway that characterizes cGVHD, vimseltinib may offer an advantage over other therapies. Objective To describe an ongoing Phase 2 study evaluating vimseltinib therapy in adults with active moderate-to-severe cGVHD. Methods This is a Phase 2, open-label, dose-finding, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of twice weekly vimseltinib in adults with active cGVHD after prior systemic therapy failure. Doses under investigation have been evaluated in patients with TGCT and advanced solid malignancy. For inclusion, patients ≥18 years of age must be hematopoietic stem cell transplant (HSCT) recipients with moderate-to-severe cGVHD requiring systemic immune suppression; patients may have persistent active acute GVHD (aGVHD) and cGVHD manifestations (ie, overlap syndrome). Patients must have failed ≥2 prior lines of systemic therapy and can only be on systemic corticosteroid use ≤1 mg/kg/day prednisone equivalent and 1 additional immunosuppressive agent, provided doses are stable for ≥2 weeks prior to starting vimseltinib. Other inclusion criteria include adequate organ and bone marrow function, and a Karnofsky Performance Scale score of ≥60. Exclusion criteria include prior use of a CSF1R inhibitor; history or other evidence of severe illness, uncontrolled infection, and/or malignancy (except for the underlying malignancy for which HSCT was performed); use of other systemic cGVHD treatment; and malabsorption syndrome. Enrolled patients across dose escalation cohorts will receive vimseltinib orally in 28-day cycles. Based on a 3+3 design (Figure), 2 of 3 dose levels have been successfully evaluated and cleared to date. The primary outcome measures for dose escalation include safety assessments (eg, frequency and severity of dose-limiting toxicities, adverse events [AEs], and serious AEs). Secondary outcome measures include objective response rate (from baseline up to Cycle 7, Day 1), duration of response, organ-specific response, failure-free survival, and PK. Enrollment is ongoing. Clinical trial information: NCT06619561. Funding Deciphera Pharmaceuticals, LLC.
PURPOSE:CD4 T-cell immunity is associated with improved survival in patients with breast cancer. We previously reported a phase I trial evaluating a folate receptor alpha (FRα) vaccine administered with cyclophosphamide (CP), demonstrating excellent safety and immunogenicity. To simplify the vaccine strategy for ease of use, we report here the results of a randomized phase II trial evaluating a lower vaccine dose alongside the original dose, administered with or without CP pretreatment. PATIENTS AND METHODS:Patients with triple-negative breast cancer who completed all systemic and local therapies were assigned to receive either low-dose (825 μg) or high-dose (2.5 mg) vaccine peptides plus GM-CSF in six 4-week cycles, with or without CP prior to vaccination. Safety was monitored, and immunogenicity was evaluated before and after vaccination. RESULTS:A total of 80 patients were dosed with vaccine, and 58 patients were evaluable for immunogenicity. Vaccination was well tolerated and elicited immunity in 83% of patients. Levels of FRα-specific T cells were high, persistent, and comparable with T-cell levels against tetanus toxoid. No differences in immunity were observed between the two doses. CP pretreatment also did not affect the immune responses. Recurrences occurred in eight evaluable patients and were unrelated to the treatment arm. No patients died during the study because of their disease. CONCLUSIONS:The reduced-dose FRα vaccine is as effective as the original dose and does not require CP to generate maximal immunity. These findings may inform the design of trials testing efficacy in triple-negative breast cancer or other cancers.
AIM:To evaluate the cost-effectiveness of sotorasib versus adagrasib in the second- and later lines of treatment for KRAS G12C non-small cell lung cancer (NSCLC) from a US private payer perspective. METHODS:A standard three-state partitioned survival model was used with a 20 year (life-time) horizon. Equivalent progression-free survival (PFS) and overall survival (OS) were assumed in the base case based on published matching-adjusted indirect comparisons (MAICs) of Phase 2 and 3 data, and time-to-death utilities applied. Treatment-related adverse events (TRAEs) common to both treatments were included. Direct costs and health benefits were discounted at 1.5% annually. Model robustness was explored through probabilistic sensitivity analysis (PSA) and inputs varied in scenario analyses. RESULTS:In the base case, sotorasib was more cost-effective than adagrasib, driven by lower acquisition cost and TRAE frequency. Total discounted costs were $18,004 higher for adagrasib than sotorasib ($246,557 vs $228,553), comprising: drug acquisition ($9,478), TRAE management ($4,103) and comedications (antiemetics and antidiarrheal agents; $4,424). Sotorasib was dominant at equivalent efficacy (1.20 quality-adjusted life-years [QALYs]). Net monetary benefit was $18,031 at a willingness-to-pay threshold (WTP) of $150,000/QALY. In the PSA, there was a higher probability of sotorasib being more cost-effective than adagrasib at all WTP thresholds (62% at a WTP of $150,000/QALY). Sotorasib was consistently more cost-effective than adagrasib in scenario analyses exploring relative efficacy, discount rate, time horizon, and utilities, with ICERs well below the $150,000/QALY WTP threshold. LIMITATIONS:MAIC-based comparative effectiveness was used in the absence of head-to-head trial data; conclusions informed by MAIC should be interpreted with caution; long-term projections are limited without mature OS data; published data sources may be based on different populations. CONCLUSION:Sotorasib was more cost-effective than adagrasib in the second- and subsequent-line treatment of KRAS G12C NSCLC, based on current efficacy and safety data.
BACKGROUND:Approximately 17% of patients with non-small cell lung cancer (NSCLC) have epidermal growth factor receptor mutations (EGFRm). Amivantamab received United States Food and Drug Administration approvals in advanced NSCLC for patients with EGFR exon 20 insertions (exon20ins) who progressed after platinum-based chemotherapy (PBC) on 05/21/2021, for first-line (1 L) EGFR exon20ins on 03/01/2024, and for 1 L and second-line or later (2 L+) EGFR exon 19 deletion and L858R on 08/20/2024 and 09/19/2024, respectively. This claims-based study describes real-world treatment patterns and healthcare resource utilization (HRU) among insured patients with advanced NSCLC initiating amivantamab in 2 L or later (2 L+). METHODS:Komodo Research Data closed claims (01/01/2016-10/31/2023) were used to analyze insured adults with a diagnosis of lung cancer who initiated amivantamab on/after 05/21/2021 in 2 L+. Treatment patterns, including prior PBC and immunotherapy (IO) use, were described by line of therapy (LOT). All-cause HRU per-patient-per-month (PPPM) was assessed during the amivantamab LOT and all LOTs preceding amivantamab. Time to next treatment or death (TTNT-D) was reported using Kaplan-Meier analysis for each LOT. RESULTS:Overall, 126 patients initiated amivantamab in 2 L+ (mean age: 60.2 years, 63.5% female). Amivantamab was initiated in 2 L by 51.6% of patients, while 32.5% and 15.9% initiated amivantamab in third-line (3 L) and fourth-line or later (4 L+), respectively. Most patients initiated amivantamab as monotherapy (2 L: 92.3%; 3 L: 73.2%; 4 L+: 80.0%), had prior PBC use (2 L: 83.1%; 3 L: 100.0%; 4 L+: 100.0%), and prior IO use (2 L: 60.0%; 3 L: 63.4%; 4 L+: 85.0%). Mean outpatient service use was 5.87 days PPPM before amivantamab initiation and 6.79 days PPPM during amivantamab treatment. Mean inpatient admissions PPPM were 0.05 before amivantamab and 0.08 during amivantamab treatment. Among patients initiating amivantamab in 2 L, 3 L, or 4 L+, median TTNT-D was 11.0 months, 5.3 months, and 6.1 months, respectively. CONCLUSIONS:Among insured patients with advanced NSCLC receiving amivantamab in 2 L+, TTNT-D aligned with results reported in clinical trials. Before initiating amivantamab, most patients received IO, despite IO use being inconsistent with treatment guidelines and limited demonstrated benefit. HRU was similar before and during amivantamab treatment, suggesting that amivantamab does not contribute to an increase in medical services compared to treatment regimens used in earlier LOTs.
7025 Background: CB-010 is an allogeneic anti-CD19 CAR-T cell therapy derived from healthy donor T cells using CRISPR hybrid RNA-DNA (chRDNA) technology. This technology is used to introduce 3 genome edits: (1) knockout of TRACto eliminate TCR expression and reduce risk of GvHD, (2) insertion of a CD19-specific CAR (scFv FMC63) into the TRAC locus, and (3) knockout of PD-1 to prevent premature CAR-T cell exhaustion and potentially enhance antitumor activity. Methods: ANTLER is a Phase 1 clinical trial (NCT04637763) with a 3+3 dose escalation phase and a dose expansion phase designed to evaluate safety, tolerability, and antitumor activity of CB-010 in patients (pts) with r/r B-NHL and determine RP2D. In dose escalation, pts must have received ≥2 prior lines of chemoimmunotherapy or had primary refractory disease to 1L therapy. Pts received lymphodepletion with sequential cyclophosphamide (60 mg/kg/day x 2 days) and fludarabine (25 mg/m2/day x 5 days) followed by a single CB-010 infusion. Results: 16 pts with r/r B-NHL (10 LBCL, 3 MCL, 2 FL with POD24, 1 MZL) received CB-010 at 40 x 106 CAR-T cells (dose level 1; N=8), 80 x 106 CAR-T cells (dose level 2; N=5), or 120 x 106 CAR-T cells (dose level 3; N=3) during dose escalation. Median age was 66 years (range 55-82). Median time since first diagnosis was 2.4 years (range 0.2-16.4). Median prior lines of therapy was 2 (range 1-8). CB-010 was generally well tolerated. No GvHD was seen. CRS occurred in 7/16 (44%) pts (no CRS grade ≥3). Median time to CRS onset was 3.5 days and median duration was 3 days. ICANS occurred in 4/16 (25%) pts (13% grade ≥3). Median time to ICANS onset was 7.5 days and median duration was 2 days. The 3 most common TEAEs grade ≥3 were thrombocytopenia (11/16; 69%), neutropenia (9/16; 56%), and anemia (8/16; 50%). One grade 3 infection (antecubital cellulitis) occurred unrelated to CB-010. After a single CB-010 infusion, 15/16 (94%) pts achieved an overall response, 11/16 (69%) achieved a CR, and 7/16 (44%) achieved a CR at ≥6 months. Median time to CR was 28 days. Among LBCL pts (n=10), 9 (90%) achieved an overall response, 7 (70%) achieved a CR, and 5 (50%) achieved a CR at ≥6 months. To date,2 pts have completed the 24-month study period with ongoing CR. Peak expansion of CB-010 occurred at days 7-10 post-infusion. T and NK cells recovered rapidly in peripheral blood (<3 weeks) after lymphodepletion, and B cells remained below the limit of quantification beyond 3 months, supporting specific targeting of B cells by CB-010. Conclusions: CB-010 showed a manageable safety profile and promising efficacy for treatment of pts with r/r B-NHL, including aggressive subtypes. The dose escalation phase is complete. Enrollment of 2L LBCL pts in dose expansion is ongoing. Initial dose expansion data at the CB-010 RP2D and translational data will be presented for the first time at the meeting. Clinical trial information: NCT04637763 .
