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Key Updates in Hemat-Oncology
Efficacy and Safety Results from the Phase II Study of Timdarpacept in Combination with Tislelizumab, in Prior Anti-PD-1 Failed Classical Hodgkin Lymphoma
Background
Timdarpacept (IMM01), a recombinant SIRPa-Fc fusion protein, can activate macrophages to enhance anti-tumor activity by blocking CD47-SIRPa interaction. Timdarpacept showed unique property of weak human erythrocyte binding in preclinical studies, and low incidence of anemia in early clinical trials with no need for a priming dose.
Methods
- Eligible patients (pts) with R/R classical Hodgkin lymphoma (cHL) who have failed prior anti-PD-1 treatment were enrolled in this study (NCT05833984).
- Timdarpacept (2.0mg/kg, QW) and tislelizumab (200mg, Q3W) were intravenously administered in 3-week treatment cycle until disease progression or intolerable toxicity.
- Primary endpoint: Objective response rate (ORR) by Lugano 2014
- Secondary endpoints: Tolerability, disease control rate (DCR), duration of response (DoR), progression free survival (PFS) and time to response (TTR).
Results
- As of 26 Mar 2024, 33 cHL pts were enrolled. The median age was 35 years. The median prior lines of therapy were 4.
- In all 33-efficacy evaluable pts with median follow up of 7.03 (4.40, 10.02) month, the ORR, complete response rate and DCR were 66.7%, 24.2% and 93.9%, respectively.
- The median TTR was 1.6 months.
- The median PFS was not reached.
- Further analysis indicated that pts could benefit from Timdarpacept combined with tislelizumab treatment regardless of primary or secondary resistance to anti-PD-1 treatment, or prior CD30-ADC treatment or not.
- All pts experienced treatment-related adverse events (TRAEs). The most common TRAEs were WBC decreased (51.5%), PLT decreased (42.4%), anemia (39.4%), ANC decreased (36.4%), lymphocyte decreased (30.3%).
- TRAEs of grade ≥3 occurred in 16 (48.5%) pts, the most common being lymphocyte decreased (30.3%), WBC decreased (15.2%), PLT decreased (12.1%), ANC decreased (12.1%). 4 (12.1%) pts had treatment related SAE. No TRAEs led to the drug discontinuation or death.
Conclusions
Timdarpacept in combination with tislelizumab showed a robust therapeutic efficacy with a well-tolerated safety profile in anti-PD-1 failed cHL patients. The study is ongoing to further evaluate secondary endpoints.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 809MO
Combination of Mitoxantrone Hydrochloride Liposome with Chidamide in Patients with Relapsed or Refractory Peripheral T Cell Lymphoma: A Phase l/II Study
Background
Relapsed or refractory (R/R) peripheral T cell lymphoma (PTCL) is an aggressive and heterogeneous malignancy without standard treatment. Mitoxantrone hydrochloride liposome (PLM60) monotherapy or chidamide (CHI) monotherapy has shown certain efficacy and safety in R/R PTCL. This study aimed to explore the safety and efficacy of PLM60 plus CHI (PLM60-CHI) in patients (pts) with R/R PTCL.
Methods
- Phase I was 3+3 design with three levels of PLM60 (14, 17 and 20mg/m2) plus chidamide 20 mg administered (biw).
- After the first cycle, dose-limiting toxicity (DLT) was assessed to determine the maximum tolerated dose (MTD) of PLM60.
- Phase II consisted of dose expansion at the recommended phase II dose (RP2D) to further evaluate the safety and efficacy of the PLM60-CHI regimen.
Results
- At data cutoff on March 10, 2024, the study has enrolled 21 pts (phase I, n=9 and phase II, n=12).
- Among all pts (median age: 49 years, range: 26-64 years; IPI score 3-5 with 8 pts (38.1%)) who had disease stage, 16 pts (76.2%) were in stage III-IV.
- Additionally, 13 pts (61.9%) were refractory to prior therapy. No DLTs were observed at 14, 17 and 20 mg/m2.
- RP2D was determined to be PLM60 at 20 mg/m2 in combination with CHI at 20 mg.
- The grade 3/4 treatment-related adverse events (TRAEs) with an incidence ≥10% were leucopenia (52.4%), neutropenia (66.7%), lymphopenia (42.9%), thrombocytopenia (23.8%) and anemia (23.8%).
- At date cutoff, the phase II study is ongoing. Eight pts in phase II were evaluable, showing an objective response rate (ORR) of 75% (6/8) and a complete response (CR) rate of 37.5% (3/8).
- The ORR of 16 pts in phases I and II was 56.3% (9/16) and the CR rate was 31.3% (5/16).
- After a median follow-up of 3.8 months, both the median progression-free survival (PFS) and median overall survival (OS) have not yet been reached.
|
Best response, N (%) |
Phase I (N=8) |
Phase II (N=8) |
Total (N=16) |
|
CR rate |
2(25.0) |
3(37.5) |
5(31.3) |
|
95%CI |
3.2%-65.1% |
8.5%-75.5% |
11.0%-58.7% |
|
ORR |
3(37.5) |
6(75.0) |
9(56.3) |
|
95%CI |
8.5%-75.5% |
34.9%-96.8% |
29.9%-80.2% |
Conclusions
PLM60-CHI regimen proves a promising efficacy in R/R PTCL with manageable safety.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 810MO
An Exploratory Study to Assess the Safety, Immunogenicity, and Preliminary Anti-tumor Activity of the EBV mRNA Vaccine (WGc-043 injection) in Patients with NK/T cell Lymphoma
Background
NK/T cell lymphoma (NKTCL) is a rare and aggressive disease that is often associated with Epstein-Barr virus (EBV) infection and requires novel therapeutic strategies. WGc-043, a therapeutic mRNA vaccine, shows promise against EBV-positive cancers and may provide therapeutic benefit to NKTCL patients by targeting EBV-driven oncogenesis. This study evaluates the safety, immunogenicity, and preliminary antitumor activity of WGc-043 in patients with NKTCL in an IIT.
Methods
- This single-center, open-label, exploratory study enrolled 7 patients with EBV-positive relapsed or refractory NKTCL.
- Primary inclusion criteria: Patients with an ECOG of 0-2 who have failed standard therapy. WGc-043 was administered intramuscularly, including 5 doses of base immunization followed by optional personalized treatment.
- The base immunization was given at week 1, 2, 3, 4 and 8.
- Primary endpoint: Safety
- Secondary endpoints: Immunogenicity, ORR and DCR
- The exploratory analysis focuses on immune biomarkers predictive of therapeutic response.
Results
WGc-043 demonstrated a favorable safety and efficacy profile in patients with NKTCL. It was well tolerated with only grade 1 or 2 adverse events. The most common adverse events were injection site reactions (57.1%) and fever (42.9%), which were transient and resolved without sequelae. Importantly, WGc-043 showed good efficacy, with 3 patients achieving PR and 1 maintaining SD, resulting in an ORR of 42.86% and a DCR of 57.14%. This suggests a potential clinical benefit of using WGc-043 as part of the therapy in this challenging malignancy.
|
Efficacy |
|
|
Response category |
|
|
PR |
3 |
|
SD |
1 |
|
PD |
3 |
|
Total |
7 |
|
ORR |
42.86% |
|
DCR |
57.14% |
|
Safety |
No of Subjects |
||||
|
Vaccine-related adverse events |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 5 |
|
Any adverse event |
6 (85.7%) |
4 (57.1%) |
0 |
0 |
0 |
|
Fever |
2 (28.6%) |
1 (14.3%) |
0 |
0 |
0 |
|
Lymphopenia |
1 (14.3%) |
2 (28.6%) |
0 |
0 |
0 |
|
Weakness |
2 (28.6%) |
0 |
0 |
0 |
0 |
|
Injection site reaction |
4 (57.1%) |
0 |
0 |
0 |
0 |
|
Oral mucositis |
0 |
1 (14.3%) |
0 |
0 |
0 |
Conclusions
WGc-043 is well tolerated with a safety profile that reflects its potential for favorable patient outcomes. The observed efficacy in the NKTCL cohort suggests a promising clinical benefit. Further research is needed to confirm these findings and to explore the full potential of the vaccine in larger studies.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 811MO
Initial Results of the Multicenter Phase II Trial of a Novel Hypofractionated Low-dose Radiotherapy for Indolent Non-Hodgkin Lymphoma
Background
Indolent non-Hodgkin lymphoma (iNHL) has been shown to be highly radiosensitive, and the most effective radiotherapy (RT) regimen has yet to be established. Recent findings suggested that hypofractionated RT may have a more pronounced antitumor effect. The study conducted was a phase 2 trial to evaluate the efficacy and toxicity of dose-deescalated hypofractionated radiotherapy in patients with iNHL.
Methods
- The study design was a multicenter, single-arm, phase 2 trial with a planned accrual of 73 sites.
- Patients with indolent non-Hodgkin lymphoma aged 18 years or older, without a history of prior radiotherapy at the same site, were deemed eligible for the study. Involved-site radiotherapy was delivered at 12 Gy in four fractions within one week.
- Primary endpoint: Complete response (CR) rate per RECIL 2017 by investigators at 6 months after radiotherapy
- Secondary endpoints: were 6-month overall response rate (ORR), 2-year progression-free survival, 2-year local control rate, acute and late toxicity, quality of life (QOL), and immunologic biomarkers induced by hypofractionated radiotherapy
Results
- A total of 73 sites from 71 patients were enrolled between May 8, 2022, and November 8, 2023, at three centers in China.
- The median age was 54 years (interquartile range [IQR], 47-64), with a male-to-female ratio of 1:1.43.
- Most patients (82.2%) had Ann Arbor stage I to II diseases. The most common subtype was marginal zone lymphoma (n = 55; 75.3%).
- With a median follow-up of 10.5 months (range, 6.0-23.9), the 6-month CR and ORR rates were 93.2% and 100%, respectively. Acute toxicities were minimal, with no grade 3 or greater adverse events.
- The most frequent grade 1 or 2 adverse events were lymphocytopenia (30.1%), and nausea (20.5%), with 79.8% of events occurring within 2 weeks following the completion of radiotherapy.
Conclusions
Hypofractionated low-dose radiotherapy of 12 Gy in 4 fractions demonstrated promising antitumor activity among patients with iNHL. No severe toxicity was observed in the novel regimen. Long-term follow-up is required to assess the durability of tumor control, late toxicity, dynamic QOL, and immune biomarkers.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 812MO
Phase I Trial of a Personalized Multi-peptide Vaccine Combined with the TLR1/2 Ligand XS15 Under Bruton-Tyrosine-Kinase inhibitor (BTKi) treatment in Chronic Lymphocytic Leukemia (CLL) Patients
Background
Targeted substances, including BTKi, greatly improved prognosis in CLL. However, frequent disease relapses occur, due to remaining treatment resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD).
Methods
- The study reports an open-label phase I clinical trial evaluating a personalized peptide vaccine in CLL patients under BTKi therapy (NCT04688385).
- The vaccine was compiled from a premanufactured warehouse of immunopeptidome-defined CLL-associated peptides (Nelde et al., Front Immunol. 2021) based on HLA allotype and individual CLL immunopeptidome, and with TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG (iVAC-CLL-XS15).
- After achievement of at least partial remission (MRD-positive) under BTKi, iVAC-CLL-XS15 was applied three times.
- BTKi was continued through the trial until 6-month follow-up (FU). Primary endpoints were safety and immunogenicity, main secondary endpoints MRD negativity and reduction rate.
Results
- 20 patients (median age 59 years, male:female 2.3:1) were enrolled (75% BTKi 1st and 25% 2nd line; CLL IPI: 0% low, 47% interm, 37% high and 16% v. high).
- Vaccination was well tolerated and no treatment-related serious adverse events reported.
- Local granuloma formation at vaccination site was observed in all patients, enabling a local stimulation of CLL-specific T cells without relevant systemic inflammation.
- Vaccine-induced T cell responses were detected in all patients analyzed so far (100%, 17/17), targeting multiple vaccine peptides (50% CLL-associated HLA-class I and 88% HLA-class II epitopes).
- Vaccine-induced T cell responses persisted in all patients until FU and were mediated by multifunctional CD4+ and CD8+ T cells. Preliminary efficacy analyses showed MRD reduction (median 45%) in 87% (13/15) of patients from 1st vaccination to FU with an association of vaccine-induced T cell response and MRD reduction in single patient analysis.
Conclusions
The beneficial safety profile, induction of profound, long-lasting CLL-specific T cell responses, and preliminary MRD efficacy data warrant further evaluation of iVAC-CLL-XS15 in an upcoming randomized Phase II trial.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 813MO
A Prospective Study of Orelabrutinib Plus Obinutuzumab (O2) in Treatment-naïve Marginal Zone Lymphoma (MZL): Preliminary Analysis on Efficacy and Safety
Background
There is no well-established standard first-line treatment for symptomatic MZL patients (pts). Orelabrutinib (ORE) was the first approved BTK inhibitor in China for relapsed or refractory MZL treatment. However, evidence supporting ORE as a first-line therapy for MZL is lacking. This prospective study evaluated a chemotherapy-free regimen of ORE plus anti-CD20 antibody obinutuzumab (OBI) in treatment-naïve MZL.
Methods
- This study enrolled pts with confirmed CD20-positive MZL, who has progressed/relapsed after or were ineligible for local therapy.
- Pts received induction therapy with ORE (orally 150 mg/day) plus OBI (intravenously 1000 mg; cycle 1: day 1, 8, 15; cycle 2-6: day 1) for 6 cycles every 4 weeks, and responders maintained with ORE for 1 year.
Results
- Nineteen pts with MZL (17 EMZL, 1 SMZL, 1 unknown) were enrolled in this study from 13 Jun. 2023 to 11 Apr. 2024.
- Pts characteristics included a median age of 60 years (range 25-77), 78.9% Ann Arbor stage II-IV disease, 73.7% intermediate and high-risk MZL-IPI scores and 31.6% prior local therapy.
- At a median follow-up of 5.4 months,14 pts had ≥1 efficacy assessment, the median time to response was 3.1 months and the best objective response rate (ORR) was 100% (57.1% complete response rate [CRR]).
- Of 13 pts evaluable for response at the end of cycle 3, ORR was 100%. Nine (69.2%) pts have completed the 6-cycle induction therapy and received ORE maintenance.
- At the end of cycle 6, 9 pts had an ORR of 100%, with a CRR of 55.6%.
- Eighteen pts had completed ≥1 cycle of therapy and were analyzed for safety. Adverse events included: neutropenia (grade [G] 1, n=1; G4, n=1), thrombocytopenia (G2, n=1), transaminase increased (G1, n=2), and leukopenia (G1, n=1).
Response during O2 treatment
|
Response, n (%) |
End of cycle 3(n=13) |
End of cycle 6(n=9) |
Best response(n=14) |
|
Objective response |
13 (100) |
9 (100) |
14 (100) |
|
Complete response |
5 (38.5) |
5 (55.6) |
8 (57.1) |
|
Partial response |
8 (61.5) |
4 (44.4) |
6 (42.9) |
|
Stable disease |
0 |
0 |
0 |
|
Progressive disease |
0 |
0 |
0 |
Conclusions
The preliminary data demonstrated that the O2 regimen was promising in treatment-naïve MZL. Trial recruitment is still ongoing. More updated data will be presented in future.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 815MO
Two Hematological Precursors and their Impact on Hematological Malignancies
Background
Monoclonal B-cell lymphocytosis (MBL) is a precursor to chronic lymphocytic leukemia (CLL) but also a risk factor for other lymphoid malignancies. Clonal hematopoiesis of indeterminate potential is a precursor to myeloid or lymphoid malignancies, depending on if the mutation is in a gene associated with lymphoid (L-CHIP) or myeloid (M-CHIP) disease, respectively. Little is known about the association between CHIP and MBL and their joint effect on risk of hematological malignancies (HM).
Methods
- Study participants were from the Mayo Clinic Biobank.
- Using whole-exome sequencing, M-CHIP and L-CHIP were, respectively, defined based on mutations in 56 genes associated with myeloid malignancies or mutations in 235 genes associated with lymphoid malignancies.
- MBL screening was done using eight-color flow cytometry, and 575 individuals provided a second blood sample for MBL screening ∼10 years later.
- Incident HM were identified using ICD codes and confirmed via medical record review.
- Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Cox regression was used to estimate hazard ratios (HR), with time defined as date between MBL sample and the first of incident HM, death, or 12/31/2023. Analyses were adjusted for age and sex.
Results
- In 9,328 individuals screened, 15% were positive for MBL, 7% were positive for M-CHIP, and 2% were positive for L-CHIP.
- No evidence was found of an association between MBL and M-CHIP (OR=1.0, 95% CI:0.85-1.3) or between MBL and L-CHIP (OR=0.9, 95% CI:0.58-1.4).
- When investigating the association between CHIP and MBL at the second timepoint, no evidence was found of an association with the development or growth of the MBL clone.
- The study next modeled the combined effect of these precursors on incident HM and found that those individuals with both MBL and M-CHIP had a 2.8% 10-year cumulative incidence of myeloid disease, similar to that of 3.2% for those with M-CHIP only.
- Conversely, individuals with both MBL and L-CHIP had a 10-year cumulative incidence of 36% for lymphoid malignancy compared to 0.7% among those with no precursor condition (HR= 40; 95% CI: 13.6-117.3).
Conclusions
MBL and CHIP are independent precursor conditions. Individuals with both MBL and L-CHIP had a 40-fold increase risk of lymphoid malignancy.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 816MO
Key Updates in Supportive Care
Adjuvant Aspirin Treatment in PIK3CA Mutated Colon Cancer Patients: The Phase III, Prospective-randomized Placebo-controlled Multicenter SAKK 41/13 Trial
Background
Many retrospective studies have provided suggestive evidence of a protective effect of aspirin as adjuvant treatment of colon cancer, particularly in patients with an activating PIK3CA mutation. The objective of the present randomized SAKK trial was to demonstrate the benefit of adjuvant aspirin in PIK3CA mutated colon cancer patients.
Methods
- This was a phase III, randomized, placebo-controlled, double-blinded, multicenter and multinational trial.
- Only stage II and III colon cancer patients with a centrally-assessed activating PIK3CA mutation in Exon 9 or 20 were included. Randomization was 2: 1 to aspirin 100mg daily for 3 years versus placebo for 3 years.
- Primary endpoint: Disease-free survival (DFS)
- Secondary endpoints: Overall survival (OS) and adverse events.
- One-sided type I error was 5% with a power of 80% to detect a hazard ratio (HR) of <0.456. The computed sample size was 185, with a number needed to screen of 1`088. Due to financial constraints, the trial was prematurely closed.
Results
- Overall, 112 patients were enrolled and included (aspirin arm: N=74, placebo arm: N=38). Median age was 66 years (range 29-89), 42.9% were female, baseline-characteristics were well-balanced between groups.
- After a median follow-up of 4 years, 19 DFS events occurred. The HR for DFS was 0.57 (90% CI 0.27-1.22) in favor of Aspirin (p=0.11).
- DFS rates at 3 years were 88.3% (90% CI: 80.1%-93.3%) in the aspirin and 82.4% (90% CI 68.3%- 90.7%) in the placebo arm.
- HR for OS was 0.70 (90% CI 0.23-2.12, p=0.3). No patient experienced aspirin-related severe adverse events.
Conclusions
The SAKK 41/13 prospective-randomized trial provides first prospective evidence of a protective effect of adjuvant aspirin in patients with resected, PIK3CA-mutant colon cancer, with a clinically relevant 43% improvement of DFS. Even though the result is not statistically significant due to the small sample size, adjuvant aspirin warrants individual consideration in patients with resected, PIK3CA-mutant stage II and III colon cancer.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 512O
SOLARIS (Alliance A021703): A Multicenter Double-blind Phase III Randomized Clinical Trial (RCT) of Vitamin D (Vit D) Combined with Standard Chemotherapy plus Bevacizumab (bev) in Patients (pts) with Previously Untreated Metastatic Colorectal Cancer (mCRC)
Background
Higher 25-hydroxyvitamin D levels are associated with improved CRC survival. The SUNSHINE phase II RCT found that pts with mCRC receiving 1st-line chemo + bev + high-dose VitD3 had improved progression-free survival (PFS) vs standard-dose VitD3. SOLARIS was designed to further evaluate the efficacy of VitD in mCRC.
Methods
- SOLARIS was a double-blind phase III RCT. Eligible pts had mCRC and no prior therapy; ECOG PS 0-1; and were not taking VitD ≥2,000 IU/d.
- Pts received mFOLFOX6 or FOLFIRI + bev with 1:1 randomization to high-dose VitD3 (8,000 IU/d x 14d then 4,000 IU/d) vs standard-dose (400 IU/d).
- Stratification factors: chemo backbone, PS, tumor sidedness. Pts were treated until disease progression, unacceptable toxicity, or withdrawal of consent. The primary intent-to-treat analysis compared PFS between arms using the unstratified log-rank test. HR (95% CI) from a Cox model and median PFS (mPFS) using Kaplan-Meier method was calculated.
- A total of 273 PFS events from 450 pts with 1 interim analysis for futility yields 90% power to detect HR 0.70 (mPFS 10 vs 14.3 mo) using a 1-sided log-rank test with α=0.05. Secondary endpoints: response rate (RR), overall survival (OS), toxicity.
Results
- 455 pts were randomized 10/2019 - 12/2022. Median age 59 yrs (range 27-92), 60% male, 52% PS 0, 64% left-sided primary.
- Median follow-up for PFS 20 mo (Q1, Q3: 7, 35 mo) with 286 events. High-dose VitD3 did not improve PFS vs standard-dose VitD3 (mPFS 11.8 vs 10.3 mo; HR 0.92, 95% CI 0.73-1.16; log-rank P=0.25), RR was 51% vs 44% (P=0.12), and mOS was 25.6 vs 27.0 mo (HR 1.05, 95% CI 0.81-1.36; log-rank P=0.34).
- Pre-planned subgroup analyses show a PFS benefit in pts with left-sided mCRC treated with high- vs standard-dose VitD3 (HR 0.74, 95% CI 0.55-1.00; P interaction=0.02).
- The most common grade ≥3 toxicities were not different between arms, including neutropenia/leukopenia, hypertension, peripheral neuropathy, and diarrhea.
Conclusions
Addition of high-dose VitD3 to standard treatment did not improve PFS vs standard-dose VitD3 in pts with mCRC, although a potential benefit was seen in pts with left-sided mCRC.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No LBA26
Adding Metformin to Androgen Deprivation Therapy (ADT) for Patients (pts) with Metastatic Hormone Sensitive Prostate Cancer (mHSPC): Overall Survival (OS) Results from the Multi-arm, Multi-stage Randomised Platform Trial STAMPEDE
Background
Metformin is a widely used, well tolerated anti-diabetic agent. Several studies suggest metformin has anti-cancer activity in different malignancies, including prostate cancer. The investigators hypothesized that metformin also reduces the development of ADT-induced metabolic adverse effects, possibly improving OS via these mechanisms.
Methods
- Non-diabetic pts with mHSPC were randomly allocated 1:1 to standard of care (SOC) or SOC + metformin within STAMPEDE.
- SOC included ADT ± radiotherapy ± docetaxel ± androgen receptor pathway inhibitor (ARPI). The primary outcome was OS.
- Target hazard ratio (HR) 0.8 (92% power, 2.5% 1-sided significance). 7 subgroup analyses were pre-specified but not pre-powered.
Results
- 1874 pts with mHSPC were randomized Sep2016-Mar2023.
- Arms were well balanced: median age 69 years, IQR 63-73; median PSA 84ng/ml, IQR 24-352; de novo 1758 (94%) vs relapsed 116 (6%).
- Planned SOC included 82% Docetaxel and 3% ARPI. After a median follow-up of 60 months, the HR for OS between arms was 0.91 (p=0.148; 95% CI 0.80-1.03).
- The median (95%CI) OS was 63 (58-69) and 69 (63-73) months in the SOC and SOC + metformin arms respectively. In patients with high versus low volume disease (CHAARTED def), HR was 0.79 (p=0.006; 0.66-0.93) and 1.0 (p=0.992; 0.79-1.26) respectively. The interaction p-value = 0.086.
- For progression-free survival: Overall HR was 0.92 (p=0.164; 0.81-1.04) with HRs of 0.76 (p=0.001; 0.64-0.89) and 1.10 (p=0.401; 0.88-1.37) in the high and low volume subgroups respectively, interaction p-value = 0.006.
- Metabolic parameters that improved significantly with metformin included reduced weight gain, fasting glucose, HbA1c and total and LDL cholesterol. Fewer patients developed a metabolic syndrome.
- Adverse events (AE) ≥grade 3 were reported in 52% and 57% in the SOC and SOC + metformin arms, respectively; Gastrointestinal AEs increased with metformin.
Conclusions
Metformin does not improve survival in unselected metastatic patients but may improve cancer outcomes and survival in high volume patients. Metabolic parameters were significantly improved overall.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No LBA70
Impact of Menadione Supplementation in the Treatment of Patients with Metastatic Gastric Cancer: A Randomized Phase II Clinical Trial
Background
Preclinical research carried out in vivo and in vitro and phase I clinical trials have demonstrated reduced toxicity and suggested the efficacy of menadione (vitamin K3) in gastric cancer (GC). The study evaluated the impact of vitamin K3 supplementation as a first-line adjuvant treatment for advanced or metastatic GC.
Methods
- In this phase II clinical trial, patients were randomized 1:1 to treatment with XELOX: capecitabine of 1,000 mg/m2 (orally administered twice a day on days 1-14) and oxaliplatin at 130 mg/m2 (on day 1, as intravenous 2 h boluses); or XELOX plus menadione (K3) 2.5g/m2 daily, from June 22, 2021 to May 30, 2022.
- Toxicities were measured according to CTCAE 5.5 and tumor response through RECIST 1.1.
Results
- 102 patients were randomized to XELOX, with 51 to each group, which completed four cycles of treatment.
- The response rate was 37.2% (n=19) in the menadione and 23.5%(n=12) in the XELOX group, whereas the disease control rate (DCR) was 84.3%(n=43) and 72.5%(n=37), respectively.
- Median overall survival (OS) and progression-free survival (PFS) were 13.2 and 12.5 months for the supplemented patients versus 10.3 and 9.34 months for the non-supplemented (OS, p=0.003; PFS, p=0.017).
- The XELOX group had a slightly higher frequency of any adverse events (AE) of any grade (94.1 versus 92.1) and grade 3/4 (7.8 versus 1.9), when compared with the menadione group, respectively.
- Some of them were asthenia (78.4 versus 74.5%), decreased appetite (76.4 versus 68.6%), alopecia (64.7 versus 54.9%), and anemia (29.4 versus 21.5%), respectively.
|
Menadione + XELOX (n=51) |
XELOX (n=51) |
|
|
Sex, n (%) |
||
|
Male |
35 (68.6) |
34 (66.6) |
|
Female |
16 (31.4) |
17 (33.4) |
|
Organs with metastasis, n |
||
|
0-2 |
37(75.5) |
39(76.4) |
|
≥3 |
14(24.5) |
12(23.6) |
|
ECOG performance status score, n (%) |
||
|
0 |
19(37.3) |
17 (33.4) |
|
1 |
30(58.8) |
29(56.8) |
|
2 |
2(3.9) |
5(9.8) |
|
Measurable disease, n (%) |
46(90.1) |
40 (78.4) |
Conclusions
The study results indicate that vitamin K3 supplementation combined with adjuvant chemotherapy is capable of significantly improving the clinical outcomes of patients with GC, not only an ORR and DCR in the menadione group, but also a significant benefit for prolonged OS and PFS when compared with the control group.
Reference
ESMO 2024 Congress. 12th Sept – 17th Sept 2024. Barcelona Spain. Abstract No 1430P
