---
title: "INCA33989 Phase 1 Clinical Trial Results in Myelofibrosis - ASH 2025 Update"
author: "Clinical Data Analysis"
date: "`r Sys.Date()`"
format:
html:
toc: true
toc-depth: 3
code-fold: true
theme: journal
pdf:
toc: true
number-sections: true
---
```{r setup, include=FALSE}
knitr::opts_chunk$set(echo = TRUE, message = FALSE, warning = FALSE)
# Load required libraries
library(knitr)
library(kableExtra)
library(dplyr)
library(ggplot2)
library(gt)
library(gtsummary)
library(flextable)
```
# Study Overview
This document presents the updated clinical trial data from the INCA33989 Phase 1 studies (NCT05936359 and NCT06034002) in patients with myelofibrosis (MF) with mutant calreticulin (mutCALR). Data cutoff: May 8, 2025, as presented at ASH 2025 (Abstract abs25-1614).
**Study Design:** Phase 1, first-in-human, multicenter, open-label dose escalation study evaluating INCA33989 (fully human, Fc-silenced, IgG1 monoclonal antibody) in patients with mutCALR myelofibrosis or essential thrombocythemia.
**Key Inclusion Criteria:** - Primary or post-ET myelofibrosis - Pathogenic CALR mutation - **MF Monotherapy Cohort**: Intolerant to JAK inhibitor (JAKi) treatment or resistant after ≥12 weeks (n=35), or ineligible for JAKi treatment (n=12) - **MF Combination Cohort**: Prior ruxolitinib treatment for ≥12 weeks with suboptimal spleen response, received INCA33989 with ongoing ruxolitinib
**Treatment:** INCA33989 (24-2500 mg) administered intravenously every 2 weeks
**Primary Endpoint:** Safety and tolerability
**Efficacy Assessments:** - Spleen volume reduction ≥25% (SVR25) and ≥35% (SVR35) - Anemia response (Tefferi A. Blood. 2024;114:1813) - Change in MPN-SAF total symptom score (TSS) - mutCALR variant allele frequency (VAF) reduction
```{r baseline-data-mono}
# Create baseline patient characteristics data for MF Monotherapy
baseline_data_mono <- data.frame(
Characteristic = c(
"Total patients enrolled",
"Median age, years (range)",
"Female, n (%)",
"Male, n (%)",
"Median baseline mutCALR VAF, % (range)",
"Median baseline spleen volume, mL (range)",
"Median baseline hemoglobin, g/L (range)",
"Median baseline MPN-SAF TSS (range)",
"Median exposure, weeks (range)",
"Patients continuing treatment, n (%)",
"Treatment discontinuation, n (%)"
),
Value = c(
"47",
"60 (34-76)",
"16 (34%)",
"31 (66%)",
"36 (31-53)",
"1229 (257-3970)",
"100 (70-143)",
"23 (0-65)",
"28 (0.4-85)",
"40 (85%)",
"2 (4%)"
)
)
# Create baseline data for MF Combination
baseline_data_combo <- data.frame(
Characteristic = c(
"Total patients enrolled",
"Median age, years (range)",
"Female, n (%)",
"Male, n (%)",
"Median baseline mutCALR VAF, % (range)",
"Median baseline spleen volume, mL (range)",
"Median baseline hemoglobin, g/L (range)",
"Median baseline MPN-SAF TSS (range)",
"Median exposure, weeks (range)",
"Patients continuing treatment, n (%)",
"Treatment discontinuation, n (%)"
),
Value = c(
"14",
"62 (51-82)",
"4 (29%)",
"10 (71%)",
"37 (30-50)",
"1853 (848-3533)",
"92 (72-118)",
"17 (6-56)",
"19 (4-40)",
"13 (93%)",
"1 (7%)"
)
)
# Create dose escalation data
dose_data <- data.frame(
Dose_mg = c("24", "50", "70", "100", "250", "400", "500", "750", "1000", "1500", "2500"),
DLT = rep("No", 11),
MTD_Reached = rep("No", 11)
)
```
## Table 1A: Baseline Patient Characteristics - MF Monotherapy
```{r baseline-table-mono}
baseline_data_mono %>%
gt() %>%
tab_header(
title = "Baseline Patient Characteristics - MF Monotherapy",
subtitle = "INCA33989 Phase 1 Study - ASH 2025"
) %>%
cols_label(
Characteristic = "Characteristic",
Value = "Value (N=47)"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#f8f9fa"),
locations = cells_body(rows = seq(2, nrow(baseline_data_mono), 2))
) %>%
tab_footnote(
footnote = "VAF = Variant Allele Frequency; mutCALR = mutant calreticulin; MPN-SAF TSS = Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score",
locations = cells_body(columns = Characteristic, rows = 5)
) %>%
tab_footnote(
footnote = "Reasons for discontinuation: 1 mantle cell lymphoma (400 mg), 1 neutropenia (750 mg)",
locations = cells_body(columns = Characteristic, rows = 11)
)
```
## Table 1B: Baseline Patient Characteristics - MF Combination (with Ruxolitinib)
```{r baseline-table-combo}
baseline_data_combo %>%
gt() %>%
tab_header(
title = "Baseline Patient Characteristics - MF Combination",
subtitle = "INCA33989 + Ruxolitinib Phase 1 Study - ASH 2025"
) %>%
cols_label(
Characteristic = "Characteristic",
Value = "Value (N=14)"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#f8f9fa"),
locations = cells_body(rows = seq(2, nrow(baseline_data_combo), 2))
) %>%
tab_footnote(
footnote = "VAF = Variant Allele Frequency; mutCALR = mutant calreticulin; MPN-SAF TSS = Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score",
locations = cells_body(columns = Characteristic, rows = 5)
) %>%
tab_footnote(
footnote = "Reason for discontinuation: 1 diffuse large B-cell lymphoma (70 mg)",
locations = cells_body(columns = Characteristic, rows = 11)
)
```
## Table 2: Dose Escalation and Safety Overview
```{r dose-table}
dose_data %>%
gt() %>%
tab_header(
title = "Dose Escalation Cohorts",
subtitle = "Safety and Tolerability Assessment (Both Cohorts)"
) %>%
cols_label(
Dose_mg = "Dose (mg)",
DLT = "Dose-Limiting Toxicity",
MTD_Reached = "MTD Reached"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#e8f5e8"),
locations = cells_body(columns = DLT, rows = DLT == "No")
) %>%
tab_footnote(
footnote = "MTD = Maximum Tolerated Dose; DLT = Dose-Limiting Toxicity. No DLTs were observed across all dose levels. MTD was not reached in either cohort.",
locations = cells_column_labels(columns = MTD_Reached)
)
```
# Safety Profile
```{r safety-data}
# Create safety/adverse events data for MF Monotherapy
safety_data_mono <- data.frame(
Adverse_Event = c(
"Any TEAE",
"Anemia",
"Fatigue",
"Thrombocytopenia",
"Neutropenia",
"Grade ≥3 TEAE",
"Treatment-related AEs (TRAEs)",
"Leukopenia (TRAE)",
"Serious TEAEs"
),
Patients_n = c(43, 16, 13, 12, NA, 16, 29, 9, 3),
Percentage = c(91, 34, 28, 26, 11, 34, 62, 19, 6),
Max_Grade = c("3", "3 (9% Gr≥3)", "2 (0% Gr≥3)", "3 (6% Gr≥3)", "3 (most common Gr≥3)", "3", NA, NA, "3")
)
# Create safety data for MF Combination
safety_data_combo <- data.frame(
Adverse_Event = c(
"Any TEAE",
"Anemia",
"Thrombocytopenia",
"Grade ≥3 TEAE",
"Treatment-related AEs (TRAEs)",
"Thrombocytopenia (TRAE)",
"Serious TEAEs"
),
Patients_n = c(12, 5, 5, 7, 8, 3, 2),
Percentage = c(86, 36, 36, 50, 57, 21, 14),
Max_Grade = c("3", "3 (21% Gr≥3)", "3 (7% Gr≥3)", "3 (most commonly anemia)", NA, NA, "Unrelated to tx")
)
# Create efficacy data for MF Monotherapy
efficacy_data_mono <- data.frame(
Response_Type = c(
"SVR25 at 24 weeks",
"SVR35 at 24 weeks",
"Any anemia response",
"Major anemia response",
"Minor anemia response",
"Mean MPN-SAF TSS change at 12 weeks (SD)",
"Mean MPN-SAF TSS change at 24 weeks (SD)",
"Any mutCALR VAF reduction",
"mutCALR VAF reduction ≥20%"
),
Evaluable = c("27", "27", "22", "22", "22", "38", "24", "39", "39"),
Responders = c("10", "8", "12", "9", "3", NA, NA, "31", "5"),
Percentage = c(37, 30, 55, 41, 14, NA, NA, 79, 13),
Details = c(
"",
"",
"",
"1/4 TDA; 8/18 non-TDA",
"1/4 TDA; 2/18 non-TDA",
"-6 (7.9)",
"-4.7 (8.5)",
"",
""
)
)
# Create efficacy data for MF Combination
efficacy_data_combo <- data.frame(
Response_Type = c(
"SVR25 at 24 weeks",
"SVR35 at 24 weeks",
"Major anemia response (non-TDA)",
"Mean MPN-SAF TSS change at 12 weeks (SD)",
"Mean MPN-SAF TSS change at 24 weeks (SD)",
"Any mutCALR VAF reduction",
"mutCALR VAF reduction ≥20%"
),
Evaluable = c("4", "4", "8", "7", "3", "8", "8"),
Responders = c("2", "1", "1", NA, NA, "6", "1"),
Percentage = c(50, 25, 13, NA, NA, 75, 13),
Details = c(
"",
"",
"",
"-12 (20.2)",
"-12.3 (15.4)",
"",
""
)
)
```
## Table 3A: Safety and Adverse Events Profile - MF Monotherapy
```{r safety-table-mono}
safety_data_mono %>%
gt() %>%
tab_header(
title = "Treatment-Emergent Adverse Events - MF Monotherapy",
subtitle = "Safety Profile (N=47) - ASH 2025"
) %>%
cols_label(
Adverse_Event = "Adverse Event",
Patients_n = "Patients (n)",
Percentage = "Percentage (%)",
Max_Grade = "Grade Details"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#fff3cd"),
locations = cells_body(rows = Adverse_Event == "Grade ≥3 TEAE")
) %>%
fmt_missing(columns = everything(), missing_text = "—") %>%
tab_footnote(
footnote = "TEAE = Treatment-Emergent Adverse Event; TRAE = Treatment-Related Adverse Event. Serious TEAEs: abdominal pain and tendonitis (70 mg; tendonitis tx-related); MCL and small intestinal obstruction (400 mg); arthritis (1500 mg). Two patients had dose reductions (50 and 750 mg) and 2 had infusion interruptions (70 and 400 mg) due to TEAEs.",
locations = cells_body(columns = Adverse_Event, rows = 9)
)
```
## Table 3B: Safety and Adverse Events Profile - MF Combination
```{r safety-table-combo}
safety_data_combo %>%
gt() %>%
tab_header(
title = "Treatment-Emergent Adverse Events - MF Combination",
subtitle = "Safety Profile (N=14) - ASH 2025"
) %>%
cols_label(
Adverse_Event = "Adverse Event",
Patients_n = "Patients (n)",
Percentage = "Percentage (%)",
Max_Grade = "Grade Details"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#fff3cd"),
locations = cells_body(rows = Adverse_Event == "Grade ≥3 TEAE")
) %>%
fmt_missing(columns = everything(), missing_text = "—") %>%
tab_footnote(
footnote = "TEAE = Treatment-Emergent Adverse Event; TRAE = Treatment-Related Adverse Event. Serious TEAEs: DLBCL (70 mg), stomatitis (750 mg); both considered unrelated to treatment.",
locations = cells_body(columns = Adverse_Event, rows = 7)
)
```
# Efficacy Outcomes
## Table 4A: Efficacy Outcomes - MF Monotherapy
```{r efficacy-table-mono}
efficacy_data_mono %>%
gt() %>%
tab_header(
title = "Efficacy Outcomes - MF Monotherapy",
subtitle = "Spleen, Anemia, Symptom, and Molecular Responses (N=47)"
) %>%
cols_label(
Response_Type = "Response Type",
Evaluable = "Evaluable (n)",
Responders = "Responders (n)",
Percentage = "Response Rate (%)",
Details = "Additional Details"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#d4edda"),
locations = cells_body(rows = c(1, 2)) # Highlight spleen responses
) %>%
tab_style(
style = cell_fill(color = "#cfe2ff"),
locations = cells_body(rows = c(3, 4, 5)) # Highlight anemia responses
) %>%
tab_style(
style = cell_fill(color = "#fff3cd"),
locations = cells_body(rows = c(8, 9)) # Highlight molecular responses
) %>%
fmt_missing(columns = everything(), missing_text = "—") %>%
tab_footnote(
footnote = "SVR25/35 = Spleen Volume Reduction ≥25%/≥35%; TDA = Transfusion-Dependent Anemia; VAF = Variant Allele Frequency; MPN-SAF TSS = MPN Symptom Assessment Form Total Symptom Score",
locations = cells_body(columns = Response_Type, rows = 1)
) %>%
tab_footnote(
footnote = "Exploratory single-cell analyses showed rapid reductions of mutCALR+ hematopoietic stem/progenitor cell fractions, confirming impact on target cells",
locations = cells_body(columns = Response_Type, rows = 8)
)
```
## Table 4B: Efficacy Outcomes - MF Combination
```{r efficacy-table-combo}
efficacy_data_combo %>%
gt() %>%
tab_header(
title = "Efficacy Outcomes - MF Combination (with Ruxolitinib)",
subtitle = "Spleen, Anemia, Symptom, and Molecular Responses (N=14)"
) %>%
cols_label(
Response_Type = "Response Type",
Evaluable = "Evaluable (n)",
Responders = "Responders (n)",
Percentage = "Response Rate (%)",
Details = "Additional Details"
) %>%
tab_style(
style = cell_text(weight = "bold"),
locations = cells_column_labels()
) %>%
tab_style(
style = cell_fill(color = "#d4edda"),
locations = cells_body(rows = c(1, 2)) # Highlight spleen responses
) %>%
tab_style(
style = cell_fill(color = "#cfe2ff"),
locations = cells_body(rows = 3) # Highlight anemia response
) %>%
tab_style(
style = cell_fill(color = "#fff3cd"),
locations = cells_body(rows = c(6, 7)) # Highlight molecular responses
) %>%
fmt_missing(columns = everything(), missing_text = "—") %>%
tab_footnote(
footnote = "SVR25/35 = Spleen Volume Reduction ≥25%/≥35%; TDA = Transfusion-Dependent Anemia; VAF = Variant Allele Frequency; MPN-SAF TSS = MPN Symptom Assessment Form Total Symptom Score",
locations = cells_body(columns = Response_Type, rows = 1)
)
```
# Summary and Clinical Implications
## Key Findings from ASH 2025 Update
### MF Monotherapy Cohort (N=47)
**1. Safety Profile:** INCA33989 monotherapy demonstrated good tolerability - 85% treatment continuation rate - No dose-limiting toxicities observed across all dose levels (24-2500 mg) - Maximum tolerated dose not reached - Most common adverse events: anemia (34%), fatigue (28%), thrombocytopenia (26%) - Grade ≥3 adverse events in 34%, most commonly neutropenia (11%) - Treatment-related AEs in 62%, most commonly leukopenia (19%) - Low rate of treatment discontinuation (4%)
**2. Efficacy in JAKi-Intolerant/Resistant/Ineligible Patients:** - **Spleen responses at 24 weeks:** - SVR25: 37% (10/27 patients) - SVR35: 30% (8/27 patients) - **Anemia responses:** 55% (12/22 patients) - Major responses: 41% (9 patients: 1/4 with TDA, 8/18 non-TDA) - Minor responses: 14% (3 patients: 1/4 with TDA, 2/18 non-TDA) - **Symptom improvement:** - Mean MPN-SAF TSS reduction of 6 points at 12 weeks - Mean MPN-SAF TSS reduction of 4.7 points at 24 weeks - **Molecular activity:** - 79% (31/39) had postbaseline mutCALR VAF reduction - 13% (5/39) achieved ≥20% VAF reduction
### MF Combination Cohort (N=14)
**1. Safety Profile with Ruxolitinib:** - 93% treatment continuation rate - No dose-limiting toxicities - Most common adverse events: anemia (36%), thrombocytopenia (36%) - Grade ≥3 adverse events in 50%, most commonly anemia - Treatment-related AEs in 57%, most commonly thrombocytopenia (21%) - Very low discontinuation rate (7%)
**2. Efficacy in Patients with Suboptimal Ruxolitinib Response:** - **Spleen responses at 24 weeks:** - SVR25: 50% (2/4 patients) - SVR35: 25% (1/4 patients) - **Anemia response:** 13% (1/8) major response in non-TDA patient - **Symptom improvement:** - Mean MPN-SAF TSS reduction of 12 points at 12 weeks - Mean MPN-SAF TSS reduction of 12.3 points at 24 weeks - **Molecular activity:** - 75% (6/8) had postbaseline mutCALR VAF reduction - 13% (1/8) achieved ≥20% VAF reduction
## Clinical Significance
### Novel Therapeutic Option for Unmet Need
- **First-in-class** mutCALR-specific antibody for myelofibrosis (\~30% of MF patients)
- Addresses critical unmet need in JAKi-intolerant, resistant, or ineligible patients
- Potential to improve outcomes in patients with suboptimal ruxolitinib response
### Multi-Dimensional Clinical Benefit
INCA33989 demonstrated activity across multiple MF disease manifestations: - **Spleen reduction** in over one-third of heavily pre-treated patients - **Anemia improvement** in more than half of patients, including those with transfusion dependence - **Symptom burden reduction** with clinically meaningful TSS improvements - **Molecular activity** with VAF reductions in majority of patients
### Favorable Safety Profile
- Well-tolerated with high treatment continuation rates (85-93%)
- No dose-limiting toxicities
- Maximum tolerated dose not reached
- Manageable cytopenias in heavily pre-treated population
- Compatible with concurrent ruxolitinib therapy
### Disease-Modifying Potential
- Single-cell analyses confirmed selective reduction of mutCALR+ hematopoietic stem/progenitor cells
- Evidence of targeting disease at the stem cell level
- Molecular responses suggest disease modification beyond symptom control
- Mechanism distinct from non-selective JAK inhibition
## Future Directions
Based on these Phase 1 results, INCA33989 has strong potential for:
1. **Phase 2/3 clinical development** in mutCALR-positive MF
- Monotherapy in JAKi-intolerant/resistant/ineligible patients
- Combination with ruxolitinib in suboptimal responders
2. **Expansion to earlier treatment lines**
- First-line therapy in mutCALR-positive MF
- Combination strategies to prevent JAKi resistance
3. **Biomarker-guided therapy**
- VAF-based patient selection
- Molecular response monitoring
4. **Comparative effectiveness studies**
- Head-to-head trials vs. current standard therapies
- Combination vs. sequential approaches
5. **Investigation in other mutCALR-driven MPNs**
- Essential thrombocythemia (companion study ongoing)
- Post-PV myelofibrosis
## Conclusion
INCA33989 demonstrated encouraging safety and preliminary efficacy signals as monotherapy in JAKi-intolerant/resistant/ineligible MF patients and in combination with ruxolitinib in suboptimal responders. The multi-dimensional clinical benefits (spleen, anemia, symptoms) and evidence of molecular activity support continued development of this novel mutCALR-targeted therapy.
The favorable safety profile with no dose-limiting toxicities and high treatment continuation rates, combined with single-cell evidence of selective targeting of mutCALR+ stem/progenitor cells, suggests INCA33989 may offer a disease-modifying approach for this significant subset of myelofibrosis patients with limited treatment options.
Despite the limited follow-up and small patient numbers in this Phase 1 dose escalation study, the observed clinical activity across multiple disease parameters in heavily pre-treated patients provides strong rationale for Phase 2/3 development in mutCALR-positive myelofibrosis.
```{r session-info}
# Session information
sessionInfo()
```