Title: Cost-effectiveness of NALIRIFOX versus Nab-paclitaxel and Gemcitabine in Previously
Untreated Metastatic Pancreatic Ductal Adenocarcinoma
Version: 2 Date: 21 Mar 2025
Reviewer's report:
Decision: revise and resubmit
Major Concerns
1.  The model relies on parametric survival distributions (Weibull for OS in NALIRIFOX,
Gamma for PFS in GemNab; Table S2) to extrapolate beyond the trial’s median follow-up
(16.7 months). However, the AIC/BIC values (Table S2) show minimal differences between
distributions (e.g., Weibull vs. Gamma for OS), raising concerns about the validity of long-term
projections. Overestimation of survival benefits could inflate QALY gains. The lack of real-
world data validation (e.g., registry data) weakens confidence in lifetime horizon results.
2. PFS utility (0.81) and PD utility (0.73) are derived from advanced pancreatic cancer studies
(Table 1, ref 13), but these values may not reflect mPDAC-specific quality of life. Disutilities for
grade #3 AEs (e.g., diarrhea: 0.288) are applied only once in the first cycle (Methods section),
ignoring recurrent or chronic effects (e.g., neuropathy).  Underestimates cumulative quality-
of-life losses, particularly for regimens like NALIRIFOX with higher AE incidence (Table 1:
diarrhea 20% vs. 5% in GemNab).
3. The ICER is highly sensitive to liposomal irinotecan costs (Figure 2: ±20% variation shifts
ICER from $56,921–$254,283/QALY). The baseline price ($63.375/mg; Table 1) assumes static
pricing, but impending generics or payer negotiations could drastically alter cost-effectiveness.
The model does not explore scenarios where price reductions (e.g., 78% discount to meet $50k/
QALY threshold; Discussion) become reality, limiting practical applicability.
4. Only 50.5–54.4% of patients received second-line therapy (Methods), with GemNab patients
defaulting to 5-FU and NALIRIFOX to gemcitabine. Real-world practices (e.g., immunotherapy
use) are ignored, potentially skewing cost estimates.   Unaccounted variability in second-line
regimens may bias incremental cost calculations (Table 2: #$19,754).
5. The 13-year lifetime horizon assumes 99% of patients reach the death state, but shortening
the horizon to the trial’s median follow-up (16.7 months) raises the ICER to $195,324 (Table 3).
Overreliance on extrapolated long-term survival exaggerates QALY differences (0.13 QALYs
gained), which may not materialize in practice.
Minor Concern
1.  While simulated median OS/PFS align with NAPOLI 3 (Table S1), the lack of internal
validation (e.g., calibration plots) or external comparators (e.g., SEER data) weakens credibility.
2. AE Cost Methodology:
- AE costs (e.g., $5,239.85 for diarrhea; Table 1) are applied once per occurrence, ignoring
recurrent management costs (e.g., chronic neuropathy).
3. Presentation and Labeling:
- Figure 2 (Tornado Diagram) includes truncated labels (e.g., “Hypoplasianina”) and unclear
parameter ranges (e.g., “Cost of hypoplasianina treatment: $144.042–$996.035”).
- Figure S3 (CEACs) lacks clarity on how the 45.7% cost-effectiveness rate at $150k/QALY
was derived.
4.  Indirect comparisons to FOLFIRINOX/GemNab studies (Discussion) lack formal network
meta-analysis, limiting interpretability of NALIRIFOX’s incremental value.
5.  A 3% discount rate is standard but not explicitly justified against alternative rates (e.g., 5%
for LMICs). Table 3’s scenario analysis (0% discounting) is inadequately discussed.
Title: Cost-effectiveness of NALIRIFOX versus Nab-paclitaxel and Gemcitabine in Previously
Untreated Metastatic Pancreatic Ductal Adenocarcinoma
Version: 2 Date: 21 Mar 2025
Reviewer's report:
Decision: revise and resubmit
Major Concerns
1.  The model relies on parametric survival distributions (Weibull for OS in NALIRIFOX,
Gamma for PFS in GemNab; Table S2) to extrapolate beyond the trial’s median follow-up
(16.7 months). However, the AIC/BIC values (Table S2) show minimal differences between
distributions (e.g., Weibull vs. Gamma for OS), raising concerns about the validity of long-term
projections. Overestimation of survival benefits could inflate QALY gains. The lack of real-
world data validation (e.g., registry data) weakens confidence in lifetime horizon results.
2. PFS utility (0.81) and PD utility (0.73) are derived from advanced pancreatic cancer studies
(Table 1, ref 13), but these values may not reflect mPDAC-specific quality of life. Disutilities for
grade #3 AEs (e.g., diarrhea: 0.288) are applied only once in the first cycle (Methods section),
ignoring recurrent or chronic effects (e.g., neuropathy).  Underestimates cumulative quality-
of-life losses, particularly for regimens like NALIRIFOX with higher AE incidence (Table 1:
diarrhea 20% vs. 5% in GemNab).
3. The ICER is highly sensitive to liposomal irinotecan costs (Figure 2: ±20% variation shifts
ICER from $56,921–$254,283/QALY). The baseline price ($63.375/mg; Table 1) assumes static
pricing, but impending generics or payer negotiations could drastically alter cost-effectiveness.
The model does not explore scenarios where price reductions (e.g., 78% discount to meet $50k/
QALY threshold; Discussion) become reality, limiting practical applicability.
4. Only 50.5–54.4% of patients received second-line therapy (Methods), with GemNab patients
defaulting to 5-FU and NALIRIFOX to gemcitabine. Real-world practices (e.g., immunotherapy
use) are ignored, potentially skewing cost estimates.   Unaccounted variability in second-line
regimens may bias incremental cost calculations (Table 2: #$19,754).
5. The 13-year lifetime horizon assumes 99% of patients reach the death state, but shortening
the horizon to the trial’s median follow-up (16.7 months) raises the ICER to $195,324 (Table 3).
Overreliance on extrapolated long-term survival exaggerates QALY differences (0.13 QALYs
gained), which may not materialize in practice.
Minor Concern
1.  While simulated median OS/PFS align with NAPOLI 3 (Table S1), the lack of internal
validation (e.g., calibration plots) or external comparators (e.g., SEER data) weakens credibility.
2. AE Cost Methodology:
- AE costs (e.g., $5,239.85 for diarrhea; Table 1) are applied once per occurrence, ignoring
recurrent management costs (e.g., chronic neuropathy).
3. Presentation and Labeling:
- Figure 2 (Tornado Diagram) includes truncated labels (e.g., “Hypoplasianina”) and unclear
parameter ranges (e.g., “Cost of hypoplasianina treatment: $144.042–$996.035”).
- Figure S3 (CEACs) lacks clarity on how the 45.7% cost-effectiveness rate at $150k/QALY
was derived.
4.  Indirect comparisons to FOLFIRINOX/GemNab studies (Discussion) lack formal network
meta-analysis, limiting interpretability of NALIRIFOX’s incremental value.
5.  A 3% discount rate is standard but not explicitly justified against alternative rates (e.g., 5%
for LMICs). Table 3’s scenario analysis (0% discounting) is inadequately discussed.
Please review this paper.
user
Title: Cost-effectiveness of NALIRIFOX versus Nab-paclitaxel and Gemcitabine in Previously
Untreated Metastatic Pancreatic Ductal Adenocarcinoma
Version: 2 Date: 21 Mar 2025
Reviewer's report:
Decision: revise and resubmit
Major Concerns
1.  The model relies on parametric survival distributions (Weibull for OS in NALIRIFOX,
Gamma for PFS in GemNab; Table S2) to extrapolate beyond the trial’s median follow-up
(16.7 months). However, the AIC/BIC values (Table S2) show minimal differences between
distributions (e.g., Weibull vs. Gamma for OS), raising concerns about the validity of long-term
projections. Overestimation of survival benefits could inflate QALY gains. The lack of real-
world data validation (e.g., registry data) weakens confidence in lifetime horizon results.
2. PFS utility (0.81) and PD utility (0.73) are derived from advanced pancreatic cancer studies
(Table 1, ref 13), but these values may not reflect mPDAC-specific quality of life. Disutilities for
grade #3 AEs (e.g., diarrhea: 0.288) are applied only once in the first cycle (Methods section),
ignoring recurrent or chronic effects (e.g., neuropathy).  Underestimates cumulative quality-
of-life losses, particularly for regimens like NALIRIFOX with higher AE incidence (Table 1:
diarrhea 20% vs. 5% in GemNab).
3. The ICER is highly sensitive to liposomal irinotecan costs (Figure 2: ±20% variation shifts
ICER from $56,921–$254,283/QALY). The baseline price ($63.375/mg; Table 1) assumes static
pricing, but impending generics or payer negotiations could drastically alter cost-effectiveness.
The model does not explore scenarios where price reductions (e.g., 78% discount to meet $50k/
QALY threshold; Discussion) become reality, limiting practical applicability.
4. Only 50.5–54.4% of patients received second-line therapy (Methods), with GemNab patients
defaulting to 5-FU and NALIRIFOX to gemcitabine. Real-world practices (e.g., immunotherapy
use) are ignored, potentially skewing cost estimates.   Unaccounted variability in second-line
regimens may bias incremental cost calculations (Table 2: #$19,754).
5. The 13-year lifetime horizon assumes 99% of patients reach the death state, but shortening
the horizon to the trial’s median follow-up (16.7 months) raises the ICER to $195,324 (Table 3).
Overreliance on extrapolated long-term survival exaggerates QALY differences (0.13 QALYs
gained), which may not materialize in practice.
Minor Concern
1.  While simulated median OS/PFS align with NAPOLI 3 (Table S1), the lack of internal
validation (e.g., calibration plots) or external comparators (e.g., SEER data) weakens credibility.
2. AE Cost Methodology:
- AE costs (e.g., $5,239.85 for diarrhea; Table 1) are applied once per occurrence, ignoring
recurrent management costs (e.g., chronic neuropathy).
3. Presentation and Labeling:
- Figure 2 (Tornado Diagram) includes truncated labels (e.g., “Hypoplasianina”) and unclear
parameter ranges (e.g., “Cost of hypoplasianina treatment: $144.042–$996.035”).
- Figure S3 (CEACs) lacks clarity on how the 45.7% cost-effectiveness rate at $150k/QALY
was derived.
4.  Indirect comparisons to FOLFIRINOX/GemNab studies (Discussion) lack formal network
meta-analysis, limiting interpretability of NALIRIFOX’s incremental value.
5.  A 3% discount rate is standard but not explicitly justified against alternative rates (e.g., 5%
for LMICs). Table 3’s scenario analysis (0% discounting) is inadequately discussed.
assistant