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SYSTEMATIC REVIEW article

Front. Immunol., 10 February 2026

Sec. Cancer Immunity and Immunotherapy

Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1747256

This article is part of the Research TopicTargeting Immune Suppression in Gastrointestinal Cancers: Unveiling Mechanisms and Therapeutic PotentialView all 3 articles

What determines value? Exploring value characteristics of novel therapies for digestive system cancers

Shunlong Ou&#x;Shunlong Ou1†Song Wang&#x;Song Wang1†Xiaoyi ChenXiaoyi Chen2Huan LiHuan Li2Chengyang ZhouChengyang Zhou1Qian Jiang*Qian Jiang1*
  • 1Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
  • 2School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

Introduction: Despite the growing arsenal of novel anti-tumor drugs for digestive system cancers, concerns persist regarding their true clinical value, as approvals often rely on surrogate endpoints with limited overall survival or quality of life data. This study systematically evaluates the clinical benefit of these drugs in China using standardized value assessment frameworks and identify factors associated with high-value treatments.

Methods: This cross-sectional study analyzed 65 indications from 33 novel anti-tumor drugs included in the Guidelines for the Clinical Application of Novel Anti-tumor Drugs for advanced digestive system cancers. Two researchers independently extracted data from drug approval documents and PubMed literature. Value assessment was performed using ASCO Value Framework v2.0 (advanced disease) and ESMO-Magnitude of Clinical Benefit Scale v2.0 (non-curative). For ASCO-VF, the net health benefit score was calculated based on clinical benefit, toxicity adjustments, and bonus points. ESMO-MCBS grading incorporated clinical benefit magnitude with adjustments for toxicity and quality of life. Statistical analyses included descriptive statistics and association testing with odds ratios for categorical variables.

Results: Among 65 indications, only 12 (18.5%) achieved value thresholds in both frameworks. Immune combinations showed superior value, particularly atezolizumab-bevacizumab in hepatocellular carcinoma (ASCO-VF: 53.4; ESMO-MCBS: grade 5) and toripalimab in esophageal squamous cell carcinoma. Quality of life improvement strongly correlated with value attainment in both frameworks (ASCO-VF OR: 28.00; ESMO-MCBS OR: 27.87). Molecular target detection requirement inversely associated with OS benefit (OR: 0.16). Value heterogeneity was observed across cancer types and treatment lines.

Conclusions: Few novel digestive system cancer drugs demonstrate substantial clinical benefit in both value frameworks. Quality of life documentation is crucial for value assessment. Stakeholders should integrate these value dimensions—survival benefit, toxicity, and quality of life—into clinical and policy decisions to guide treatment selection and resource allocation.

Introduction

In recent years, digestive system tumors (including colorectal cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, etc.) have remained highly prevalent worldwide (1). Characterized by complex pathogenesis and poor prognosis, they pose a serious threat to human health. With the rapid development of precision medicine and molecular targeting technologies, novel anti-tumor drugs for digestive system tumors—such as molecular targeted agents and immune checkpoint inhibitors—continue to emerge, providing patients with more personalized treatment options. However, the clinical development and regulatory review and approval of novel drugs often rely on surrogate endpoints such as progression-free survival (PFS) and objective response rate (ORR), while the supporting evidence for critical outcome indicators like overall survival (OS) and quality of life (QoL) remains relatively weak (24). International studies indicate that a majority of anticancer drugs approved by the FDA and EMA lack sufficient evidence of OS and QoL improvement (5, 6), a trend that is similarly pronounced in the field of digestive system tumors. Furthermore, to address urgent clinical needs, some drugs are accelerated to market through priority review or conditional approval pathways, resulting in a weak correlation between their clinical value and regulatory standards. This may lead to drugs with uncertain value entering clinical use (7).

On the level of value assessment, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have developed ASCO Value Framework (ASCO-VF) and the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS), respectively, to systematically quantify drug value across dimensions including survival benefits, quality of life, safety, and economic burden (8, 9). Existing research indicates that clinically meaningful net health benefits have been observed only in a limited proportion of solid tumor drugs (7, 10, 11), while specialized value assessments for novel drugs targeting digestive system tumors remain a gap. The lack of a mechanism for value identification and drug selection in this field may impact the scientific formulation of clinical treatment strategies.

A systematic assessment of the value of novel gastrointestinal cancer drugs is essential. It can identify the most clinically valuable treatments among approved options to inform clinical pathways and drug policies. This study will apply and compare these established multidimensional frameworks to evaluate these drugs, explore factors affecting their value, and support the development of value-driven cancer care strategies. It is important to clarify that this study relies on applying and comparing these existing frameworks rather than proposing a new one.

Methods

Data sources

This study focused on the novel anti-tumor drugs included in the Guidelines for the Clinical Application of Novel Anti-tumor Drugs (2024 Edition). Drugs indicated for advanced digestive system tumors were selected, while those for non-digestive system tumors or used in adjuvant therapy were excluded. The literature retrieval process was conducted as follows: First, two researchers systematically retrieved pivotal clinical studies from the marketing approval reports issued by the Center for Drug Evaluation of the National Medical Products Administration, with key studies listed in the drug labeling serving as supplementary sources. Next, trial registration numbers were extracted from the relevant registration documents. Subsequent searches were conducted in PubMed to identify any post-marketing study updates. For agents supported by multiple clinical trials, the study with the largest sample size was selected. Finally, research reports on patient-reported outcomes (PROs) from the associated clinical trials were collected. Any discrepancies were resolved through discussion with a third researcher to reach a consensus.

Data extraction

For each included trial, two researchers independently extracted data from the literature using a pre-designed structured Excel form. The accuracy and completeness of the extracted information were cross-verified between them. The extracted data included, but were not limited to: drug approval details (accelerated approval or regular approval), reimbursement status, trial characteristics (e.g., trial name, tumor type, study design, phase, treatment regimen, and line of therapy), primary efficacy endpoints (OS, PFS and their HR values for randomized controlled trials; PFS, ORR and duration of response for single-arm studies), as well as information on toxicity and QoL.

OS benefit was defined as a statistically significant difference observed between the trial and control groups (4). QoL benefit was defined as a significant advantage in PROs for the intervention group compared to the control group in randomized controlled trials, or a significant improvement from baseline after treatment in single-arm studies (4).

Value scoring

We employed the ASCO-VF version 2.0 (advanced disease) and ESMO-MCBS version 2.0 (non-curative) to quantify the value scores of the included indications (8, 9). The ASCO-VF is applicable only to phase II or III randomized controlled trial (RCT) and consists of three modules: clinical benefit, toxicity, and bonus points. These are ultimately combined into a net health benefit (NHB) score, which is a continuous measure ranging from -20 to 180. While the framework itself does not specify a definitive value threshold, this study referenced our previous research and defined an NHB score ≥ 38.2 as meeting the value threshold (11). The clinical benefit score is calculated as (1 − Hazard Ratio (HR)) × 100 × weight (with weights of 1 for OS, 0.8 for PFS) and (Complete Response rate + Partial Response rate) × 100 × 0.7 for ORR. When OS data are immature, PFS is used, and then ORR. The toxicity score is derived from the percentage difference in total toxicity points between the intervention and control groups, multiplied by 20. The NHB score is adjusted by subtracting the toxicity score for a more toxic intervention or adding it for a more toxic control. Bonus points comprise: long-term survival (up to 20 points; OS weight 1, PFS 0.8), cancer-related symptom improvement (10 points), QoL gain (10 points), and the percentage improvement in treatment-free interval × 20.

The ESMO-MCBS designed for positive clinical trials, integrates evaluations from two modules: clinical benefit and toxicity/QoL, to produce a final grade on a 1–5 scale. Grades may be elevated by one level upon documented improvement in specific grade 3–4 adverse events or QoL; conversely, an improvement confined to PFS that fails to translate into OS benefit or QoL enhancement may result in a one-level downgrade. The clinical benefit grade is assigned based on where the lower limit of the HR’s 95% confidence interval falls within pre-defined thresholds. For example, with a control median PFS <6 months and HR ≤0.65, a PFS gain of ≥1.5 months corresponds to grade 3; a smaller gain results in grade 2. Grades 4 and 5 are explicitly considered to meet the value threshold for therapies in advanced cancer.

Since this study considered only non-curative treatments, we employed the ASCO-VF for advanced disease and utilized ESMO-MCBS forms 2a, 2b, 2c, and 3 for scoring.

Statistical analysis

Descriptive statistics were employed to summarize the data, with categorical variables presented as proportions and continuous variables described using median and range. We investigated the associations between trial characteristics and OS, QoL, as well as the threshold for value benefit. Statistical significance for these associations was initially assessed using either the Chi-square test or Fisher’s exact test, as appropriate. For 2×2 contingency tables, odds ratios (OR) were subsequently calculated to quantify the strength of the associations. The results are presented as odds ratios along with their corresponding 95% confidence intervals. All analyses were performed using R language (version 4.3.1). All hypothesis tests were two-sided, with the significance level set at α = 0.05.

Results

Characteristics of included trials

In this analysis, 33 novel anti-tumor drugs covering 65 indications were included (1287). Of these indications, 83.1% were supported by Phase III RCT, providing compelling evidence, and nearly 70% of the drugs were monoclonal antibodies or other large-molecule agents. In terms of regulatory approval and market access, 43.1% of the indications were approved through accelerated pathways, while 61.5% were included in the National Reimbursement Drug List (NRDL)—comprising 21.5% formally listed and 40.0% granted temporary NRDL access via national price−negotiated. Additionally, over 70% of indications required no molecular target detection, and more than half were approved for first-line treatment, suggesting notable clinical convenience and potential for earlier use in treatment algorithms. Table 1; Supplementary Table S1 present the detailed characteristics of the included trials.

Table 1
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Table 1. Characteristics of included indications and trails.

Among the 54 RCTs evaluated using the ACSO-VF framework, the NHB scores ranged from 1.0 to 74.0, with a median of 32.5 (IQR 17.5-41.0). Of these, 18 (33.3%) treatments met the value threshold (Table 2). When the entire cohort of 54 RCTs and 11 single-arm studies was assessed with the ESMO-MCBS, 26 (40.0%) treatments met the value threshold.

Table 2
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Table 2. Clinical benefit of novel anti-tumor drugs for digestive system cancers.

ASCO-VF and ESMO-MCBS scores for colorectal cancer

First-line pembrolizumab was the only regimen that achieved high value in both tools, with an ASCO-VF NHB score of 61.7 and an ESMO-MCBS grade of 4 (Table 2; Supplementary Tables S2, S3). Other first-line biologics, including bevacizumab and cetuximab (both combined with chemotherapy), yielded ASCO-VF scores (34.0 and 15.9, respectively) and ESMO-MCBS grade 3, falling short of the value threshold in both frameworks.

Among later-line therapies, third-line regorafenib and fruquintinib showed meaningful survival benefits (OS HR: 0.55 and 0.65) and attained ESMO-MCBS grade 3, but their ASCO-VF scores failed to meet the value threshold (25 and 15) due to toxicity penalties and lack of bonus points. Serplulimab, a domestically developed programmed cell death-1 (PD-1) inhibitor, reached ESMO-MCBS grade 4 in later-line settings, whereas other similar agents, including tislelizumab, envafolimab, and pucotenlimab, received ESMO-MCBS grade 3.

ASCO-VF and ESMO-MCBS scores for esophageal squamous cell carcinoma

Among first-line regimens combining PD-1 inhibitors with chemotherapy, toripalimab plus chemotherapy demonstrated the highest clinical benefit under both frameworks, achieving an ESMO-MCBS grade 4 and an ASCO-VF NHB score of 39.1. Tislelizumab, sugemalimab, serplulimab plus chemotherapy also attained ESMO-MCBS grade 4 but but failed to meet the value threshold on the ASCO-VF framework, with scores ranging from 24.5 to 32.7.

In later-line settings, PD-1 monotherapy demonstrated enhanced value. Both camrelizumab and tislelizumab in second-line treatment achieved high ASCO-VF scores (73.2 and 70.0 respectively) along with ESMO-MCBS grade 4, representing meaningful clinical benefit under both frameworks. Pembrolizumab in CPS≥10 patients also attained ESMO-MCBS grade 4 with an ASCO-VF score of 45.9.

ASCO-VF and ESMO-MCBS scores for gastroesophageal junction cancer

Among first-line treatments, trastuzumab combined with chemotherapy achieved an ESMO-MCBS grade 4 and an ASCO-VF NHB score of 43.5, representing one of the few regimens to meet value thresholds in both frameworks. Similarly, cadonilimab plus chemotherapy attained ESMO-MCBS grade 4 with an ASCO-VF score of 31.3. Sintilimab plus chemotherapy showed a moderate ESMO-MCBS grade 2 but reached the ASCO value threshold with a score of 43, largely due to the improvement in long-term survival rates.

In later-line settings, trastuzumab deruxtecan demonstrated substantial clinical benefit with an ESMO-MCBS grade 4, though its ASCO-VF score of 34.9 fell slightly below the meaningful benefit threshold. Nivolumab monotherapy in third-line treatment achieved an ASCO-VF score of 37, approaching the value threshold, despite a low ESMO-MCBS grade 1.

ASCO-VF and ESMO-MCBS scores for hepatocellular carcinoma

In the value assessment of hepatocellular carcinoma (HCC) therapies, immune checkpoint inhibitor-based combinations demonstrated superior value compared to tyrosine kinase inhibitor monotherapies across both ASCO-VF and ESMO-MCBS.

Among first-line regimens, atezolizumab plus bevacizumab achieved the highest value recognition with an ESMO-MCBS grade 5 and an ASCO-VF NHB score of 53.4, representing the most substantial clinical benefit. Similarly, bevacizumab plus sintilimab and camrelizumab plus apatinib regimens attained ESMO-MCBS grade 4 with ASCO-VF scores of 41 and 43.3 respectively, all meeting meaningful benefit thresholds in both evaluation systems.

Traditional TKIs showed limited value across both frameworks. Sorafenib, regorafenib, and lenvatinib achieved only ESMO-MCBS grade 3 with ASCO-VF scores (12-20.8), failing to reach meaningful benefit thresholds. Later-line monotherapies including pembrolizumab, apatinib, and ramucirumab demonstrated particularly poor performance in ASCO-VF assessments (scores 1-9) due to significant toxicity penalties.

ASCO-VF and ESMO-MCBS scores for gastrointestinal stromal tumours

In the value assessment of gastrointestinal stromal tumors (GIST), ripretinib emerged as the only regimen demonstrating substantial clinical benefit under both evaluation frameworks, achieving an ESMO-MCBS grade 5 and an ASCO-VF NHB score of 74.0 in the fourth-line setting. This represents the highest value assessment among all GIST therapies evaluated.

Among earlier-line treatments, imatinib attained an ESMO-MCBS grade 4 in the first-line setting based on durable response, though it was not assessed using the ASCO-VF framework. Avapritinib in the first-line setting achieved only ESMO-MCBS grade 3, below the value threshold.

Later-line therapies demonstrated variable performance. Regorafenib failed to reach meaningful benefit thresholds in either framework, with an ESMO-MCBS grade 2 and ASCO-VF score of 3. Sunitinib in the second-line showed discordant results, achieving ESMO-MCBS grade 4 but falling short of the ASCO-VF threshold with a score of 31.5.

Associations with OS, QoL, and clinical benefit

Table 3 shows the associations with OS, QoL, ASCO-VF, ESMO-MCBS benefit. For OS benefit, a statistically significant inverse association was observed with molecular target detection requirement (OR 0.16, 95% CI 0.03-0.83, P = 0.04), indicating that therapies requiring companion diagnostics were less likely to demonstrate significant OS improvements. No other characteristics showed significant associations with OS benefit. No significant associations were found between any of the examined characteristics and QoL benefit.

Table 3
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Table 3. Associations With OS, QoL and clinical benefit.

For clinical benefit as measured by the ASCO-VF framework, double-blind trial design showed a strong negative association (OR 0.09, 95% CI 0.03-0.35, P<0.01), while QoL benefit demonstrated a strong positive association (OR 28.00, 95% CI 3.12-251.30, P<0.01). Similarly, for the ESMO-MCBS framework, QoL benefit showed a substantial positive association with substantial clinical benefit (OR 27.87, 95% CI 3.30-235.10, P<0.01). No other factors were significantly associated with ESMO-MCBS benefit.

These findings identify distinct patterns of association across value dimensions, with QoL improvement emerging as a critical factor for substantial clinical benefit in both assessment frameworks, while molecular target detection requirement and blinded trial design showed inverse associations with OS benefit and ASCO-VF benefit, respectively.

Discussion

This study conducted a systematic value assessment of 65 indications associated with 33 novel anti-tumor drugs, revealing both consistencies and discrepancies in value measurement for digestive system tumors between the ASCO-VF and ESMO-MCBS. The results demonstrate that only a minority of treatment regimens simultaneously met the “meaningful clinical benefit” threshold in both frameworks, highlighting the complexity of contemporary oncology drug value assessment and its dependence on the chosen evaluation methodology (88, 89).

Complementarity and clinical application of value assessment frameworks

The distinct focuses of the two frameworks provide complementary references for clinical decision-making at different levels. This divergence stems from their inherent design purposes: the ESMO-MCBS is designed as a population-level tool to grade the objective magnitude of clinical benefit and strength of evidence, primarily to inform public health policy; whereas the ASCO-VF NHB score is intended as an individual-level aid to guide shared doctor-patient decision-making by incorporating a broader set of patient-centered value dimensions, including toxicity, QoL, and treatment burden. Consequently, while both frameworks can correlate with outcomes like QoL—as observed in our analysis—their primary emphasis differs. The ESMO-MCBS prioritizes quantifiable survival gains and evidence hierarchy within its scoring, while the ASCO-VF explicitly integrates and weighs a wider spectrum of factors relevant to individual patient choices (8, 9, 90). This difference is particularly evident in the assessment of Esophageal Squamous Cell Carcinoma (ESCC): camrelizumab and tislelizumab in the second-line setting achieved high ASCO-VF scores (73.2 and 70.0, respectively) (3032), primarily due to bonuses for quality of life and palliation, while also receiving ESMO-MCBS grade 4. Conversely, in colorectal cancer, although fruquintinib and regorafenib demonstrated significant survival benefits (HR 0.65 and 0.55), their ASCO-VF scores were low due to toxicity penalties (20, 21). Therefore, the lack of perfect concordance between the frameworks is not a limitation but rather a reflection of their complementary roles. For China, a synergistic application is warranted: the ESMO-MCBS can provide a high-level, evidence-based benchmark for drug evaluation and NRDL negotiations, while the ASCO-VF can offer a structured approach for clinicians and patients to weigh benefits against risks and burdens in individual cases, especially when multiple therapeutic options exist. Given their differing assessment orientations, clinicians should individualize the choice of framework based on treatment goals—such as survival prolongation versus toxicity reduction—to support personalized decision-making (91).

Identification of high-value treatment modalities across cancer types

This study successfully identified treatment regimens with outstanding value across different cancer types. In HCC, atezolizumab plus bevacizumab demonstrated exceptional performance, achieving both ESMO-MCBS grade 5 and an ASCO-VF score of 53.4, establishing its benchmark status in first-line treatment for advanced HCC (57, 58). In GIST, ripretinib set a cross-cancer type value assessment record in the fourth-line setting (ESMO-MCBS grade 5, ASCO-VF score 74), reflecting the breakthrough progress in late-line drug innovation (74, 75). Toripalimab plus chemotherapy in ESCC and trastuzumab plus chemotherapy in gastroesophageal junction cancer both reached the value threshold in both frameworks (26, 39, 40); these regimens share the common characteristic of balancing efficacy, safety, and quality of life.

Analysis of the relationship between endpoints and value assessment

This study systematically analyzed the association between different endpoints and value assessment outcomes. Notably, improvements in QoL showed strong correlations with achieving value thresholds in both frameworks (ASCO-VF OR 28.00, ESMO-MCBS OR 27.87), underscoring the central role of PROs in value assessment (11, 92). However, it is important to highlight that 25 (38.5%) trials in this study did not report QoL data, reflecting that the measurement of PROs has not yet received sufficient attention in current oncology drug development. Another counterintuitive finding was that drugs requiring molecular target detection showed a negative correlation with OS benefit (OR 0.16), potentially indicating heterogeneity in biomarker-selected populations or limitations of companion diagnostics (93). In our assessment, drugs receiving accelerated approval (typically based on surrogate endpoints such as PFS and ORR) showed no correlation with value benefit, indicating a disconnect between initial surrogate endpoint gains and ultimate value attainment. Drugs approved based on PFS often failed to demonstrate significant OS benefit, suggesting that surrogate endpoints should be treated cautiously in value assessment (5, 94). Of note, we found that open-label studies were associated with ASCO-VF benefit, raising concerns about determination bias (95).

Evolution of treatment line and value patterns

The study found the impact of treatment line on value patterns. In esophageal cancer, the value scores of PD-1 inhibitor monotherapy in the second-line setting were significantly higher than those of first-line combination regimens, mainly due to the accumulation of quality of life and palliative care bonus points in later lines. In contrast, first-line treatments generally demonstrated more stable value performance in colorectal and gastric cancers. These line-specific differences offer practical insights for clinical decision-making, suggesting that treatment choices should be tailored to therapeutic priorities—such as rapid tumor control in the first line versus quality-of-life preservation in later lines. Furthermore, they highlight the need for line-specific value assessment in drug reimbursement and resource allocation, as a therapy may demonstrate high value in later-line settings even if its first-line performance is modest. Finally, the strong association between quality of life and value in later lines underscores the importance of incorporating PRO as key endpoints in trials of later-line therapies. This line-aware perspective provides an important reference for evaluating value in line-specific treatment strategies.

Value implications of approval pathways and insurance coverage

The accelerated approval pathway offers the promise of timely access to innovative therapies, particularly for advanced-stage patients lacking effective treatment options. However, this benefit comes with inherent uncertainties. For instance, while immune-combination regimens in HCC showed excellent value (57, 58), drugs approved based on single-arm trials may prove to have limited efficacy in subsequent studies, potentially exposing patients to uncertainties in therapeutic outcomes and toxicity risks (92). Therefore, to safeguard public health, clinicians must carefully evaluate the quality of evidence, and patients should make treatment decisions on a fully informed basis, thereby maximizing the benefits of the accelerated approval pathway while minimizing its potential risks.

Analysis of insurance coverage revealed that not all drugs meeting the value threshold received insurance coverage, while some drugs not meeting the value threshold obtained temporary insurance access, reflecting the incomplete consistency between value assessment and reimbursement policies.

Practical implications and future directions for value assessment

The application of value frameworks in practice requires contextual interpretation. ASCO-VF and ESMO-MCBS serve complementary roles—the former aids individualized decision-making by integrating toxicity and quality of life, whereas the latter supports population-level policy with its focus on survival benefit and evidence strength (90). Discordant results between frameworks reflect different value dimensions and should prompt stakeholders to explicitly weigh priorities (e.g., survival vs.QoL). Current frameworks do not fully capture important real−world elements such as treatment convenience, financial toxicity, or caregiver burden (96). Future assessments should systematically integrate patient−reported outcomes and broaden scope to include these factors. Ultimately, these frameworks serve as essential guides for structured deliberation but must be complemented by multidisciplinary judgment to determine true value in specific clinical and health system contexts.

Limitations

This study has several limitations. First, the value assessment frameworks derive scores based on the specific comparator used in pivotal trials. This poses a contextual challenge when the comparator is a high-cost drug not reimbursed in a given setting, as the measured benefit may not accurately reflect the new drug’s incremental value over the locally accessible and affordable standard of care, potentially affecting the interpretation of its value for domestic policy. Second, our analysis relies on surrogate endpoints for some assessments, faces the inherent evidence constraints of single-arm trials, and lacks long-term follow-up data for a number of included studies. Additionally, missing QoL data in a significant proportion of trials may have led to an underestimation of true clinical value within frameworks that prioritize patient-centered outcomes.

Conclusion

Value assessment based on ASCO-VF and ESMO-MCBS provides multi-dimensional evidence support for the clinical positioning of gastrointestinal cancer drugs. Immune-combination therapies have established treatment standards in several cancer types. QoL improvement serves as a key bridge connecting the two value assessment systems and should be given full attention in future drug development and value assessment. It is recommended that clinical decision-makers, payers, and regulatory agencies adopt multi-dimensional value frameworks in drug assessment, balancing multiple value dimensions such as survival benefit, toxicity, and QoL, ultimately maximizing patient benefit.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Author contributions

SO: Funding acquisition, Writing – original draft, Writing – review & editing, Conceptualization, Investigation. SW: Investigation, Validation, Data curation, Writing – review & editing. XC: Writing – review & editing, Validation, Data curation, Methodology. HL: Data curation, Writing – review & editing, Methodology. CZ: Formal analysis, Writing – review & editing, Software. QJ: Funding acquisition, Conceptualization, Investigation, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was supported Wu Jieping Medical Foundation Clinical Research Special Grant (grant number 320.6750.2025-6-29); National Natural Science Foundation of China (grant number 72204039).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1747256/full#supplementary-material

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. (2021) 71:209–49. doi: 10.3322/caac.21660

PubMed Abstract | Crossref Full Text | Google Scholar

2. Haslam A, Hey SP, Gill J, and Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology. Eur J Cancer (Oxford England: 1990). (2019) 106:196–211. doi: 10.1016/j.ejca.2018.11.012

PubMed Abstract | Crossref Full Text | Google Scholar

3. Hwang TJ and Gyawali B. Association between progression-free survival and patients’ quality of life in cancer clinical trials. Int J cancer. (2019) 144:1746–51. doi: 10.1002/ijc.31957

PubMed Abstract | Crossref Full Text | Google Scholar

4. Zettler M, Basch E, and Nabhan C. Surrogate end points and patient-reported outcomes for novel oncology drugs approved between 2011 and 2017. JAMA Oncol. (2019) 5:1358–9. doi: 10.1001/jamaoncol.2019.1760

PubMed Abstract | Crossref Full Text | Google Scholar

5. Kim C and Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US food and drug administration approvals. JAMA Internal Med. (2015) 175:1992–4. doi: 10.1001/jamainternmed.2015.5868

PubMed Abstract | Crossref Full Text | Google Scholar

6. Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, and Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ (Clinical Res ed). (2017) 359:j4530. doi: 10.1136/bmj.j4530

PubMed Abstract | Crossref Full Text | Google Scholar

7. Vivot A, Jacot J, Zeitoun JD, Ravaud P, Crequit P, and Porcher R. Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000-2015. Ann Oncol Off J Eur Soc Med Oncol. (2017) 28:1111–6. doi: 10.1093/annonc/mdx053

PubMed Abstract | Crossref Full Text | Google Scholar

8. Schnipper LE, Davidson NE, Wollins DS, Blayney DW, Dicker AP, Ganz PA, et al. Updating the american society of clinical oncology value framework: revisions and reflections in response to comments received. J Clin Oncol Off J Am Soc Clin Oncol. (2016) 34:2925–34. doi: 10.1200/JCO.2016.68.2518

PubMed Abstract | Crossref Full Text | Google Scholar

9. Cherny NI, Oosting SF, Dafni U, Latino NJ, Galotti M, Zygoura P, et al. ESMO-Magnitude of Clinical Benefit Scale version 2.0 (ESMO-MCBS v2.0). Ann Oncol Off J Eur Soc Med Oncol. (2025) 36:866–908. doi: 10.1016/j.annonc.2025.04.006

PubMed Abstract | Crossref Full Text | Google Scholar

10. Luo J, Ou S, Wei H, Qin X, Peng R, Wang S, et al. Value assessment of NMPA-approved new cancer drugs for solid cancer in China, 2016-2020. Front Public Health. (2023) 11:1109668. doi: 10.3389/fpubh.2023.1109668

PubMed Abstract | Crossref Full Text | Google Scholar

11. Ou SL, Luo J, Wei H, Qin XL, and Jiang Q. Value assessment of PD-1/PD-L1 inhibitors in the treatment of oesophageal and gastrointestinal cancers. Front Pharmacol. (2023) 14:1106961. doi: 10.3389/fphar.2023.1106961

PubMed Abstract | Crossref Full Text | Google Scholar

12. Diaz LA, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. (2022) 23:659–70. doi: 10.1016/S1470-2045(22)00197-8

PubMed Abstract | Crossref Full Text | Google Scholar

13. Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. (2021) 22:665–77. doi: 10.1016/S1470-2045(21)00064-4

PubMed Abstract | Crossref Full Text | Google Scholar

14. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med. (2004) 350:2335–42. doi: 10.1056/NEJMoa032691

PubMed Abstract | Crossref Full Text | Google Scholar

15. Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, et al. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. (2018) 36:3031–9. doi: 10.1200/JCO.2018.78.3183

PubMed Abstract | Crossref Full Text | Google Scholar

16. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New Engl J Med. (2004) 351:337–45. doi: 10.1056/NEJMoa033025

PubMed Abstract | Crossref Full Text | Google Scholar

17. Li J, Deng Y, Zhang W, Zhou AP, Guo W, Yang J, et al. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol. (2021) 14:95. doi: 10.1186/s13045-021-01095-1

PubMed Abstract | Crossref Full Text | Google Scholar

18. Qin S, Li J, Zhong H, Jin C, Chen L, Yuan X, et al. Serplulimab, a novel anti-PD-1 antibody, in patients with microsatellite instability-high solid tumours: an open-label, single-arm, multicentre, phase II trial. Br J cancer. (2022) 127:2241–8. doi: 10.1038/s41416-022-02001-3

PubMed Abstract | Crossref Full Text | Google Scholar

19. Zhang B, Song Y, Luo S, Yin X, Li E, Wang H, et al. Pucotenlimab in patients with advanced mismatch repair-deficient or microsatellite instability-high solid tumors: A multicenter phase 2 study. Cell Rep Med. (2023) 4:101301. doi: 10.1016/j.xcrm.2023.101301

PubMed Abstract | Crossref Full Text | Google Scholar

20. Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. Jama. (2018) 319:2486–96. doi: 10.1001/jama.2018.7855

PubMed Abstract | Crossref Full Text | Google Scholar

21. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2015) 16:619–29. doi: 10.1016/S1470-2045(15)70156-7

PubMed Abstract | Crossref Full Text | Google Scholar

22. Li J, Xu Y, Zang A, Gao Y, Gao Q, Zhang Y, et al. Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors. Chin J Cancer Res = Chung-kuo yen cheng yen chiu. (2024) 36:257–69. doi: 10.21147/j.issn.1000-9604.2024.03.03

PubMed Abstract | Crossref Full Text | Google Scholar

23. Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ (Clinical Res ed). (2022) 377:e068714. doi: 10.1136/bmj-2021-068714

PubMed Abstract | Crossref Full Text | Google Scholar

24. Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, et al. Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: the ESCORT-1st randomized clinical trial. Jama. (2021) 326:916–25. doi: 10.1001/jama.2021.12836

PubMed Abstract | Crossref Full Text | Google Scholar

25. Xu J, Kato K, Raymond E, Hubner RA, Shu Y, Pan Y, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. (2023) 24:483–95. doi: 10.1016/S1470-2045(23)00108-0

PubMed Abstract | Crossref Full Text | Google Scholar

26. Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. (2022) 40:277–288.e273. doi: 10.1016/j.ccell.2022.02.007

PubMed Abstract | Crossref Full Text | Google Scholar

27. Kato K, Doki Y, Chau I, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial. Cancer Med. (2024) 13:e7235. doi: 10.1002/cam4.7235

PubMed Abstract | Crossref Full Text | Google Scholar

28. Li J, Chen Z, Bai Y, Liu B, Li Q, Zhang J, et al. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. (2024) 30:740–8. doi: 10.1038/s41591-024-02797-y

PubMed Abstract | Crossref Full Text | Google Scholar

29. Song Y, Zhang B, Xin D, Kou X, Tan Z, Zhang S, et al. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Nat Med. (2023) 29:473–82. doi: 10.1038/s41591-022-02179-2

PubMed Abstract | Crossref Full Text | Google Scholar

30. Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, et al. Camrelizumab versus investigator’s choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. (2020) 21:832–42. doi: 10.1016/S1470-2045(20)30110-8

PubMed Abstract | Crossref Full Text | Google Scholar

31. Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): A randomized phase III study. J Clin Oncol. (2022) 40:3065–76. doi: 10.1200/JCO.21.01926

PubMed Abstract | Crossref Full Text | Google Scholar

32. Van Cutsem E, Kato K, Ajani J, Shen L, Xia T, Ding N, et al. Tislelizumab versus chemotherapy as second-line treatment of advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302): impact on health-related quality of life. ESMO Open. (2022) 7:100517. doi: 10.1016/j.esmoop.2022.100517

PubMed Abstract | Crossref Full Text | Google Scholar

33. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. (2020) 38:4138–48. doi: 10.1200/JCO.20.01888

PubMed Abstract | Crossref Full Text | Google Scholar

34. Adenis A, Kulkarni AS, Girotto GC, de la Fouchardiere C, Senellart H, van Laarhoven HWM, et al. Impact of pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer on health-related quality of life in KEYNOTE-181. J Clin Oncol. (2022) 40:382–91. doi: 10.1200/JCO.21.00601

PubMed Abstract | Crossref Full Text | Google Scholar

35. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet (London England). (2021) 398:759–71. doi: 10.1016/S0140-6736(21)01234-4

PubMed Abstract | Crossref Full Text | Google Scholar

36. Mansoor W, Joo S, Norquist JM, Kato K, Sun JM, Shah MA, et al. Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer. oncologist. (2024) 29:e1324–35. doi: 10.1093/oncolo/oyae087

PubMed Abstract | Crossref Full Text | Google Scholar

37. Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. Jama. (2023) 330:2064–74. doi: 10.1001/jama.2023.19918

PubMed Abstract | Crossref Full Text | Google Scholar

38. Qiu MZ, Oh DY, Kato K, Arkenau T, Tabernero J, Correa MC, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ (Clinical Res ed). (2024) 385:e078876. doi: 10.1136/bmj-2023-078876

PubMed Abstract | Crossref Full Text | Google Scholar

39. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London England). (2010) 376:687–97. doi: 10.1016/S0140-6736(10)61121-X

PubMed Abstract | Crossref Full Text | Google Scholar

40. Satoh T, Bang YJ, Gotovkin EA, Hamamoto Y, Kang YK, Moiseyenko VM, et al. Quality of life in the trastuzumab for gastric cancer trial. oncologist. (2014) 19:712–9. doi: 10.1634/theoncologist.2014-0058

PubMed Abstract | Crossref Full Text | Google Scholar

41. Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III checkMate 649 trial. J Clin Oncol. (2024) 42:2012–20. doi: 10.1200/JCO.23.01601

PubMed Abstract | Crossref Full Text | Google Scholar

42. Moehler M, Xiao H, Blum SI, Elimova E, Cella D, Shitara K, et al. Health-related quality of life with nivolumab plus chemotherapy versus chemotherapy in patients with advanced gastric/gastroesophageal junction cancer or esophageal adenocarcinoma from checkMate 649. J Clin Oncol. (2023) 41:5388–99. doi: 10.1200/JCO.23.00170

PubMed Abstract | Crossref Full Text | Google Scholar

43. Zhang X, Wang J, Wang G, Zhang Y, Fan Q, Lu C, et al. First-line sugemalimab plus chemotherapy for advanced gastric cancer: the GEMSTONE-303 randomized clinical trial. Jama. (2025) 333:1305–14. doi: 10.1001/jama.2024.28463

PubMed Abstract | Crossref Full Text | Google Scholar

44. Shen L, Zhang Y, Li Z, Zhang X, Gao X, Liu B, et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med. (2025) 31:1163–70. doi: 10.1038/s41591-024-03450-4

PubMed Abstract | Crossref Full Text | Google Scholar

45. Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet (London England). (2023) 402:2197–208. doi: 10.1016/S0140-6736(23)02033-0

PubMed Abstract | Crossref Full Text | Google Scholar

46. Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. (2023) 24:1181–95. doi: 10.1016/S1470-2045(23)00515-6

PubMed Abstract | Crossref Full Text | Google Scholar

47. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. (2014) 15:1224–35. doi: 10.1016/S1470-2045(14)70420-6

PubMed Abstract | Crossref Full Text | Google Scholar

48. Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, et al. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. (2016) 27:673–9. doi: 10.1093/annonc/mdv625

PubMed Abstract | Crossref Full Text | Google Scholar

49. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. (2016) 34:1448–54. doi: 10.1200/JCO.2015.63.5995

PubMed Abstract | Crossref Full Text | Google Scholar

50. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London England). (2017) 390:2461–71. doi: 10.1016/S0140-6736(17)31827-5

PubMed Abstract | Crossref Full Text | Google Scholar

51. Peng Z, Liu T, Wei J, Wang A, He Y, Yang L, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Commun (London England). (2021) 41:1173–82. doi: 10.1002/cac2.12214

PubMed Abstract | Crossref Full Text | Google Scholar

52. Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. New Engl J Med. (2020) 382:2419–30. doi: 10.1056/NEJMoa2004413

PubMed Abstract | Crossref Full Text | Google Scholar

53. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. (2009) 10:25–34. doi: 10.1016/S1470-2045(08)70285-7

PubMed Abstract | Crossref Full Text | Google Scholar

54. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet (London England). (2018) 391:1163–73. doi: 10.1016/S0140-6736(18)30207-1

PubMed Abstract | Crossref Full Text | Google Scholar

55. Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, et al. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol hepatology. (2021) 6:649–58. doi: 10.1016/S2468-1253(21)00110-2

PubMed Abstract | Crossref Full Text | Google Scholar

56. Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: A randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol. (2021) 39:3002–11. doi: 10.1200/JCO.21.00163

PubMed Abstract | Crossref Full Text | Google Scholar

57. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J hepatology. (2022) 76:862–73. doi: 10.1016/j.jhep.2021.11.030

PubMed Abstract | Crossref Full Text | Google Scholar

58. Galle PR, Finn RS, Qin S, Ikeda M, Zhu AX, Kim TY, et al. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. (2021) 22:991–1001. doi: 10.1016/S1470-2045(21)00151-0

PubMed Abstract | Crossref Full Text | Google Scholar

59. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. Lancet Oncol. (2021) 22:977–90. doi: 10.1016/S1470-2045(21)00252-7

PubMed Abstract | Crossref Full Text | Google Scholar

60. Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet (London England). (2023) 402:1133–46. doi: 10.1016/S0140-6736(23)00961-3

PubMed Abstract | Crossref Full Text | Google Scholar

61. Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, et al. Tislelizumab vs sorafenib as first-line treatment for unresectable hepatocellular carcinoma: A phase 3 randomized clinical trial. JAMA Oncol. (2023) 9:1651–9. doi: 10.1001/jamaoncol.2023.4003

PubMed Abstract | Crossref Full Text | Google Scholar

62. Finn RS, Kudo M, Barnes G, Meyer T, Boisserie F, Abdrashitov R, et al. Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: impact on health-related quality of life in RATIONALE-301 study. Liver cancer. (2024) 13:548–60. doi: 10.1159/000537966

PubMed Abstract | Crossref Full Text | Google Scholar

63. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London England). (2017) 389:56–66. doi: 10.1016/S0140-6736(16)32453-9

PubMed Abstract | Crossref Full Text | Google Scholar

64. Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. (2020) 21:571–80. doi: 10.1016/S1470-2045(20)30011-5

PubMed Abstract | Crossref Full Text | Google Scholar

65. Ren Z, Ducreux M, Abou-Alfa GK, Merle P, Fang W, Edeline J, et al. Tislelizumab in patients with previously treated advanced hepatocellular carcinoma (RATIONALE-208): A multicenter, non-randomized, open-label, phase 2 trial. Liver cancer. (2023) 12:72–84. doi: 10.1159/000527175

PubMed Abstract | Crossref Full Text | Google Scholar

66. Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, et al. Pembrolizumab versus placebo as second-line therapy in patients from asia with advanced hepatocellular carcinoma: A randomized, double-blind, phase III trial. J Clin Oncol. (2023) 41:1434–43. doi: 10.1200/JCO.22.00620

PubMed Abstract | Crossref Full Text | Google Scholar

67. Qin S, Li Q, Gu S, Chen X, Lin L, Wang Z, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol hepatology. (2021) 6:559–68. doi: 10.1016/S2468-1253(21)00109-6

PubMed Abstract | Crossref Full Text | Google Scholar

68. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2019) 20:282–96. doi: 10.1016/S1470-2045(18)30937-9

PubMed Abstract | Crossref Full Text | Google Scholar

69. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Engl J Med. (2002) 347:472–80. doi: 10.1056/NEJMoa020461

PubMed Abstract | Crossref Full Text | Google Scholar

70. Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer (Oxford England: 1990). (2021) 145:132–42. doi: 10.1016/j.ejca.2020.12.008

PubMed Abstract | Crossref Full Text | Google Scholar

71. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet (London England). (2006) 368:1329–38. doi: 10.1016/S0140-6736(06)69446-4

PubMed Abstract | Crossref Full Text | Google Scholar

72. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet (London England). (2013) 381:295–302. doi: 10.1016/S0140-6736(12)61857-1

PubMed Abstract | Crossref Full Text | Google Scholar

73. Poole CD, Connolly MP, Chang J, and Currie CJ. Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo. Gastric Cancer. (2015) 18:627–34. doi: 10.1007/s10120-014-0391-x

PubMed Abstract | Crossref Full Text | Google Scholar

74. Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. (2020) 21:923–34. doi: 10.1016/S1470-2045(20)30168-6

PubMed Abstract | Crossref Full Text | Google Scholar

75. Schöffski P, George S, Heinrich MC, Zalcberg JR, Bauer S, Gelderblom H, et al. Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial. BMC cancer. (2022) 22:1302. doi: 10.1186/s12885-022-10379-9

PubMed Abstract | Crossref Full Text | Google Scholar

76. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (London England). (2023) 401:1853–65. doi: 10.1016/S0140-6736(23)00727-4

PubMed Abstract | Crossref Full Text | Google Scholar

77. Oh DY, He AR, Bouattour M, Okusaka T, Qin S, Chen LT, et al. Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study. Lancet Gastroenterol hepatology. (2024) 9:694–704. doi: 10.1016/S2468-1253(24)00095-5

PubMed Abstract | Crossref Full Text | Google Scholar

78. Burris HA, Okusaka T, Vogel A, Lee MA, Takahashi H, Breder V, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2024) 25:626–35. doi: 10.1016/S1470-2045(24)00082-2

PubMed Abstract | Crossref Full Text | Google Scholar

79. Vogel A, Sahai V, Hollebecque A, Vaccaro GM, Melisi D, Al Rajabi RM, et al. An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202. ESMO Open. (2024) 9:103488. doi: 10.1016/j.esmoop.2024.103488

PubMed Abstract | Crossref Full Text | Google Scholar

80. Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. (2020) 21:1500–12. doi: 10.1016/S1470-2045(20)30496-4

PubMed Abstract | Crossref Full Text | Google Scholar

81. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet (London England). (2016) 387:968–77. doi: 10.1016/S0140-6736(15)00817-X

PubMed Abstract | Crossref Full Text | Google Scholar

82. Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, et al. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. (2017) 18:1411–22. doi: 10.1016/S1470-2045(17)30471-0

PubMed Abstract | Crossref Full Text | Google Scholar

83. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. New Engl J Med. (2011) 364:514–23. doi: 10.1056/NEJMoa1009290

PubMed Abstract | Crossref Full Text | Google Scholar

84. Faivre S, Niccoli P, Castellano D, Valle JW, Hammel P, Raoul JL, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol Off J Eur Soc Med Oncol. (2017) 28:339–43. doi: 10.1093/annonc/mdw561

PubMed Abstract | Crossref Full Text | Google Scholar

85. Vinik A, Bottomley A, Korytowsky B, Bang YJ, Raoul JL, Valle JW, et al. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Targeted Oncol. (2016) 11:815–24. doi: 10.1007/s11523-016-0462-5

PubMed Abstract | Crossref Full Text | Google Scholar

86. Qin S, Li J, Bai Y, Wang Z, Chen Z, Xu R, et al. Nimotuzumab plus gemcitabine for K-ras wild-type locally advanced or metastatic pancreatic cancer. J Clin Oncol. (2023) 41:5163–73. doi: 10.1200/JCO.22.02630

PubMed Abstract | Crossref Full Text | Google Scholar

87. Xu J, Shen L, Bai C, Wang W, Li J, Yu X, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. (2020) 21:1489–99. doi: 10.1016/S1470-2045(20)30493-9

PubMed Abstract | Crossref Full Text | Google Scholar

88. Karas BL, Picone MF, Werner S, and Holsopple M. Verifying the value of existing frameworks for formulary review at a large academic health system: assessing inter-rater reliability. J managed Care specialty pharmacy. (2021) 27:488–96. doi: 10.18553/jmcp.2021.27.4.488

PubMed Abstract | Crossref Full Text | Google Scholar

89. Walter E. Approaches to capturing value in oncology. Recent results Cancer Res Fortschr der Krebsforschung Progres dans les recherches sur le cancer. (2019) 213:85–108. doi: 10.1007/978-3-030-01207-6

Crossref Full Text | Google Scholar

90. Cherny NI, de Vries EGE, Dafni U, Garrett-Mayer E, McKernin SE, Piccart M, et al. Comparative assessment of clinical benefit using the ESMO-magnitude of clinical benefit scale version 1.1 and the ASCO value framework net health benefit score. J Clin Oncol. (2019) 37:336–49. doi: 10.1200/JCO.18.00729

PubMed Abstract | Crossref Full Text | Google Scholar

91. Becker DJ, Lin D, Lee S, Levy BP, Makarov DV, Gold HT, et al. Exploration of the ASCO and ESMO value frameworks for antineoplastic drugs. J Oncol practice. (2017) 13:e653–65. doi: 10.1200/JOP.2016.020339

PubMed Abstract | Crossref Full Text | Google Scholar

92. Bujosa A, Moltó C, Hwang TJ, Tapia JC, Vokinger KN, Templeton AJ, et al. Associations with definitive outcomes and clinical benefit of cancer drugs at the time of marketing approval and in the postmarketing period. J Natl Compr Cancer Network: JNCCN. (2021) 24:1–9. doi: 10.6004/jnccn.2021.7003

PubMed Abstract | Crossref Full Text | Google Scholar

93. Hibino Y, Ito M, Satake T, and Kondo S. Clinical benefits of precision medicine in treating solid cancers: European Society of Medical Oncology-Magnitude of Clinical Benefit Scale score-based analysis. ESMO Open. (2021) 6:100187. doi: 10.1016/j.esmoop.2021.100187

PubMed Abstract | Crossref Full Text | Google Scholar

94. Cheng S, Cheung MC, Jiang DM, McDonald E, Arciero VS, Ezeife DA, et al. Are surrogate endpoints unbiased metrics in clinical benefit scores of the ASCO value framework? J Natl Compr Cancer Network: JNCCN. (2019) 17:1489–96. doi: 10.6004/jnccn.2019.7333

PubMed Abstract | Crossref Full Text | Google Scholar

95. Roydhouse JK, King-Kallimanis BL, Howie LJ, Singh H, and Kluetz PG. Blinding and patient-reported outcome completion rates in US food and drug administration cancer trial submissions, 2007-2017. J Natl Cancer Institute. (2019) 111:459–64. doi: 10.1093/jnci/djy181

PubMed Abstract | Crossref Full Text | Google Scholar

96. Wang S, Chino F, and Dee EC. Financial toxicity among Asian American cancer survivors. JAMA Oncol. (2024). doi: 10.1001/jamaoncol.2024.5016

PubMed Abstract | Crossref Full Text | Google Scholar

Keywords: ASCO-VF, clinical benefit, digestive system cancers, ESMO-MCBS, factors associated value, novel anti-tumor drugs

Citation: Ou S, Wang S, Chen X, Li H, Zhou C and Jiang Q (2026) What determines value? Exploring value characteristics of novel therapies for digestive system cancers. Front. Immunol. 17:1747256. doi: 10.3389/fimmu.2026.1747256

Received: 16 November 2025; Accepted: 22 January 2026; Revised: 19 January 2026;
Published: 10 February 2026.

Edited by:

Eriko Katsuta, Institute of Science Tokyo, Japan

Reviewed by:

Jens Grueger, University of Washington, United States
Catalina González-Browne, Fundación Arturo López Pérez, Chile

Copyright © 2026 Ou, Wang, Chen, Li, Zhou and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Qian Jiang, amlhbmdxaWFuQHNjc3pseXkub3JnLmNu

These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.