Biomarker-guided immuno-angiogenic therapy in biliary tract cancer: insights from IMbrave151

Biliary tract cancers (BTCs), encompassing intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), ampullary cholangiocarcinoma and gallbladder carcinoma (GBC), remain among the most lethal malignancies of the digestive tract. Curative management relies on surgery and adjuvant chemotherapy, yet recurrence is common even after complete resection, with median overall survival (OS) rarely exceeding five years (1). Outcomes differ substantially across anatomical subtypes: iCCA generally has a better prognosis than eCCA and GBC, while GBC, particularly when diagnosed at an advanced stage, carries the poorest outcomes. It should be noted that ampullary carcinomas, while included in epidemiological classifications, were excluded in IMbrave151 (2) and are therefore not addressed in the subsequent trial-based discussion. These differences are underpinned not only by clinical behaviour but also by distinct molecular and immunological landscapes. For patients with advanced disease, outcomes were historically measured in months, until a succession of randomized trials progressively reshaped expectations toward one year.

The ABC-02 trial established gemcitabine-cisplatin (GemCis) as the standard first-line therapy for advanced BTC (3), later confirmed by real-world analyses with marked geographic variation (4). In second line, ABC-06 showed that modified FOLFOX (5-FU, leucovorin and oxaliplatin) modestly extended survival versus best supportive care (5), underscoring the aggressiveness of BTC and the need for novel strategies.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of several cancer types, including lung, melanoma, as well as mismatch repair-deficient (MMRd) tumours (6). To that end, the TOPAZ-1 trial demonstrated that adding durvalumab to GemCis improved OS to 12.9 months compared with 11.3 months [hazard ratio (HR) 0.76] and doubled two-year survival rates (7). Shortly thereafter, KEYNOTE-966 confirmed the findings with pembrolizumab, reporting OS of 12.7 versus 10.9 months (HR 0.83) (8). These findings established immuno-chemotherapy as the standard first-line therapy, irrespective of programmed death-ligand 1 (PD-L1) status. Importantly, both trials demonstrated that a reproducible subset of patients achieved long-term benefit. Notably, subsequent therapies were well balanced between arms in both pivotal trials, including the use of targeted agents, alleviating concerns regarding confounding from post-progression treatments. Taken together, and despite the gradual introduction of FGFR, IDH1, BRAF and HER2 inhibitors into later lines, OS remained superior with first-line GemCis plus PD-(L)1 blockade.

In parallel, biomarker-guided therapy became part of routine care, since iCCA and eCCA cholangiocarcinomas display distinct mutational landscapes and therapeutic vulnerabilities (9,10). Genomic profiling consistently shows that IDH1/2 mutations, FGFR2 fusions or rearrangements, and BRAF^V600E occur almost exclusively in iCCA, whereas KRAS and ERBB2 (HER2) alterations predominate in eCCA, with HER2 amplification sometimes higher, but inconsistently, observed in gallbladder cancer (11-14). PIK3CA mutations are detected across both intrahepatic and extrahepatic sites (14,15). Thus, the two anatomical subtypes represent biologically distinct entities requiring targeted therapeutic strategies: pemigatinib in FGFR2-rearranged iCCA (16), ivosidenib in IDH1-mutant iCCA (17), trastuzumab-based combinations in HER2-positive disease (18,19), and dabrafenib plus trametinib in BRAF^V600E-mutated tumours (20). Real-world cohorts confirmed that appropriate targeted therapy is associated with improved survival.

Within this evolving context, the IMbrave151 trial evaluated whether combining atezolizumab, bevacizumab, and GemCis could further improve outcomes (2). Indeed, vascular endothelial growth factor (VEGF) not only drives angiogenesis but also mediates immune escape through dendritic-cell suppression, recruitment of regulatory T cells and myeloid-derived suppressor cells, and promotion of hypoxia. Preclinical studies have demonstrated that VEGF blockade normalises tumour vasculature, enhances immune infiltration, and synergises with PD-(L)1 blockade [reviewed in ref. (21)]. Clinically, this concept was validated in hepatocellular carcinoma (HCC), where the IMbrave150 trial demonstrated a major survival advantage for atezolizumab-bevacizumab over sorafenib (22), later confirmed in IMbrave152 (23).

Between February and September 2021, the trial accrued 162 patients across 48 sites in 13 countries, a remarkably short enrolment period. Importantly, enrolment occurred after approval of pemigatinib but before widespread access to other targeted agents such as futibatinib, ivosidenib, or HER2-directed therapies. From a statistical standpoint, IMbrave151 was exploratory. With a prespecified 90 progression-free survival (PFS) events and a two-sided α of 0.05, the trial was powered at 68% to detect a HR of 0.6, below the conventional 80–90% power typically required for confirmatory phase III studies. Although a protocol amendment permitted evaluation of OS after 90 deaths, the limited number of events constrains the interpretability of OS results. Accordingly, the absence of a statistically significant OS difference should be interpreted with caution, and IMbrave151 is best viewed as a hypothesis-generating study rather than a definitive negative trial.

The IMbrave151 efficacy results illustrate both the promise and the limitations of adding anti-angiogenic therapy to chemo-immunotherapy in BTC. Although the primary outcomes may appear modest, both median PFS and OS numerically exceeded those reported in TOPAZ-1 and KEYNOTE-966, although cross-trial comparisons are inherently unreliable. Indeed, median PFS was 8.3 versus 7.9 months (HR 0.67), while OS was virtually identical at 14.9 versus 14.6 months (HR 0.97). Objective response rates (ORRs) were 26.6% in both arms. Despite limited PFS improvement and negative OS results, duration of response was encouraging, 10.3 versus 6.2 months, with nearly half of responders in the bevacizumab arm progression-free at one year, compared with fewer than 10% in the control. The modest separation of survival curves despite encouraging duration of response suggests that only a biologically defined subset of tumours may derive meaningful benefit from the addition of VEGF blockade, and that durable responses within this subgroup may require longer follow-up before translating into an OS advantage. However, there is currently no signal suggesting late divergence. Exploratory analyses suggested that VEGFA-high tumours, evaluated through an angiogenic signature based on RNA sequencing, could derive greater benefit, though significance was confined to PFS. The absence of OS benefit despite these signals could suggest that BTC harbours organ-specific angiogenic programs not fully addressed by VEGF inhibition alone. Taken together, these ob

Beyond tumour biology, treatment efficacy in immuno-angiogenic combinations may also be determined by the choice of chemotherapy backbone. Cisplatin may be an important factor, as it can induce endothelial injury and oxidative stress (24), effects that could undermine the vascular normalization required for synergy with bevacizumab (24). Successful immuno-angiogenic regimens in non-small cell lung cancer (NSCLC) (25,26) [NO_PRINTED_FORM] paired bevacizumab with carboplatin-paclitaxel or carboplatin-pemetrexed, while in HCC and renal cell carcinoma (RCC), combinations with atezolizumab-bevacizumab were achieved without chemotherapy (Table 1) (22,36). Cisplatin may therefore represent a mechanistically suboptimal chemotherapy partner for anti-angiogenic strategies, although this hypothesis remains speculative. Indeed, the clinical relevance of these effects at therapeutic dosing remains uncertain and alternative explanations, including tumour-intrinsic biolo servations support a conceptual model in which tumour molecular architecture influences angiogenic programming, which in turn shapes the immune microenvironment and may ultimately modulate sensitivity to immunotherapy alone or in combination with anti-angiogenic strategies. Therefore, it provides a biological framework for future biomarker-driven patient selection. However, it should be acknowledged that this framework largely derives from biological extrapolation and cross-tumour evidence rather than from comprehensive translational analyses embedded within IMbrave151 itself. gy, may also account for the observed results. However, a small retrospective Chinese study may provide a rationale for this hypothesis. Atezolizumab plus bevacizumab combined with gemcitabine-oxaliplatin (GEMOX) in 30 patients with advanced BTC achieved an ORR of 77% and median PFS of 12 months (44). Follow-up was short and the sample size limited, but these results suggest that oxaliplatin-based regimens may be more compatible with immuno-angiogenic strategies and warrant further prospective evaluation.

Genomic context further modulates therapeutic response, particularly in relation to platinum sensitivity and immune resistance mechanisms. Homologous recombination deficiency (HRD) is a well-recognised genomic alteration associated with increased sensitivity to platinum-based chemotherapy. Although rare in BTC, a more comprehensive genomic annotation would strengthen the interpretability of chemo-immuno-angiogenic trials such as IMbrave151. While the study profiled the most recurrent and actionable alterations, broader sequencing could uncover molecular subsets with distinct sensitivity to the addition of an antiangiogenic agent to a chemo-immunotherapy backbone. For instance, mutations in Breast Cancer Gene 1/2 (BRCA1/2) or Partner and Localizer of BRCA2 (PALB2) may enhance cisplatin responsiveness, whereas alterations such as Serine/Threonine Kinase 11 (STK11), known to mediate resistance to immune checkpoint blockade in other malignancies (45), could attenuate the benefit of immunotherapy. Capturing these infrequent yet biologically relevant variants would help contextualise clinical outcomes and inform the design of future biomarker-driven strategies.

Molecular profiling reveals marked heterogeneity across BTC, with direct implications for treatment response. In eCCA, four transcriptomic subtypes, namely metabolic, proliferative, mesenchymal, and immune, show distinct pathways and prognoses: the mesenchymal class, enriched in transforming growth factor-beta (TGF-β) signalling, associates with poor outcomes, whereas the immune class, rich in lymphocyte infiltration and checkpoint activation, may predict ICI benefit (46). In iCCA, immune microenvironment-based subtyping defined immune-desert (45%), lymphoid, myeloid, and mesenchymal phenotypes, as well as the inflamed subtype (11%) showing T-cell infiltration, checkpoint activation, and longest survival (47). BTCs are further characterised by myeloid-rich stroma and immunosuppressive cytokines such as IL-10 and TGF-β, and by alternative checkpoints (TIM-3, LAG-3, TIGIT) mediating resistance (48,49). These data suggest distinct immune niches across subtypes, and the VEGFA-high subgroup in IMbrave151 may represent one such inflamed phenotype potentially sensitive to bevacizumab. From a clinical perspective, translating such complex molecular and transcriptomic subtyping frameworks into routine practice remains challenging, particularly with respect to assay standardisation, reproducibility and global accessibility. In NSCLC, benefit from atezolizumab-bevacizumab was confined to low VEGFA isoforms (50), while in colorectal cancer, AtezoTRIBE efficacy correlated with MMRd, high tumour mutational burden (TMB), or high Immunoscore Immune-Checkpoint (Immunoscore-IC) (30). Across studies, CD8 density and PD-L1 proximity remain key correlates of response. In this context, angiogenic positron emission tomography (PET)-radiomics has emerged as a potential tool to inform antiangiogenic treatment decisions by non-invasively capturing vascular normalisation dynamics, although current clinical evidence remains limited (51,52). Yet, for meaningful clinical translation, biomarkers must ultimately be simple, reproducible, cost-effective and globally deployable, ensuring equitable access to precision oncology beyond specialised centres.

Immuno-chemotherapy has now become the cornerstone of first-line therapy for advanced BTC. The durable benefits of TOPAZ-1 and KEYNOTE-966 have confirmed that the addition of a PD-(L)1 inhibitor to GemCis consistently prolongs survival, with a reproducible subset of patients achieving long-term benefit. By contrast, IMbrave151 was neutral for OS, suggesting that further treatment intensification with an antiangiogenic antibody is not required for most patients, although the trial was not powered to detect a statistically significant difference in OS and longer follow-up may yet reveal delayed benefit, as has been observed in other immunotherapy-based studies. Nevertheless, one could argue that overall response rate does not fully capture the clinical relevance of combining bevacizumab with atezolizumab. The depth of tumour regression, though not formally assessed in IMbrave151, may allow for secondary surgical resection in selected patients with initially unresectable or oligometastatic disease, a hypothesis deserving prospective evaluation.

Beyond IMbrave151, recent studies have explored refined immuno-angiogenic strategies in BTC. The phase II COMBATBIL trial combined atezolizumab, bevacizumab, and mFOLFOX6 after GemCis, achieving an ORR of 31%, disease control rate of 77%, median PFS of 8.4 months, and OS of 13.8 months, surpassing ABC-06 benchmarks with manageable toxicity (53). The bispecific antibody tovecimig (CTX-009), targeting DLL4 and VEGFA, also showed promise in COMPANION-002 (NCT05506943): when added to paclitaxel, it improved overall response rate to 17.1% versus 5.3%, suggesting dual Notch-VEGF inhibition as a promising therapeutic strategy [ref (54) and Compass Therapeutics Press Release April 1st 2025]. Similarly, the VEGF-PD-1 bispecific ivonescimab (AK112) doubled median PFS compared with pembrolizumab in PD-L1-positive NSCLC (11.1 vs. 5.8 months; HR 0.51), with consistent benefit across subgroups (55). In HCC, Bai et al. (56) demonstrated durable responses with the bispecific anti-PD-1/anti-CTLA-4 antibody cadonilimab (AK104) plus lenvatinib, reinforcing the synergy between angiogenesis and immune modulation. Collectively, these data suggest that either dual angiogenic blockade in combination with chemotherapy or dual angio-immuno-bispecific antibodies combined with chemotherapy warrant further investigation in larger cohorts and as potential first-line therapeutic strategies.

Earlier antiangiogenic trials provided mechanistic insights but limited efficacy. In ABC-03, cediranib plus GemCis increased overall response rate (44% vs. 19%) without PFS or OS improvement, although high baseline platelet-derived growth factor-BB (PDGF-BB) concentrations predicted benefit while rising VEGFA or VEGFR2 correlated with poorer outcomes (57,58). The JVBF study evaluated ramucirumab or merestinib with GemCis in 309 unselected patients, showing no survival gain but good tolerability (59). Together, these data suggest that empirical VEGF blockade offers modest benefit, while rational, biomarker-driven bispecific approaches may better exploit immuno-angiogenic synergy in BTC.

Identifying robust predictive biomarkers remains central to optimising patient selection for immuno-angiogenic strategies in BTC (Table 1). In IMbrave151, high VEGFA expression measured by RNA sequencing correlated with longer PFS, supporting the hypothesis that tumours with a more angiogenic phenotype may derive greater benefit from VEGF blockade. Evidence from other malignancies illustrates the complexity of this interaction. In NSCLC, low circulating VEGF levels measured by enzyme-linked immunosorbent assay (ELISA) were associated with improved efficacy of bevacizumab, and epidermal growth factor receptor (EGFR) mutations abrogated the PFS benefit of adding bevacizumab to atezolizumab, whereas patients with liver metastases appeared to derive greater benefit (33,60). Similarly, KRAS-mutated tumours without co-occurring STK11 or KEAP1 alterations showed enhanced benefit from atezolizumab-bevacizumab-chemotherapy, whereas in mucosal melanoma NRAS mutations were associated with improved outcomes with atezolizumab–bevacizumab combinations (31,43). In BTC, however, TP53 mutations are common while KRAS alterations are less frequent, limiting direct extrapolation across tumour types. Notably, PIK3CA mutations were associated with inferior OS in patients receiving bevacizumab in IMbrave151, raising the hypothesis that constitutive PI3K/AKT signalling may foster a pro-angiogenic and immunosuppressive microenvironment, consistent with pan-cancer evidence linking PI3K pathway activation to HIF-1α-driven angiogenic programmes and myeloid-rich tumour niches, although this interpretation remains exploratory and requires prospective validation in BTC (61,62). Baseline imbalances and differences in biomarker assessment further complicate interpretation (33,60).

In conclusion, BTC has entered a new therapeutic era. Immuno-chemotherapy has become the established first-line standard, while targeted agents and biomarker-guided strategies are increasingly shaping subsequent treatment lines. The IMbrave151 experience reinforces a recurring lesson in BTC: empirical intensification is unlikely to outperform biologically informed strategy. As our therapeutic armamentarium expands, the challenge is no longer whether to combine treatments, but how to select the right combination for the right vascular and immune context. In this regard, IMbrave151 should not necessarily be interpreted as definitively negative, but rather than closing the door on immuno-angiogenic strategies in BTC, these findings underscore the need for biologically informed patient selection in future studies. Future studies should integrate angiogenic and immune signatures with genomic, spatial, and imaging-based biomarkers to refine patient selection for immuno-angiogenic strategies. Ultimately, precision oncology in BTC will rely on deciphering the intricate interplay between vasculature, immunity, and tumour evolution to design truly personalised therapeutic approaches. This integrative perspective will be essential for translating biological insight into durable clinical benefit.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0038/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0038/coif). C.C. reports research funding from Fondation Gonella, Société Académique Vaudoise, and Fondation Ancrage. I.C. reports grants from Eli Lilly; honoraria from Eli Lilly, Servier, AstraZeneca, BMS, Astellas, Roche, Eisai, and Jazz Pharmaceuticals; and advisory board participation with AstraZeneca, Bristol Myers Squibb, Merck Serono, Gilead, Revolution Medicines, Astellas, GSK, Daiichi Sankyo, Novartis, Takeda, BeiGene, Jazz Pharmaceuticals, Taiho, BioNTech, and Elevation Oncology. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bridgewater J, Fletcher P, Palmer DH, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol 2022;40:2048-57. [Crossref] [PubMed]
2. Macarulla T, Ren Z, Chon HJ, et al. Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial. J Clin Oncol 2025;43:545-57. [Crossref] [PubMed]
3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
4. Bridgewater J, Sah J, Szende A, et al. Real-world treatment patterns and challenges of patients with biliary tract cancer: retrospective chart review survey in Europe (GARNET-2). ESMO Real World Data Digit Oncol 2024;5:100060. [Crossref] [PubMed]
5. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 2021;22:690-701. [Crossref] [PubMed]
6. Emens LA, Romero PJ, Anderson AC, et al. Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision. J Immunother Cancer 2024;12:e009063. [Crossref] [PubMed]
7. Oh DY, He AR, Qin S, et al. Durvalumab plus chemotherapy in advanced biliary tract cancer: 3-year overall survival update from the phase III TOPAZ-1 study. J Hepatol 2025;83:1092-101. [Crossref] [PubMed]
8. 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 2023;401:1853-65. [Crossref] [PubMed]
9. Zorigtbaatar A, Li Z, Magyar CTJ, et al. Perioperative approaches for patients with biliary tract cancer. Nat Rev Clin Oncol 2026; Epub ahead of print. [Crossref]
10. Ceniceros L, Torre M, Landa Magdalena A, et al. Immune-Checkpoint Inhibitors for Biliary Tract Cancer: Who Benefits and What Is Next? Cancers (Basel) 2025;17:2811.
11. Vivaldi C, Fornaro L, Ugolini C, et al. HER2 Overexpression as a Poor Prognostic Determinant in Resected Biliary Tract Cancer. Oncologist 2020;25:886-93. [Crossref] [PubMed]
12. Kim H, Kim R, Kim HR, et al. HER2 Aberrations as a Novel Marker in Advanced Biliary Tract Cancer. Front Oncol 2022;12:834104. [Crossref] [PubMed]
13. Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev 2017;36:141-57. [Crossref] [PubMed]
14. Spencer K, Pappas L, Baiev I, et al. Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma. J Natl Cancer Inst 2023;115:870-80. [Crossref] [PubMed]
15. Normanno N, Martinelli E, Melisi D, et al. Role of molecular genetics in the clinical management of cholangiocarcinoma. ESMO Open 2022;7:100505. [Crossref] [PubMed]
16. Vogel A, Sahai V, Hollebecque A, et al. An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202. ESMO Open 2024;9:103488. [Crossref] [PubMed]
17. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020;21:796-807. [Crossref] [PubMed]
18. Sweeney CJ, Hainsworth JD, Bose R, et al. MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors. J Clin Oncol 2024;42:258-65. [Crossref] [PubMed]
19. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 2024;42:47-58. [Crossref] [PubMed]
20. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med 2023;29:1103-12. [Crossref] [PubMed]
21. Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 2020;52:1475-85. [Crossref] [PubMed]
22. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
23. Finn RS, Singal AG, Cheng AL, et al. LBA50 IMbrave152/SKYSCRAPER-14: A phase III study of first-line tiragolumab (tira) + atezolizumab (atezo) + bevacizumab (bev) vs placebo (pbo) + atezo + bev for patients (pts) with untreated locally advanced or metastatic hepatocellular carcinoma (HCC). Ann Oncol 2025;36:S1594.
24. Terwoord JD, Beyer AM, Gutterman DD. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacology & Therapeutics 2022;237:108116.
25. Zhou C, Dong X, Chen G, et al. Atezolizumab plus bevacizumab and chemotherapy in metastatic nonsquamous NSCLC: the randomized double-blind phase 3 IMpower151 trial. Nat Med 2025;31:2375-84. [Crossref] [PubMed]
26. Socinski MA, Nishio M, Jotte RM, et al. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol 2021;16:1909-24. [Crossref] [PubMed]
27. Lu L, Zheng P, Pan Y, et al. Trajectories of α-fetoprotein and unresectable hepatocellular carcinoma outcomes receiving atezolizumab plus bevacizumab: a secondary analysis of IMbrave150 study. Br J Cancer 2023;129:620-5. [Crossref] [PubMed]
28. Yim SY, Lee SH, Baek SW, et al. Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial. Clin Mol Hepatol 2024;30:807-23. [Crossref] [PubMed]
29. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022;76:862-73.
30. Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Bevacizumab With or Without Atezolizumab for Patients With Metastatic Colorectal Cancer: Updated and Overall Survival Results of the ATEZOTRIBE Study. J Clin Oncol 2024;42:2637-44. [Crossref] [PubMed]
31. West HJ, McCleland M, Cappuzzo F, et al. Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. J Immunother Cancer 2022;10:e003027. [Crossref] [PubMed]
32. Nogami N, Barlesi F, Socinski MA, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol 2022;17:309-23. [Crossref] [PubMed]
33. Zhou C, Dong X, Chen G, et al. Atezolizumab plus bevacizumab and chemotherapy in metastatic nonsquamous NSCLC: the randomized double-blind phase 3 IMpower151 trial. Nat Med 2025;31:2375-84. [Crossref] [PubMed]
34. Ohe Y, Han B, Nishio M, et al. BEAT-SC: A randomized phase III study of bevacizumab or placebo in combination with atezolizumab and platinum-based chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). J Clin Oncol 2024;42:8001.
35. Felip E, Popat S, Dafni U, et al. A randomised phase III study of bevacizumab and carboplatin–pemetrexed chemotherapy with or without atezolizumab as first-line treatment for advanced pleural mesothelioma: results of the ETOP 13-18 BEAT-meso trial. Ann Oncol 2025;36:548-60. [Crossref] [PubMed]
36. Motzer RJ, Powles T, Atkins MB, et al. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients with Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol 2022;8:275-80. [Crossref] [PubMed]
37. Landen CN, Molinero L, Hamidi H, et al. Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial. Clin Cancer Res 2023;29:1698-707. [Crossref] [PubMed]
38. Pignata S, Bookman M, Sehouli J, et al. Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer. Gynecol Oncol 2023;177:20-31. [Crossref] [PubMed]
39. Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol 2021;39:1842-55. Erratum in: J Clin Oncol 2021;39:2420.
40. You B, Anderson C, Cecere SC, et al. Impact of adding the immune checkpoint inhibitor atezolizumab to first-line chemotherapy on progression-free survival in poor-prognosis ovarian cancer: A retrospective analysis from the IMagyn050 trial. Gynecol Oncol 2025;197:66-73. [Crossref] [PubMed]
41. Oaknin A, Gladieff L, Martínez-García J, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 2024;403:31-43. [Crossref] [PubMed]
42. Gion M, Blancas I, Cortez-Castedo P, et al. Atezolizumab plus paclitaxel and bevacizumab as first-line treatment of advanced triple-negative breast cancer: the ATRACTIB phase 2 trial. Nat Med 2025;31:2746-54. [Crossref] [PubMed]
43. Dai J, Xu T, Li L, et al. Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis. Clin Transl Med 2025;15:e70169. [Crossref] [PubMed]
44. Wang K, Liu ZH, Yu HM, et al. Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study. Ther Adv Gastroenterol 2023;16:17562848231160630. [Crossref] [PubMed]
45. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822-35. [Crossref] [PubMed]
46. Guest RV, Goeppert B, Nault JC, et al. Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma. Am J Pathol 2025;195:345-61. [Crossref] [PubMed]
47. Job S, Rapoud D, Dos Santos A, et al. Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma. Hepatology 2020;72:965-81. [Crossref] [PubMed]
48. Gentilini A, Pastore M, Marra F, et al. The role of stroma in cholangiocarcinoma: The intriguing interplay between fibroblastic component, immune cell subsets and tumor epithelium. Int J Mol Sci 2018;19:2885. [Crossref] [PubMed]
49. Montal R, Sia D, Montironi C, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol 2020;73:315-27. [Crossref] [PubMed]
50. Tanaka K, Sugisaka J, Shiraishi Y, et al. Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC. Nat Commun 2025;16:2825. [Crossref] [PubMed]
51. Hernández-Agudo E, Mondejar T, Soto-Montenegro ML, et al. Monitoring vascular normalization induced by antiangiogenic treatment with (18)F-fluoromisonidazole-PET. Mol Oncol 2016;10:704-18. [Crossref] [PubMed]
52. Chen H, Tong X, Lang L, et al. Quantification of Tumor Vascular Permeability and Blood Volume by Positron Emission Tomography. Theranostics 2017;7:2363-76. [Crossref] [PubMed]
53. Ponz-Sarvise M, Gromke T, Magdalena AL, et al. 44P Chemo-immunotherapy combination of mFOLFOX6, bevacizumab and atezolizumab after first-line therapy for advanced biliary tract cancer: The COMBATBIL imCORE trial. Ann Oncol 2024;35:S229.
54. Azad N, Hu Z, Sahin I, et al. COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC. Future Oncol 2024;20:2241-8. [Crossref] [PubMed]
55. Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet 2025;405:839-49. [Crossref] [PubMed]
56. Bai L, Sun M, Xu A, et al. Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma. J Clin Oncol 2026;39:4101.
57. Valle JW, Wasan H, Lopes A, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol 2015;16:967-78. [Crossref] [PubMed]
58. Backen AC, Lopes A, Wasan H, et al. Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial. Br J Cancer 2018;119:27-35. [Crossref] [PubMed]
59. Valle JW, Vogel A, Denlinger CS, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol 2021;22:1468-82. [Crossref] [PubMed]
60. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019;7:387-401. [Crossref] [PubMed]
61. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 2015;5:378-89. [Crossref] [PubMed]
62. Collins NB, Al Abosy R, Miller BC, et al. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment. J Immunother Cancer 2022;10:e003402. [Crossref] [PubMed]