{"product_id":"adding-bevacizumab-to-immunotherapy-and-chemotherapy-in-advanced-biliary-tract-cancer-results-from-the-imbrave151-trial","title":"Adding Bevacizumab to Immunotherapy and Chemotherapy in Advanced Biliary Tract Cancer: Results From the IMbrave151 Trial","description":"\u003cp\u003eIn a randomized phase II trial called IMbrave151, researchers tested whether adding bevacizumab (an anti-VEGF antibody) to atezolizumab (an anti-PD-L1 immunotherapy) plus standard chemotherapy improved outcomes for 162 patients with previously untreated advanced biliary tract cancer. The triplet regimen modestly extended progression-free survival (PFS) from 7.9 to 8.3 months (hazard ratio [HR] 0.67), but did not improve overall survival (14.9 vs 14.6 months; HR 0.97). Side effects were similar in both arms, with grade 3 or 4 adverse events occurring in 74% of patients in each group. Exploratory biomarker analysis suggested that high VEGFA gene expression may identify patients most likely to benefit from bevacizumab.\u003c\/p\u003e\n\n\u003ch1\u003eAdding Bevacizumab to Immunotherapy and Chemotherapy in Advanced Biliary Tract Cancer: Results From the IMbrave151 Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#what-is-btc\"\u003eWhat Is Biliary Tract Cancer?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#study-design\"\u003eHow the Study Was Designed\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#who-participated\"\u003eWho Participated in the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#treatments\"\u003eWhat Treatments Patients Received\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#outcomes\"\u003eWhat the Study Measured\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#key-findings\"\u003eKey Findings: Progression-Free Survival\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#survival\"\u003eOverall Survival Results\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#response\"\u003eTumor Response and Duration of Response\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#subgroups\"\u003eResults in Patient Subgroups\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#biomarkers\"\u003eBiomarker Findings: VEGFA and Gene Expression\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#safety\"\u003eSide Effects and Safety\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a 162-patient trial, adding bevacizumab to atezolizumab plus chemotherapy modestly improved progression-free survival (8.3 vs 7.9 months; hazard ratio 0.67) but not overall survival (14.9 vs 14.6 months; hazard ratio 0.97).\u003c\/li\u003e\n\u003cli\u003eObjective response rates were nearly identical (26.6% vs 26.5%), but responses lasted longer with bevacizumab (median 10.3 vs 6.2 months).\u003c\/li\u003e\n\u003cli\u003eGrade 3 or 4 side effects occurred in 74% of patients in both arms; corticosteroid use for immune-related effects was higher with bevacizumab (16.7% vs 4.9%).\u003c\/li\u003e\n\u003cli\u003eHigh VEGFA gene expression was linked to better progression-free survival with bevacizumab in an exploratory analysis of 95 tumor samples, but this needs confirmation.\u003c\/li\u003e\n\u003cli\u003eThe standard first-line treatment for advanced biliary tract cancer remains a PD-1 or PD-L1 inhibitor plus cisplatin and gemcitabine; adding bevacizumab is not recommended for routine use.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eBiliary tract cancers are notoriously difficult to treat once they have spread. For more than a decade, the standard first-line treatment has been a chemotherapy combination of \u003cstrong\u003ecisplatin plus gemcitabine\u003c\/strong\u003e (together called CisGem). This regimen was established based on the ABC-02 trial, which showed that CisGem improved overall survival compared with gemcitabine alone.\u003c\/p\u003e\n\n\u003cp\u003eNewer immunotherapy drugs called \u003cstrong\u003ePD-1 or PD-L1 inhibitors\u003c\/strong\u003e have shown promise when added to chemotherapy. Two large phase III trials — TOPAZ-1 and KEYNOTE-966 — found that adding durvalumab (an anti-PD-L1 drug) or pembrolizumab (an anti-PD-1 drug) to CisGem improved overall survival compared with CisGem plus placebo. However, the survival benefit was modest, which has driven researchers to look for ways to make immunotherapy work better.\u003c\/p\u003e\n\n\u003cp\u003eOne promising strategy involves targeting \u003cstrong\u003evascular endothelial growth factor\u003c\/strong\u003e (VEGF), a protein that helps tumors grow new blood vessels (a process called angiogenesis). VEGF is overexpressed in 40%–75% of biliary tract cancers. Beyond feeding the tumor, VEGF also suppresses the immune system inside the tumor, making it harder for immunotherapy to work.\u003c\/p\u003e\n\n\u003cp\u003eBevacizumab is an antibody that blocks VEGF. Combining atezolizumab (an anti-PD-L1 immunotherapy) with bevacizumab is already the first-line standard of care for unresectable hepatocellular carcinoma (liver cancer) based on the IMbrave150 trial. The IMbrave151 trial was designed to test whether this same combination — triplet therapy with atezolizumab, bevacizumab, and chemotherapy — could help patients with advanced biliary tract cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is-btc\"\u003eWhat Is Biliary Tract Cancer?\u003c\/h2\u003e\n\n\u003cp\u003eBiliary tract cancer (BTC) is a group of invasive cancers that arise in the bile ducts and gallbladder. It includes:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIntrahepatic cholangiocarcinoma (iCCA)\u003c\/strong\u003e — cancer inside the liver\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eExtrahepatic cholangiocarcinoma (eCCA)\u003c\/strong\u003e — cancer in the bile ducts outside the liver\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGallbladder cancer (GBC)\u003c\/strong\u003e — cancer in the gallbladder\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese cancers are highly heterogeneous, meaning they differ in their genetic changes and behavior depending on where they start. Cholangiocarcinoma is the second most common primary liver cancer after hepatocellular carcinoma, accounting for about 15% of liver cancers and 3% of all gastrointestinal cancers. Both the incidence and death rates from cholangiocarcinoma are rising, primarily because of increases in intrahepatic cases.\u003c\/p\u003e\n\n\u003cp\u003eBTC is often diagnosed at an advanced, inoperable stage. This limits treatment options and leads to poor outcomes. Most of these tumors are considered \"immunologically cold\" — they have a dense, scar-like tumor microenvironment (TME) that blocks immune cells from entering and suppresses the ones that do, allowing the cancer to escape immune attack.\u003c\/p\u003e\n\n\u003ch2 id=\"study-design\"\u003eHow the Study Was Designed\u003c\/h2\u003e\n\n\u003cp\u003eIMbrave151 was a global, randomized, double-blind, placebo-controlled phase II trial conducted at 48 sites across 13 countries in the United States, Europe, and Asia. It followed Good Clinical Practice guidelines and the Declaration of Helsinki and was approved by institutional review boards at each participating site (ClinicalTrials.gov identifier: NCT04677504).\u003c\/p\u003e\n\n\u003cp\u003eThe study was designed as a \u003cstrong\u003eproof-of-concept\u003c\/strong\u003e trial — meaning its goal was to see whether the combination showed enough promise to justify a larger, more definitive study. The trial was not powered to formally prove statistical significance. With 90 planned PFS events, the study had only a 68% chance of detecting a statistically significant hazard ratio of 0.6.\u003c\/p\u003e\n\n\u003cp\u003ePatients were randomly assigned in a 1:1 ratio to one of two groups. Randomization was stratified (balanced) based on:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003eThe location of the primary tumor (intrahepatic vs extrahepatic vs gallbladder)\u003c\/li\u003e\n  \u003cli\u003eThe presence or absence of metastatic disease\u003c\/li\u003e\n  \u003cli\u003eGeographic region (Asia vs the rest of the world)\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe study was initially designed to enroll about 150 patients but ultimately enrolled 162 — 12 more than planned, which is within 10% of target and was due to rapid enrollment. An amendment extended follow-up so that overall survival could be evaluated once at least 90 deaths had occurred. The data cutoff for the final analysis was January 16, 2023, with a minimum follow-up of 16 months from the last patient enrolled.\u003c\/p\u003e\n\n\u003ch2 id=\"who-participated\"\u003eWho Participated in the Study\u003c\/h2\u003e\n\n\u003cp\u003ePatients were enrolled between February and September 2021. Eligible patients had to meet the following criteria:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eHistologically or cytologically confirmed advanced (unresectable, recurrent, or metastatic) BTC, including iCCA, eCCA, or gallbladder cancer\u003c\/li\u003e\n  \u003cli\u003eNo previous systemic treatment for advanced disease (prior adjuvant or neoadjuvant therapy was allowed if completed at least 6 months before starting study treatment)\u003c\/li\u003e\n  \u003cli\u003eAge 18 years or older\u003c\/li\u003e\n  \u003cli\u003eEastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, indicating that patients were fully active or able to carry out light work\u003c\/li\u003e\n  \u003cli\u003eAdequate biliary drainage with no ongoing infection\u003c\/li\u003e\n  \u003cli\u003eMeasurable disease by RECIST 1.1 criteria\u003c\/li\u003e\n  \u003cli\u003eAdequate organ and blood function\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePatients with esophagogastric varices (enlarged veins in the esophagus or stomach) or those at high risk of variceal bleeding had to undergo an upper endoscopy during screening or within 6 months before starting treatment. Patients with ampulla of Vater cancer or mixed cholangiocarcinoma\/hepatocellular carcinoma histology were excluded.\u003c\/p\u003e\n\n\u003cp\u003eThe baseline characteristics were generally balanced between the two groups. Of the 162 patients:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMedian age:\u003c\/strong\u003e 61 years (range 36–79) in the bevacizumab arm and 65 years (range 37–79) in the placebo arm; overall median was 63 years\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMale:\u003c\/strong\u003e 53.7% overall (62% bevacizumab, 45.8% placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRace:\u003c\/strong\u003e 53.7% White, 44.4% Asian, 1.2% Black\/African American\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRegion:\u003c\/strong\u003e 42.6% enrolled in Asia, 57.4% in the rest of the world\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eECOG PS 0:\u003c\/strong\u003e 52.5%; ECOG PS 1: 47.5%\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMetastatic disease:\u003c\/strong\u003e 82.6% overall (85.3% bevacizumab, 80% placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrimary tumor location:\u003c\/strong\u003e 54.9% iCCA, 18.5% eCCA, 26.5% GBC\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMedian CA-19.9 (tumor marker) at baseline:\u003c\/strong\u003e 46.3 kU\/L (bevacizumab) vs 66.9 kU\/L (placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrevious BTC surgery:\u003c\/strong\u003e 33.3% overall (27.8% bevacizumab, 38.6% placebo)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePD-L1 tumor area positivity score ≥1:\u003c\/strong\u003e 43.3% of evaluable patients (38.6% bevacizumab, 47.6% placebo)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"treatments\"\u003eWhat Treatments Patients Received\u003c\/h2\u003e\n\n\u003cp\u003ePatients in the bevacizumab arm (79 patients) received:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAtezolizumab\u003c\/strong\u003e 1,200 mg intravenously every 3 weeks on day 1 of each 21-day cycle\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBevacizumab\u003c\/strong\u003e 15 mg\/kg intravenously every 3 weeks\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePatients in the placebo arm (83 patients) received:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAtezolizumab\u003c\/strong\u003e 1,200 mg intravenously every 3 weeks\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBevacizumab placebo\u003c\/strong\u003e (an inactive substance) intravenously every 3 weeks\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBoth groups also received \u003cstrong\u003ecisplatin\u003c\/strong\u003e 25 mg\/m² and \u003cstrong\u003egemcitabine\u003c\/strong\u003e 1,000 mg\/m² every 3 weeks (given on days 1 and 8 of each 21-day cycle) for up to eight cycles. After finishing chemotherapy, patients continued receiving either atezolizumab\/bevacizumab or atezolizumab\/placebo until unacceptable toxicity, disease progression, or loss of clinical benefit.\u003c\/p\u003e\n\n\u003cp\u003eTumor assessments (computed tomography [CT] or magnetic resonance imaging [MRI] scans of the chest, abdomen, and pelvis) were performed at screening and then every 9 weeks (±1 week) until disease progression. Adverse events were recorded at every cycle and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.\u003c\/p\u003e\n\n\u003cp\u003eIn the bevacizumab arm, the median number of atezolizumab and bevacizumab cycles administered was 11 (range 1–32) and 10 (range 1–32). In the placebo arm, the median number of atezolizumab and placebo cycles was 10 (range 1–30) and 9 (range 1–30). In both arms, the median number of cisplatin or gemcitabine cycles was 8 (range 1–8).\u003c\/p\u003e\n\n\u003ch2 id=\"outcomes\"\u003eWhat the Study Measured\u003c\/h2\u003e\n\n\u003cp\u003eThe \u003cstrong\u003eprimary endpoint\u003c\/strong\u003e was investigator-assessed progression-free survival (PFS), which is the time from random assignment until disease progression (per RECIST 1.1 criteria) or death from any cause, whichever occurred first.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c\/strong\u003e included:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eOverall survival (OS)\u003c\/li\u003e\n  \u003cli\u003eConfirmed objective response rate (ORR) per RECIST 1.1\u003c\/li\u003e\n  \u003cli\u003eDuration of response (DOR)\u003c\/li\u003e\n  \u003cli\u003eDisease control rate\u003c\/li\u003e\n  \u003cli\u003eSafety (incidence and severity of adverse events)\u003c\/li\u003e\n  \u003cli\u003ePatient-reported outcomes\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBiomarker studies were conducted as exploratory analyses. RNA sequencing (using TruSeq RNA Access technology by Illumina) was performed on baseline tumor samples from 95 patients, and genetic profiling (using FoundationOne CDx) was performed on samples from 102 patients.\u003c\/p\u003e\n\n\u003ch2 id=\"key-findings\"\u003eKey Findings: Progression-Free Survival\u003c\/h2\u003e\n\n\u003cp\u003eThe study met its primary endpoint by showing a modest improvement in progression-free survival with the addition of bevacizumab. Specifically:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMedian PFS:\u003c\/strong\u003e 8.3 months in the bevacizumab arm (95% CI, 6.8–10.6) vs 7.9 months in the placebo arm (95% CI, 6.2–8.5)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHazard ratio (HR):\u003c\/strong\u003e 0.67 (95% CI, 0.46–0.95), favoring bevacizumab\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e6-month PFS rate:\u003c\/strong\u003e 78.1% in the bevacizumab arm vs 63.4% in the placebo arm\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e12-month PFS rate:\u003c\/strong\u003e 33.5% in the bevacizumab arm vs 19.6% in the placebo arm\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eWhat does the hazard ratio of 0.67 mean in plain language? It means that the risk of disease progression or death was about 33% lower in the bevacizumab arm compared to the placebo arm. This result was statistically significant, with the upper bound of the confidence interval (0.95) falling below 1.0, meaning the benefit is unlikely to be due to chance.\u003c\/p\u003e\n\n\u003cp\u003eBy the data cutoff, 63 patients (80%) in the bevacizumab arm and 73 patients (88%) in the placebo arm had experienced a PFS event. An exploratory post-hoc analysis looked at whether tumor response was linked to PFS benefit. Among 43 patients with a confirmed response (complete or partial), PFS was improved in the bevacizumab arm (HR 0.32; 95% CI, 0.13–0.75). Among 91 patients whose best response was stable disease, there was no PFS difference between arms (HR 0.95; 95% CI, 0.59–1.53).\u003c\/p\u003e\n\n\u003ch2 id=\"survival\"\u003eOverall Survival Results\u003c\/h2\u003e\n\n\u003cp\u003eDespite the improvement in progression-free survival, there was \u003cstrong\u003eno meaningful difference in overall survival\u003c\/strong\u003e between the two groups. This is a critical finding.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMedian OS:\u003c\/strong\u003e 14.9 months in the bevacizumab arm (95% CI, 11.6–18.0) vs 14.6 months in the placebo arm (95% CI, 11.2–not estimable)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHazard ratio:\u003c\/strong\u003e 0.97 (95% CI, 0.64–1.47), which crosses 1.0 and indicates no significant difference\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e6-month survival rate:\u003c\/strong\u003e 92% bevacizumab (95% CI, 85.8%–98.1%) vs 80.5% placebo (95% CI, 72%–89.1%)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003e12-month survival rate:\u003c\/strong\u003e 59% bevacizumab (95% CI, 47.7%–70.3%) vs 54.6% placebo (95% CI, 43.7%–65.4%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBy the data cutoff, 47 patients (59.5%) in the bevacizumab arm and 48 patients (57.8%) in the placebo arm had died.\u003c\/p\u003e\n\n\u003ch2 id=\"response\"\u003eTumor Response and Duration of Response\u003c\/h2\u003e\n\n\u003cp\u003eThe objective response rates were nearly identical between the two arms, indicating that adding bevacizumab did not increase the proportion of patients whose tumors shrank.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eConfirmed ORR:\u003c\/strong\u003e 26.6% in the bevacizumab arm (95% CI, 17.3%–37.7%) vs 26.5% in the placebo arm (95% CI, 17.4%–37.3%)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eComplete response (CR):\u003c\/strong\u003e 1 patient (1.3%) in each arm\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eHowever, one notable difference emerged: for patients who did respond, the responses lasted much longer in the bevacizumab arm.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMedian duration of response (DOR):\u003c\/strong\u003e 10.3 months in the bevacizumab arm (95% CI, 6.7–16.7) vs 6.2 months in the placebo arm (95% CI, 4.3–6.7)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHazard ratio for duration of response:\u003c\/strong\u003e 0.28 (95% CI, 0.12–0.68), strongly favoring bevacizumab\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eOngoing response at 1 year:\u003c\/strong\u003e 47.8% in the bevacizumab arm vs 9.6% in the placebo arm\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe striking difference in response duration — despite similar ORR — prompted the post-hoc analysis described above, showing that PFS was also much better in responders who received bevacizumab.\u003c\/p\u003e\n\n\u003ch2 id=\"subgroups\"\u003eResults in Patient Subgroups\u003c\/h2\u003e\n\n\u003cp\u003eResearchers conducted descriptive subgroup analyses to see whether certain groups of patients benefited more than others. A PFS benefit (HR less than 1) was seen in almost all subgroups for the bevacizumab arm. Here are the detailed results:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAge \u0026lt;65:\u003c\/strong\u003e HR 0.86 (95% CI, 0.54–1.36) — no clear benefit\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAge ≥65:\u003c\/strong\u003e HR 0.52 (95% CI, 0.29–0.91) — benefit seen\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMale:\u003c\/strong\u003e HR 0.84 (95% CI, 0.53–1.34)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFemale:\u003c\/strong\u003e HR 0.55 (95% CI, 0.32–0.95) — benefit seen\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsia:\u003c\/strong\u003e HR 1.05 (95% CI, 0.61–1.79) — no benefit\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRest of the world:\u003c\/strong\u003e HR 0.50 (95% CI, 0.32–0.80) — benefit seen\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMetastatic disease (yes):\u003c\/strong\u003e HR 0.75 (95% CI, 0.51–1.11)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMetastatic disease (no):\u003c\/strong\u003e HR 0.48 (95% CI, 0.20–1.18)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIntrahepatic CCA:\u003c\/strong\u003e HR 0.66 (95% CI, 0.41–1.07) — trend toward benefit\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eExtrahepatic CCA:\u003c\/strong\u003e HR 0.90 (95% CI, 0.41–1.99)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGallbladder cancer:\u003c\/strong\u003e HR 0.63 (95% CI, 0.32–1.22) — trend toward benefit\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrior surgery (yes):\u003c\/strong\u003e HR 1.13 (95% CI, 0.63–2.03)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrior surgery (no):\u003c\/strong\u003e HR 0.60 (95% CI, 0.39–0.92) — benefit seen\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePD-L1 status unknown:\u003c\/strong\u003e HR 0.40 (95% CI, 0.20–0.81)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePD-L1 TAP \u0026lt;1%:\u003c\/strong\u003e HR 0.86 (95% CI, 0.51–1.44)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePD-L1 TAP ≥1%:\u003c\/strong\u003e HR 0.88 (95% CI, 0.47–1.67)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThere was a trend toward improved PFS in patients with intrahepatic or gallbladder cancer in the bevacizumab arm. However, since these subgroup analyses were not designed for formal hypothesis testing, the findings should be considered exploratory and interpreted with caution.\u003c\/p\u003e\n\n\u003ch2 id=\"biomarkers\"\u003eBiomarker Findings: VEGFA and Gene Expression\u003c\/h2\u003e\n\n\u003cp\u003eOne of the most interesting parts of the study involved looking for biological markers (biomarkers) that might predict which patients benefit most from adding bevacizumab.\u003c\/p\u003e\n\n\u003cp\u003eUsing RNA sequencing on tumor samples from 95 patients, researchers analyzed an \u003cstrong\u003eangiogenesis gene signature\u003c\/strong\u003e — a panel of genes involved in blood vessel formation, including VEGFA, KDR, ESM1, PECAM1, FLT1, ANGPTL4, and CD34.\u003c\/p\u003e\n\n\u003cp\u003eThe key finding: \u003cstrong\u003eHigh VEGFA gene expression was associated with improved PFS\u003c\/strong\u003e in the bevacizumab arm compared with the placebo arm (HR 0.44; 95% CI, 0.23–0.83). This suggests that patients whose tumors produce large amounts of VEGF may be the ones most likely to benefit from bevacizumab, which blocks this protein.\u003c\/p\u003e\n\n\u003cp\u003eGenetic profiling was also performed using FoundationOne CDx sequencing on samples from 102 patients. The researchers also used a technique called xCell deconvolution analysis to estimate the different types of immune cells within the tumor.\u003c\/p\u003e\n\n\u003cp\u003eThe biomarker analyses were exploratory and were not adjusted for multiple testing, meaning they should be viewed as hypothesis-generating rather than definitive.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSide Effects and Safety\u003c\/h2\u003e\n\n\u003cp\u003eThe safety profiles of the two treatment regimens were very similar. Importantly, adding bevacizumab did not significantly increase the overall rate of serious side effects.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGrade 3 or 4 adverse events:\u003c\/strong\u003e 74% in both treatment arms\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eGrade 3 events are serious side effects that typically require medical intervention, and grade 4 events are life-threatening. The fact that three-quarters of patients in both arms experienced a grade 3 or 4 event reflects the challenging nature of treating advanced biliary tract cancer with combination therapy.\u003c\/p\u003e\n\n\u003cp\u003eOne notable difference: treatment with systemic corticosteroids (anti-inflammatory drugs used to manage immune-related side effects) occurred in \u003cstrong\u003e16.7% of patients in the bevacizumab arm\u003c\/strong\u003e compared with \u003cstrong\u003e4.9% in the placebo arm\u003c\/strong\u003e. This may reflect a higher rate of immune-related adverse events when bevacizumab is added, though overall grade 3\/4 rates were identical.\u003c\/p\u003e\n\n\u003cp\u003eFor patients in the bevacizumab arm, three patients did not receive any study treatment (one in the bevacizumab arm, two in the placebo arm). At the time of analysis, 27 patients in the bevacizumab arm and 33 in the placebo arm remained on study (10 vs 8 still receiving active treatment, 17 vs 25 in follow-up). Fifty-two patients in the bevacizumab arm and 50 in the placebo arm discontinued treatment. The most common reason for discontinuation was death (47 patients in each arm), followed by withdrawal of consent (5 vs 2 patients).\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe IMbrave151 trial provides a nuanced picture of the role of bevacizumab in treating advanced biliary tract cancer.\u003c\/p\u003e\n\n\u003cp\u003eThe study met its primary endpoint by showing that adding bevacizumab to atezolizumab plus chemotherapy modestly improved progression-free survival (median 8.3 vs 7.9 months; HR 0.67). However, this improvement did not translate into a meaningful overall survival benefit (14.9 vs 14.6 months; HR 0.97).\u003c\/p\u003e\n\n\u003cp\u003eThere was no increase in the objective response rate (26.6% vs 26.5%), but for patients who did respond, responses lasted much longer in the bevacizumab arm (median 10.3 vs 6.2 months).\u003c\/p\u003e\n\n\u003cp\u003eBased on these results, the study authors and the JCO Associate Editor concluded that \u003cstrong\u003eadding anti-VEGF therapy to chemoimmunotherapy should not be routinely used in clinical practice\u003c\/strong\u003e for patients with advanced biliary tract cancer. This is an important takeaway for patients and their doctors when discussing treatment options.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the biomarker findings open an important door. The association between high VEGFA gene expression and improved PFS suggests that future studies could potentially use VEGF levels to select patients most likely to benefit from bevacizumab — potentially enriching future trials with patients who have the highest chance of responding. This is an active area of research interest.\u003c\/p\u003e\n\n\u003cp\u003eMeanwhile, patients and their clinicians should be aware that the current standard of care for first-line advanced biliary tract cancer (based on the larger phase III trials) remains a PD-1 or PD-L1 inhibitor plus CisGem chemotherapy, as established by the TOPAZ-1 and KEYNOTE-966 trials.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eSeveral important limitations should be kept in mind when interpreting these results:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe study was not powered for formal hypothesis testing.\u003c\/strong\u003e With only 162 patients and 68% power to detect a hazard ratio of 0.6, the trial was designed as a proof-of-concept study rather than a definitive test of efficacy.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSubgroup analyses were exploratory.\u003c\/strong\u003e Findings in patient subgroups (such as by age, sex, region, or tumor location) were descriptive and did not involve statistical testing, meaning they could be due to chance.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBiomarker analyses were not adjusted for multiple testing.\u003c\/strong\u003e The association between VEGFA expression and clinical benefit is hypothesis-generating and needs confirmation in larger studies.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNo overall survival benefit was observed,\u003c\/strong\u003e which limits the clinical value of the modest progression-free survival improvement.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eResponse rates were identical\u003c\/strong\u003e between treatment arms, suggesting that bevacizumab did not meaningfully change the biology of treatment response in most patients.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePatient characteristics were somewhat imbalanced\u003c\/strong\u003e in age and sex between the arms, which could have influenced outcomes.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on the results of IMbrave151, here is what patients and clinicians should take away:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCurrent practice:\u003c\/strong\u003e Adding bevacizumab to atezolizumab plus chemotherapy should not be adopted as routine first-line treatment for advanced biliary tract cancer. The benefit was modest and did not improve overall survival.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eStandard of care remains:\u003c\/strong\u003e A PD-L1 or PD-1 inhibitor combined with cisplatin and gemcitabine, based on the phase III TOPAZ-1 and KEYNOTE-966 trials.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBiomarker-enriched future trials:\u003c\/strong\u003e The VEGFA finding warrants further investigation in trials specifically designed to test whether patients with high VEGF expression benefit more from anti-VEGF therapy.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk your oncologist:\u003c\/strong\u003e If you have advanced biliary tract cancer, ask about your tumor's molecular profile (including VEGF status and other actionable alterations such as IDH1 mutation, FGFR2 fusion, NTRK fusion, BRAF V600E mutation, HER2 amplification, and RET fusion), as targeted therapies are approved for selected patients in later lines of treatment.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eConsider clinical trials:\u003c\/strong\u003e Given the ongoing need for better treatments, participation in a clinical trial may offer access to promising experimental therapies.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003ePatients should discuss all treatment options with their oncology team, including expected benefits, side effects, and quality-of-life considerations.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is advanced biliary tract cancer?\u003c\/h3\u003e\n\u003cp\u003eBiliary tract cancer is a group of invasive cancers that start in the bile ducts and gallbladder. It includes intrahepatic cholangiocarcinoma inside the liver, extrahepatic cholangiocarcinoma in the ducts outside the liver, and gallbladder cancer. These cancers are often diagnosed at an advanced, inoperable stage, which limits treatment options and leads to poor outcomes.\u003c\/p\u003e\n\u003ch3\u003eWhat is the current standard first-line treatment for advanced biliary tract cancer?\u003c\/h3\u003e\n\u003cp\u003eBased on the phase III TOPAZ-1 and KEYNOTE-966 trials, the standard first-line treatment for advanced biliary tract cancer is a PD-1 or PD-L1 inhibitor combined with cisplatin and gemcitabine chemotherapy. Adding bevacizumab to this regimen is not recommended for routine use because it did not improve overall survival in the IMbrave151 trial.\u003c\/p\u003e\n\u003ch3\u003eWhat does a hazard ratio of 0.67 for progression-free survival mean?\u003c\/h3\u003e\n\u003cp\u003eA hazard ratio of 0.67 means the risk of disease progression or death was about 33% lower in the bevacizumab arm compared to the placebo arm. In the IMbrave151 trial, this result was statistically significant because the upper bound of the confidence interval (0.95) fell below 1.0, indicating the benefit was unlikely due to chance.\u003c\/p\u003e\n\u003ch3\u003eDid adding bevacizumab improve overall survival in the IMbrave151 trial?\u003c\/h3\u003e\n\u003cp\u003eNo. In the IMbrave151 trial of 162 patients with previously untreated advanced biliary tract cancer, median overall survival was 14.9 months with bevacizumab versus 14.6 months with placebo. The hazard ratio was 0.97, crossing 1.0, which indicates no significant difference between the two treatment groups.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects occurred in the IMbrave151 trial?\u003c\/h3\u003e\n\u003cp\u003eGrade 3 or 4 adverse events occurred in 74% of patients in both treatment arms. Treatment with systemic corticosteroids for immune-related side effects was more common in the bevacizumab arm (16.7%) than in the placebo arm (4.9%). Overall, adding bevacizumab did not significantly increase the rate of serious side effects.\u003c\/p\u003e\n\u003ch3\u003eWhat did the biomarker analysis find about VEGFA?\u003c\/h3\u003e\n\u003cp\u003eIn an exploratory analysis of tumor samples from 95 patients, high VEGFA gene expression was associated with improved progression-free survival in the bevacizumab arm compared with placebo (hazard ratio 0.44). This finding suggests that patients whose tumors produce large amounts of VEGF may be most likely to benefit from bevacizumab, but it needs confirmation in larger studies.\u003c\/p\u003e\n\u003ch3\u003eShould I ask my oncologist about molecular testing for biliary tract cancer?\u003c\/h3\u003e\n\u003cp\u003eYes. The article recommends asking your oncologist about your tumor's molecular profile, including VEGF status and other actionable alterations such as IDH1 mutation, FGFR2 fusion, NTRK fusion, BRAF V600E mutation, HER2 amplification, and RET fusion. Targeted therapies are approved for selected patients with these alterations in later lines of treatment.\u003c\/p\u003e\n\u003ch3\u003eI have advanced biliary tract cancer and my oncologist wants to add bevacizumab to atezolizumab plus chemotherapy — should I get a second opinion before starting?\u003c\/h3\u003e\n\u003cp\u003eAdding bevacizumab to atezolizumab plus cisplatin and gemcitabine improved progression-free survival only modestly (8.3 vs 7.9 months) and produced no overall survival benefit (14.9 vs 14.6 months), with grade 3 or 4 side effects in 74% of patients in both arms. The trial authors concluded this triplet should not be routinely used, and standard first-line care remains a PD-1 or PD-L1 inhibitor plus cisplatin and gemcitabine. A second opinion can help confirm whether this regimen or a clinical trial is appropriate for you. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Teresa Macarulla, MD, PhD; Zhenggang Ren, MD, PhD; Hong Jae Chon, MD; Joon Oh Park, MD; Jin Won Kim, PhD; Tiziana Pressiani, MD; Daneng Li, MD; Lyudmila Zhukova, PhD; Andrew X. Zhu, MD, PhD; Ming-Huang Chen, MD, PhD; Stephen P. Hack, MD, PhD; Stephanie Wu, PharmD; Bo Liu, PhD; Xiangnan Guan, PhD; Shan Lu, MD; Yulei Wang, PhD; and Anthony B. El-Khoueiry, MD\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e Journal of Clinical Oncology, Volume 43, Issue 5, pages 545–557. Published online October 18, 2024. DOI: https:\/\/doi.org\/10.1200\/JCO.24.00337\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eStudy registration:\u003c\/strong\u003e ClinicalTrials.gov identifier NCT04677504\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding and disclosures:\u003c\/strong\u003e The study was published by the American Society of Clinical Oncology and made available under a Creative Commons Attribution Non-Commercial No-Derivatives 4.0 License. The trial was conducted by F. Hoffmann-La Roche\/Genentech.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace discussion with your healthcare provider. Always consult your oncology team about your individual treatment options.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47738962739356,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/sv\/products\/adding-bevacizumab-to-immunotherapy-and-chemotherapy-in-advanced-biliary-tract-cancer-results-from-the-imbrave151-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}