Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial.

BACKGROUND: Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival. METHODS: TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18-65 years, with Eastern Cooperative Oncology Group performance score 0-1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0-29·0) versus 17·0 cycles (12·0-24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6-10 ng/mL days 1-14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5-8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete. FINDINGS: Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0-59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4-60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2-74·1) for liver transplantation plus chemotherapy and 12·6% (5·2-30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21-0·65]; p=0·0003) and 73·3% (95% CI 59·6-90·0) and 9·3% (3·2-26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure. INTERPRETATION: In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases. FUNDING: French National Cancer Institute and Assistance Publique-Hôpitaux de Paris.

Oxaliplatin-induced peripheral neuropathy with hepatic arterial versus intravenous infusion in metastatic colorectal cancer.

BACKGROUND: Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far. METHODS: We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety. RESULTS: A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23). CONCLUSION: The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN.

A plain language summary of the results from the phase 2b HERIZON-BTC-01 study of zanidatamab in participants with HER2-amplified biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks. WHAT ARE THE KEY TAKEAWAYS?: In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%). WHAT ARE THE CONCLUSIONS REPORTED BY THE RESEARCHERS?: The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results.Clinical Trial Registration: NCT04466891 (HERIZON-BTC-01 study).

The HERIZON-BTC-01 study revealed zanidatamab as a potentially effective treatment for HER2-positive biliary tract cancer after standard chemotherapy fails. Read more in the lay summary by @hardingjjmd, @DrShubhamPant, and coauthors. #BiliaryTractCancer #HER2 #zanidatamab.

Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.

PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Clinical and molecular features of early onset pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

Safety and efficacy of percutaneous arterial port Implantation for Hepatic Arterial Infusion Chemotherapy.

OBJECTIVES: Approximately 40% of patients with colorectal cancer will develop liver metastases. Hepatic arterial infusion chemotherapy (HAIC) represents a valuable treatment option, with curative, palliative, or adjuvant intent. The aim of our study was to describe technical considerations, safety, and oncological outcomes of patients receiving HAIC. MATERIALS AND METHODS: All patients who underwent percutaneous hepatic arterial port placement in our institution between 2004 and 2021 were included in this retrospective analysis. Demographic, anatomical and technical data were collected. Tumor response was assessed using RECIST 1.1. Kaplan-Meier estimates were used for overall survival (OS) and hepatic progression-free survival (PFS). Adverse events (AEs) were graded using the Clavien-Dindo classification. RESULTS: A total of 360 patients (median age, 58.6 years [interquartile range (IQR): 49.5-65.4]; 208 men [57.8%]) were included. Percutaneous hepatic arterial port placement was successful in 87.9% of cases, resulting in 379 port placements (431 attempts). Overall, 394 HAIC courses were delivered, mostly oxaliplatin-based (94.7%), with a median of 6 cycles per course (IQR: 3-8). AEs (all grades) were observed in 42.0% of ports (grade IIIb-V: 1.1%). Most port dysfunctions could be resolved, resulting in a 73.1% rate of HAIC resumption, without impact on OS. Median OS was 22 months (IQR: 18-24), and median hepatic PFS was 11 months (IQR: 9.5-13). Tumor downstaging allowed surgery in 35.6% of patients, with significantly longer median OS than non-operated patients (39 months [IQR: 33-79] versus 14 months [IQR: 12-16], p < 0.001). CONCLUSION: This retrospective cohort study demonstrates the feasibility, safety, and efficacy of percutaneous hepatic arterial port placement with an impact on survival for selected patients. CLINICAL RELEVANCE STATEMENT: Percutaneous hepatic arterial port placement is feasible, safe and effective with an impact on the survival of selected patients. KEY POINTS: Hepatic arterial infusion chemotherapy provides promising tumor response and overall survival, especially in cases of resection/ablation. Total complication rate of hepatic arterial infusion chemotherapy port use is high, but serious complications are rare. Port revision is often necessary but allows the resumption of hepatic arterial infusion chemotherapy without affecting overall survival.

Role of molecular biology in the management of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in patient management due to a dismal prognosis, increasing incidence, and limited treatment options. In this regard, precision medicine, which personalizes treatments based on tumour molecular characteristics, has gained great interest. However, its widespread implementation is not fully endorsed in current recommendations. This review explores key molecular alterations in PDAC, while emphasizing differences between KRAS-mutated and KRAS-wild-type tumours. It assesses the practical application of precision medicine in clinical settings and outlines potential future directions with respect to PDAC. Actionable molecular targets are examined with the aim of enhancing our understanding of PDAC molecular biology. Insights from this analysis may contribute to a more refined and personalized approach to pancreatic cancer treatment, ultimately improving patient outcomes.

COLUMBIA-1: a randomised study of durvalumab plus oleclumab in combination with chemotherapy and bevacizumab in metastatic microsatellite-stable colorectal cancer.

BACKGROUND: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC). METHODS: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy. RESULTS: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm. CONCLUSION: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC. REGISTRATION: NCT04068610.

Organoids for Functional Precision Medicine in Advanced Pancreatic Cancer.

BACKGROUND & AIMS: Patient-derived organoids (PDOs) are promising tumor avatars that could enable ex vivo drug tests to personalize patients' treatments in the frame of functional precision oncology. However, clinical evidence remains scarce. This study aims to evaluate whether PDOs can be implemented in clinical practice to benefit patients with advanced refractory pancreatic ductal adenocarcinoma (PDAC). METHODS: During 2021 to 2022, 87 patients were prospectively enrolled in an institutional review board-approved protocol. Inclusion criteria were histologically confirmed PDAC with the tumor site accessible. A panel of 25 approved antitumor therapies (chemogram) was tested and compared to patient responses to assess PDO predictive values and map the drug sensitivity landscape in PDAC. RESULTS: Fifty-four PDOs were generated from 87 pretreated patients (take-on rate, 62%). The main PDO mutations were KRAS (96%), TP53 (88%), and CDKN2A/B (22%), with a 91% concordance rate with their tumor of origin. The mean turnaround time to chemogram was 6.8 weeks. In 91% of cases, ≥1 hit was identified (gemcitabine (n = 20 of 54), docetaxel (n = 18 of 54), and vinorelbine (n = 17 of 54), with a median of 3 hits/patient (range, 0-12). Our cohort included 34 evaluable patients with full clinical follow-up. We report a chemogram sensitivity of 83.3% and specificity of 92.9%. The overall response rate and progression-free survival were higher when patients received a hit treatment as compared to patients who received a nonhit drug (as part of routine management). Finally, we leveraged our PDO collection as a platform for drug validation and combo identification. We tested anti-KRASG12D (MRTX1133), alone or combined, and identified a specific synergy with anti-EGFR therapies in KRASG12D variants. CONCLUSIONS: We report the largest prospective study aiming at implementing PDO-based functional precision oncology and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. Although this remains to be confirmed in interventional precision oncology trials, PDO collection already provides powerful opportunities for drugs and combinatorial treatment development.

Safety and feasibility of chemotherapy followed by liver transplantation for patients with definitely unresectable colorectal liver metastases: insights from the TransMet randomised clinical trial.

Background: Despite the increasing efficacy of chemotherapy (C), the 5-year survival rate for patients with unresectable colorectal liver metastases (CLM) remains around 10%. Liver transplantation (LT) might offer a curative approach for patients with liver-only disease, yet its superior efficacy compared to C alone remains to be demonstrated. Methods: The TransMet randomised multicentre clinical trial (NCT02597348) compares the curative potential of C followed by LT versus C alone in patients with unresectable CLM despite stable or responding disease on C. Patient eligibility criteria proposed by local tumour boards had to be validated by an independent committee via monthly videoconferences. Outcomes reported here are from a non-specified interim analysis. These include the eligibility of patients to be transplanted for non resectable colorectal liver metastases, as well as the feasibility and the safety of liver transplantation in this indication. Findings: From February 2016 to July 2021, 94 (60%) of 157 patients from 20 centres in 3 countries submitted to the validation committee, were randomised. Reasons for ineligibility were mainly tumour progression in 50 (32%) or potential resectability in 13 (8%). The median delay to LT after randomisation was 51 (IQR 30-65) days. Nine of 47 patients (19%, 95% CI: 9-33) allocated to the LT arm failed to undergo transplantation because of intercurrent disease progression. Three of the 38 transplanted patients (8%) were re-transplanted, one of whom (3%) died post-operatively from multi-organ failure. Interpretation: The selection process of potential candidates for curative intent LT for unresectable CLM in the TransMet trial highlighted the critical role of an independent multidisciplinary validation committee. After stringent selection, the feasibility of LT was 81%, as 19% had disease progression while on the waiting list. These patients should be given high priority for organ allocation to avoid dropout from the transplant strategy. Funding: No source of support or funding from any author to disclose for this work. The trial was supported by the Assistance Publique - Hôpitaux de Paris (AP-HP).

Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Molecular profiling of biliary tract cancers reveals distinct genomic landscapes between circulating and tissue tumor DNA.

Biliary tract cancers (BTCs) are heterogeneous malignancies with dismal prognosis due to tumor aggressiveness and poor response to limited current therapeutic options. Tumor exome profiling has allowed to successfully establish targeted therapeutic strategies in the clinical management of cholangiocarcinoma (CCA). Still, whether liquid biopsy profiling could inform on BTC biology and patient management is unknown. In order to test this and generate novel insight into BTC biology, we analyzed the molecular landscape of 128 CCA patients, using a 394-gene NGS panel (Foundation Medicine). Among them, 32 patients had matched circulating tumor (ct) DNA and tumor DNA samples, where both samples were profiled. In both tumor and liquid biopsies, we identified an increased frequency of alterations in genes involved in genome integrity or chromatin remodeling, including ARID1A (15%), PBRM1 (9%), and BAP1 (14%), which were validated using an in-house-developed immunohistochemistry panel. ctDNA and tumor DNA showed variable concordance, with a significant correlation in the total number of detected variants, but some heterogeneity in the detection of actionable mutations. FGFR2 mutations were more frequently identified in liquid biopsies, whereas KRAS alterations were mostly found in tumors. All IDH1 mutations detected in tumor DNA were also identified in liquid biopsies. These findings provide novel insights in the concordance between the tumor and liquid biopsies genomic landscape in a large cohort of patients with BTC and highlight the complementarity of both analyses when guiding therapeutic prescription.

Precision medicine for KRAS wild-type pancreatic adenocarcinomas.

BACKGROUND: KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRASWT). METHODS: A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy). RESULTS: 342 patients were included with 54 KRASWT PDAC (16%) compared to 288 patients with KRASm PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRASWT patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRASm patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRASWT (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRASWT group compared to KRASm (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9-23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRASWT. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRASWT pts and 46 (16%) KRASm patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRASWT harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRASWT patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRASm patients. CONCLUSIONS: KRASWT patients display distinct disease characteristics and outcomes with prolonged overall survival. KRASWT patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial.

BACKGROUND: The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. METHODS: In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). RESULTS: 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death. CONCLUSION: HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Albumin-Bilirubin Grade Analyses of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma: A Post Hoc Analysis of the Phase III IMbrave150 Study.

Introduction: Atezolizumab + bevacizumab showed survival benefit in patients with unresectable hepatocellular carcinoma (HCC) versus sorafenib in the Phase III IMbrave150 study. This exploratory analysis examined the prognostic impact of a baseline albumin-bilirubin (ALBI) score. Methods: Patients with treatment-naïve unresectable HCC, ≥1 measurable untreated lesion, and Child-Pugh class A liver function were randomized 2:1 to receive atezolizumab 1,200 mg + bevacizumab 15 mg/kg every 3 weeks or sorafenib 400 mg twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed in the intention-to-treat population by ALBI/modified (m)ALBI grade. Time to deterioration (TTD; defined as time to 0.5-point increase from the baseline ALBI score over 2 visits or death) of liver function and safety were investigated. Results: Of 501 enrolled patients, 336 were randomized to receive atezolizumab + bevacizumab (ALBI grade [G] 1: n = 191; G2: n = 144 [mALBI G2a: n = 72, G2b: n = 72]; missing ALBI grade: n = 1) and 165 to sorafenib (ALBI G1: n = 87; G2: n = 78 [mALBI G2a: n = 37; G2b: n = 41]). Median follow-up was 15.6 months. OS and PFS improved with atezolizumab + bevacizumab versus sorafenib in patients with ALBI G1 (OS HR: 0.50 [95% CI: 0.35, 0.72]; PFS HR: 0.61 [95% CI: 0.45, 0.82]). In patients with ALBI G2 or mALBI G2a or G2b, PFS was numerically longer with atezolizumab + bevacizumab versus sorafenib, but no OS benefit was seen. Median TTD in the intention-to-treat population was 10.2 months (95% CI: 8.0, 11.0) with atezolizumab + bevacizumab versus 8.6 months (95% CI: 6.2, 11.8) with sorafenib (HR: 0.82 [95% CI: 0.65, 1.03]). Safety profiles of atezolizumab and bevacizumab were consistent with previous analyses, regardless of ALBI grade. Conclusion: ALBI grade appeared to be prognostic for outcomes with both atezolizumab + bevacizumab and sorafenib treatment in patients with HCC. Atezolizumab + bevacizumab preserved liver function for a numerically longer duration than sorafenib.

EORTC 1409 GITCG/ESSO 01 - A prospective colorectal liver metastasis database for borderline or initially unresectable diseases (CLIMB): Lessons learnt from real life. From paradigm to unmet need.

AIM: Multidisciplinary management of metastatic colorectal liver metastases (CRLM) is still challenging. To assess postoperative complications in initially unresectable or borderline resectable CRLM, the prospective EORTC-1409 ESSO 01-CLIMB trial capturing 'real-life data' of European centres specialized in liver surgery was initiated. MATERIAL AND METHODS: A total of 219 patients were registered between May 2015 and January 2019 from 15 centres in nine countries. Eligible patients had borderline or initially unresectable CRLM assessed by pre-operative multidisciplinary team discussion (MDT). Primary endpoints were postoperative complications, 30-day and 90-days mortality post-surgery, and quality indicators. We report the final results of the 151 eligible patients that underwent at least one liver surgery. RESULTS: Perioperative chemotherapy with or without targeted treatment were administered in 100 patients (69.4%). One stage resection (OSR) was performed in 119 patients (78.8%). Two stage resections (TSR, incl. Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS)) were completed in 24 out of 32 patients (75%). Postoperative complications were reported in 55.5% (95% CI: 46.1-64.6%), 64.0% (95% CI: 42.5-82%), and 100% (95% CI: 59-100%) of the patients in OSR, TSR and ALPPS, respectively. Post-hepatectomy liver failure occurred in 6.7%, 20.0%, and 28.6% in OSR, TSR, and ALPPS, respectively. In total, four patients (2.6%) died after surgery. CONCLUSION: Across nine countries, OSR was more often performed than TSR and tended to result in less postoperative complications. Despite many efforts to register patients across Europe, it is still challenging to set up a prospective CRLM database.

Implementing patient derived organoids in functional precision medicine for patients with advanced colorectal cancer.

BACKGROUND: Patient Derived Organoids (PDOs) emerged as the best technology to develop ex vivo tumor avatars. Whether drug testing on PDOs to identify efficient therapies will bring clinical utility by improving patient survival remains unclear. To test this hypothesis in the frame of clinical trials, PDO technology faces three main challenges to be implemented in routine clinical practices: i) generating PDOs with a limited amount of tumor material; ii) testing a wide panel of anti-cancer drugs; and iii) obtaining results within a time frame compatible with patient disease management. We aimed to address these challenges in a prospective study in patients with colorectal cancer (CRC). METHODS: Fresh surgical or core needle biopsies were obtained from patients with CRC. PDOs were established and challenged with a panel of 25 FDA-approved anti-cancer drugs (chemotherapies and targeted therapies) to establish a scoring method ('chemogram') identifying in vitro responders. The results were analyzed at the scale of the cohort and individual patients when the follow-up data were available. RESULTS: A total of 25 PDOs were successfully established, harboring 94% concordance with the genomic profile of the tumor they were derived from. The take-on rate for PDOs derived from core needle biopsies was 61.5%. A chemogram was obtained with a 6-week median turnaround time (range, 4-10 weeks). At least one hit (mean 6.16) was identified for 92% of the PDOs. The number of hits was inversely correlated to disease metastatic dissemination and the number of lines of treatment the patient received. The chemograms were compared to clinical data obtained from 8 patients and proved to be predictive of their response with 75% sensitivity and specificity. CONCLUSIONS: We show that PDO-based drug tests can be achieved in the frame of routine clinical practice. The chemogram could provide clinicians with a decision-making tool to tailor patient treatment. Thus, PDO-based functional precision oncology should now be tested in interventional trials assessing its clinical utility for patients who do not harbor activable genomic alterations or have developed resistance to standard of care treatments.

Primary Colorectal Tumor Displays Differential Genomic Expression Profiles Associated with Hepatic and Peritoneal Metastases.

BACKGROUND: Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes. METHODS: Primary tumor specimens obtained from CRC patients with either isolated LM (CRC-Liver) or PM (CRC-Peritoneum) were analyzed by transcriptomic mRNA sequencing, gene set enrichment analyses (GSEA) and immunohistochemistry. We further assessed the clinico-pathological associations and prognostic value of our signature in the COAD-TCGA independent cohort. RESULTS: We identified a significantly different distribution of Consensus Molecular Subtypes between CRC-Liver and CRC-peritoneum groups. A transcriptomic signature based on 61 genes discriminated between liver and peritoneal metastatic routes. GSEA showed a higher expression of immune response and epithelial invasion pathways in CRC-Peritoneum samples and activation of proliferation and metabolic pathways in CRC-Liver samples. The biological relevance of RNA-Seq results was validated by the immunohistochemical expression of three significantly differentially expressed genes (ACE2, CLDN18 and DUSP4) in our signature. In silico analysis of the COAD-TCGA showed that the CRC-Peritoneum signature was associated with negative prognostic factors and poor overall and disease-free survivals. CONCLUSIONS: CRC primary tumors spreading to the liver and peritoneum display significantly different transcriptomic profiles. The implementation of this signature in clinical practice could contribute to identify new therapeutic targets for stage IV CRC and to define individualized follow-up programs in stage II-III CRC.