bluuebunny/crossref_metadata_2025 huggingface dataset:
Associating liver partition and portal vein ligation for staged hepatectomy versus portal vein embolization in staged hepatectomy for hepatocellular carcinoma: A randomized comparative study.
Authors: Huang Gang
Published: May 2020

4578

Background: Both Portal Vein Embolization (PVE) and Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) have been used in patients with unresectable hepatocellular carcinoma (HCC) due to insufficient volumes in future liver remnant (FLR). But it remains unclear for which thetapy has better long-term overall survival. Methods: This study was a single-center, prospective randomized comparative study. Patients were randomly assigned in a 1:1 ratio to the 2 groups. The primary endpoints was three-year overall survival rates. Results: Between November 2014 to June 2016, 76 patients with unresectable HCC due to inadequate volume of FLR were randomly assigned to ALPPS groups (n = 38) and PVE groups (n = 38). Thirty-seven patients (97.4%) in the ALPPS Group compared with 25 patients (65.8%) in the PVE Group were able to undergo staged hepatectomy (risk ratio 1.48, 95% CI 1.17-1.87, p < 0.001). The three-year overall survival (OS) rate of the ALPPS group (65.8%) (95% CI 50.7-80.9) was significantly better than the PVE Group (42.1%) (95% CI 26.4-57.8), (HR 0.50, 95% CI 0.26-0.98, two-sided p = 0.036). Major postoperative complications rates after the stage-2 hepatectomy were 54.1% in the ALPPS group and 20.0% in the PVE group ((risk ratio 2.70, 95% CI 1.17-6.25, p = 0.007). Conclusions: ALPPS resulted in significantly better long-term overall survival outcomes, at the expenses of a significantly higher perioperative morbidity rate compared with PVE in patients who had initially unresectable HCC. Clinical trial information: ChiCTR-IOC-14005646 .
A randomized phase II feasibility study of individualized stereotactic body radiation therapy (SBRT) versus transarterial chemoembolization (TACE) with DEBDOX beads as a bridge to transplant in hepatocellular carcinoma (HCC).
Authors: Nugent Francis W. , Hunter Klaudia , Molgaard Chris , Qamar Amir , Gunturu Krishna , Stuart Keith E. , Gordon Frederic , Flacke Sebastian
Published: May 2020

4586

Background: For HCC pts undergoing LT, loco-regional treatment as a "bridge" is standard. The best bridging modality is unclear. SBRT is safe and effective when used in pts with advanced HCC. We prospectively compared SBRT to TACE as a bridge for HCC pts undergoing LT. Methods: From 9/2014-10/2019, 60 pts within Milan Criteria with CTP Class A/B8 cirrhosis were consented. 54 pts were randomized to TACE vs. SBRT. TACE pts (n =30) were scheduled to receive 2 treatments one month apart utilizing DEBDOX beads. TACE pts were hospitalized after each TACE. Pts receiving SBRT (n =24) received a median total dose of 45Gy delivered over 5 fractions using fiducials. Mean liver dose, Veff, and NTCP determined prescription dose. Pts were assessed by using mRECIST criteria at 2 months and every 3 months thereafter until LT or death. Toxicity and QOL were assessed before treatment, during treatment, two weeks post-treatment, and then every three months using the PIQ-6 Pain Impact Questionnaire and the SF-36v2 Health Survey. The 1° endpoint was time to recurrent or residual dz. Secondary endpoints were toxicity, pathologic response, radiologic response, number of subsequent treatments, cost, and QOL. 50 pts are evaluable for review. Results: See table. Conclusions: For early stage HCC patients with CTP Class A/B liver cirrhosis, SBRT appears as effective as TACE at controlling HCC prior to LT, may engender less toxicity, and eliminates the need for hospitalization. A larger multi-center trial is ongoing. Clinical trial information: NCT02182687. [Table: see text]
Effect of pembrolizumab (pembro) on hepatitis B viral (HBV) load and aminotransferase (ALT) levels in patients (pts) with advanced hepatocellular carcinoma (aHCC) in KEYNOTE-224 and KEYNOTE-240.
Authors: Chan Stephen Lam , Zhu Andrew X. , Finn Richard S. , Edeline Julien , Ogasawara Sadahisa , Knox Jennifer J. , Daniele Bruno , Ryoo Baek-Yeol , Merle Philippe , Bouattour Mohamed , Lim Ho-Yeong , Chao Yee , Yau Thomas , Haber Barbara Anne , Malhotra Usha , Liu Chih-Chin , Kudo Masatoshi , Cheng Ann-Lii
Published: May 2020

4587

Background: The effect of PD-1 inhibition on HBV infection is unclear, and pts with HBV are often excluded from trials. This analysis evaluated HBV viral load and liver function (ALT levels) in pts with HBV infection in 2 trials of pembro: KEYNOTE-224 and KEYNOTE-240. Methods: Eligible pts with aHCC post first-line sorafenib and controlled HBV received pembro 200 mg IV Q3W until progression. Pts with active HBV (HBsAg positive and/or HBV DNA detectable) and inactive HBV (anti-HBc positive, HBsAg negative, and HBV DNA not detectable) at baseline (BL) were included. Results: Of 104 pts in KEYNOTE-224 and 413 pts in KEYNOTE-240, 8 (7.7%) and 101 (24.5%) had active HBV and 13 (12.5%) and 102 (24.7%) had inactive HBV, respectively. All pts with HBV received nucleos(t)ide analogs. In KEYNOTE-240, 2 (2.8%) pts with active HBV in the pembro arm and 1 (3.4%) in placebo (pbo) had a > 1 log increase (incr) of HBV DNA and 1000 IU/mL over BL; none in the pembro arm were associated with ALT elevation. No pts with inactive HBV in KEYNOTE-240 and no pts in KEYNOTE-224 had a > 1 log incr and 1000 IU/mL over BL. No pts in KEYNOTE-224 and 28 (38.9%) with active HBV and 1 (1.4%) with inactive HBV in the pembro arm, and 8 (27.6%) with active HBV and 0 with inactive HBV in the pbo arm in KEYNOTE-240 had a > 1 log decrease (decr) in HBV DNA. Conclusions: Few pts with aHCC and HBV had viral load incr with pembro. In KEYNOTE-240 no clinically meaningful differences between pembro and pbo were observed. ALT elevation was not associated with viral load incr with pembro. These data suggest that pembro is unlikely to significantly affect underlying HBV infection in pts with aHCC receiving HBV antiviral therapy. Clinical trial information: KEYNOTE-224, NCT02702414; KEYNOTE-240, NCT02702401 . [Table: see text]
Comprehensive gene expression analysis of IDH1/2 mutant biliary cancers (BC).
Authors: Battaglin Francesca , Xiu Joanne , Baca Yasmine , Zeng Jia , Shields Anthony Frank , Goldberg Richard M. , Seeber Andreas , Habib Diane , Puccini Alberto , Tokunaga Ryuma , Arai Hiroyuki , Wang Jingyuan , Berger Martin D. , Astsaturov Igor A. , Lockhart Albert Craig , Zhang Wu , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef , El-Khoueiry Anthony B.
Published: May 2020

4598

Background: Isocitrate dehydrogenases (IDH) mutations (mut) identify a distinct subtype of BC that has yet to be fully characterized. We recently showed that IDH1/2 mutant (mIDH) BC harbor specific gene alterations involving chromatin remodeling and DNA repair, and a differential immune markers profile compared to other mIDH GI tumors. Here we aim to further dissect the molecular profile of mIDH BC through a comprehensive gene expression profiling analysis. Methods: 524 BC samples (303 intrahepatic cholangiocarcinoma, IHCC, 67 extrahepatic cholangiocarcinoma, EHCC, 141 gallbladder, 13 unspecified) collected between February to December of 2019 were included. Samples were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel), whole transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). EBseq was used to identify differentially expressed genes in mIDH vs wild type (WT) tumors with control for FDR ( Q < 0.2). Pathway and functional enrichment analysis was performed using g:Profiler and Enrichr. Results: mIDH frequency in our cohort was 11.4% (60/524), with higher prevalence of IDH1 mut (8.8%). IHCC showed the highest mut prevalence: IDH1 13.5%, IDH2 4.6%. mIDH was more common in females ( P = 0.0036). A total of 774 genes were significantly differentially expressed between mIDH and WT: 582 underexpressed (Fold change, FC: 0.025~0.699); 192 overexpressed (FC: 1.43~3.3). Pathway enrichment showed a significant decrease of gene expression in cytokine-cytokine receptor interaction ( Q = 0.002) and inflammatory response genes ( Q = 0.005) in mIDH. Interferon-γ- and PD1 signaling-related genes expression was significantly lower in mIDH vs WT ( Q = 0.02) including IFNG (FC 0.32), NKG7 (FC 0.36), CD8B (FC 0.37), BATF (FC 0.40), PD1 (FC 0.53), SLAMF6 (FC 0.55) and PD-L2 (FC 0.60). Wnt and cadherin signaling were also enriched for altered expression in several genes in mIDH BC ( Q = 3.86e-7 and < 0.00001, respectively). Conclusions: To our knowledge, this is the largest and most extensive gene expression profiling study focused on mIDH BC. Our data show for the first time a distinct gene expression profile characterizing mIDH tumors which display significant downregulation of inflammatory response pathways and immune-related genes. These findings contribute to further the understanding of mIDH BC and may inform the future development of rational combination therapies.
Final results of a randomized, open label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Kaseb Ahmed Omar , Tran Cao Hop Sanderson , Mohamed Yehia I. , Qayyum Aliya , Vence Luis M. , Blando Jorge M. , Singh Shalini , Lee Sunyoung S. , Raghav Kanwal Pratap Singh , Altameemi Lina , Rashid Asif , Vauthey Jean-Nicolas , Carter Kristen , Tzeng Ching-Wei David , Chun Yun Shin , Yao James C. , Wolff Robert A. , Allison James Patrick , Sharma Padmanee ,   Kaseb's
Published: May 2020

4599

Background: In resectable hepatocellular carcinoma (HCC) surgical resection is associated with high recurrence rates. However, there is no approved neoadjuvant or adjuvant therapies yet. Neoadjuvant immunotherapy effect has never been reported in this setting in HCC. Methods: This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pts) with HCC who are eligible for surgical resection. Pts in Arm A are given nivolumab 240 mg iv, every 2 weeks (wks) for a total of 3 doses followed by surgery on week 6. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg on day 1. Adjuvant part of study starts 4 weeks after surgery, with Nivolumab at 480 mg iv every 4 weeks for 2 years in arm A. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg every 6 weeks times 4 doses after resection. The primary objective was the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, pathologic complete response (pCR) rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 30 patients were enrolled, 2 patients withdrew consent, one patient was not eligible at time of therapy, and 27 randomized (13 to Arm A and 14 to Arm B). 21 patients proceeded with resection as planned and surgery was aborted for 6 patients; 1 for frozen abdomen due to old surgery, 2 for small residual volume, and 3 for progressive disease. Pts age ranged between 32-83 yo, 75 % were males, 7 pts had HCV, 7 had HBV and 7 had no hepatitis. Pathologic complete response (pCR) was observed in 5/21 pts (24% pCR rate) – 2 in Arm A and 3 Arm B, and 3/21 pts (16%) – 1 in Arm A, 2 in Arm B, achieved major pathologic response (necrosis effect of 50-99%). 5 patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed and surgery was not delayed or cancelled due to oxicity. Conclusions: Our study reached its primary endpoint of safety. Importantly, we report a 40% pathologic response rate = pCR rate of 24%, and major necrosis rate of 16% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. After future validation, these promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC. Clinical trial information: NCT03222076 .
Risk of cancer-specific death for patients diagnosed with neuroendocrine tumors: A population-based analysis.
Authors: Hallet Julie , Law Calvin , Singh Simron , Mahar Alyson , Myrehaug Sten , Zuk Victoria , Zhao Haoyu , Assal Angela , Coburn Natalie
Published: May 2020

4605

Background: While patients with neuroendocrine tumours (NETs) are known to experience prolonged overall survival, the contribution of cancer-specific and non-cancer deaths is undefined. We examined cancer-specific and non-cancer death after NET diagnosis. Methods: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001-2015 by linking administrative healthcare datasets. Using competing-risks methods, we estimated the cumulative incidence of cancer-specific and non-cancer death and stratified by primary NET site and metastatic status. Sub-distribution hazard models examined prognostic factors. Results: Among 8,607 included patients, median follow-up was 42 months (interquartile range: 17-82). The risk of cancer-specific was higher than that of non-cancer death, with 27.3% (95%CI: 26.3-28.4%) and 5.6% (95%CI: 5.1-6.1%) at 5 years. Cancer-specific deaths largely exceeded non-cancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumour site, with highest risks of cancer-specific death in broncho-pulmonary and pancreatic NETs. For non-metastatic gastric, small intestine, colonic, and rectal NETs, the risk of non-cancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. Conclusions: Among all NETs, the risk of dying from cancer is higher than that of dying from other causes. Heterogeneity exists by primary NET site. Some patients with non-metastatic NETs are more likely to die from non-cancer than from cancer causes. This information is important for counselling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.
Correlation of DLL3 expression in gastroenteropancreatic neuroendocrine neoplasms with loss of RB1 and prognostic significance.
Authors: Liverani Chiara , Bongiovanni Alberto , Mercatali Laura , Pieri Federica , Spadazzi Chiara , Miserocchi Giacomo , Di Menna Giandomenico , Foca Flavia , Ravaioli Sara , De Vita Alessandro , Cocchi Claudia , Recine Federica , Ibrahim Toni
Published: May 2020

4611

Background: Neuroendocrine neoplasms (NENs) are a rare subgroup of tumors with challenging management due to their unpredictable and heterogeneous behaviour. The identification of clinically useful biomarkers is a top priority need in this disease. The negative notch regulator DLL3 has gained increasing attention in small cell lung carcinoma, large cell neuroendocrine carcinoma and neuroendocrine prostate cancer, confirming the tumor suppressor function of Notch-1 signaling in neuroendocrine cells. Methods: A retrospective immunohistochemical analysis of DLL3, PD-L1 and RB1 was performed on FFPE samples from 43 patients with gastroenteropancreatic (GEP)-NENs and correlated with clinical characteristics. Results: DLL3 was expressed in high-grade (G3) GEP-NENs. The presence of DLL3 was significantly associated with poorly differentiated NEC (77.8% positive tumors), while none of the patients with well-differentiated NET expressed this marker. Expression of DLL3 was correlated with loss of RB1 and negative 68Ga-PET/CT scan. The 85.7% of DLL3- positive tumors showed loss of RB1 expression, while only 1 out of 35 DLL3- negative tumors had RB1 loss. DLL3 was expressed in 75% of patients with negative 68Ga-PET/CT, while only in 25% of patients with positive 68Ga-PET/CT scan. The presence of DLL3 was negatively associated with PFS and OS. Median PFS was 41.9 months in DLL3-negative patients versus 7.9 months in DLL3-positive patients; median OS was 72.9 months in DLL3-negative patients versus 11.7 months in DLL3-positive patients. No correlation was found with DLL3 and PD-L1 expression. The presence of PD-L1 was not associated with any clinical characteristics. Conclusions: DLL3 is expressed in high grade GEP-NENs and is associated with loss of RB1, negative 68Ga-PET/CT scan and unfavourable clinical outcome. The presence of DLL3 discriminates poorly differentiated NEC from well-differentiated NET. DLL3 could represent the ideal prognostic factor to stratify patients with GEP-NENs and a candidate therapeutic target in NEC patients.
Inefficacy of chromogranin a assays as neuroendocrine tumor diagnostic tools compared to the NETest.
Authors: Malczewska Anna , Kidd Mark S. , Kitz Alexandra , Kos-Kudla Beata , Modlin Irvin Mark
Published: May 2020

4612

Background: Chromogranin A (CgA) remains a commonly used diagnostic and monitoring tool for neuroendocrine tumor disease despite NCCN guidelines identifying it as a category 3 (major concerns about utility) biomarker. Several commercial assays have been developed to measure this protein (or its fragments) and are available both at CLIA-certified laboratories (USA) as well as in NET Centres of Excellence (CoEs - Europe). CgA is typically reimbursed by insurance companies and appears in several guidelines (e.g., ENETS). We sought to directly evaluate the accuracy of detecting NET disease using two different CgA assays, one in the USA (NEOLISA, EuroDiagnostica, IBL-America, CLIA-certified laboratory) and one in an ENETS CoE (CgA ELISA, Demeditec Diagnostics, Germany). We compared the results to the NETest, a circulating mRNA assay, recently validated as an IVD for NETs. Methods: Patients: NETs ( n=258) including lung: n=43; duodenum n=9; gastric: n=44; pancreas: n=67; small bowel: n=40; appendix: n=10; rectum: n=45. No image-evidence of disease ( n=122) (IND) and image-positive disease (IPD) ( n=136). CgA assays (plasma): NEOLISA, ULN >108ng/ml, DD: ULN>99ng/ml. Data mean±SEM. NETest (whole blood): qRT-PCR - multianalyte algorithmic analyses, CLIA-laboratory. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation & McNemar-test. Results: In the entire group ( n=258), NEOLISA assay CgA levels were significantly ( p<0.0001) higher (216±91ng/ml) vs. the DD-assay (76±8ng/ml). The assays exhibited a high concordance in output (Pearson r=0.81, p<0.0001), but there were 10.9% ( n=31) discordant results. This reflected the NEOLISA assay detecting more CgA-positive samples. IPD group: CgA-positives were detected in 48/136 (35%, NEOLISA) vs. 28 (21%, DD-assay). McNemar’s Chi2=15.04, p<0.001 OR: 11.0, indicating the NEOLISA was significantly better than the DD-assay. The NETest, in contrast, was positive in 135/136 (99%; OR: 87-106, p<0.0001). IND group: CgA-positives were detected in 12/122 (10%, NEOLISA) vs. 9 (7%, DD-assay; p=NS). The majority (75%) of positives were associated with gastric NETs. The NETest was positive in 7 (6%); 4 were gastric NETs and 3 exhibited elevated CgA. Conclusions: Two standard CgA assays used for NET management (one accepted by Medicare in the USA, the second used at a CoE in Europe) only detect NET disease in 21-35% of cases. In contrast, a circulating mRNA fingerprint, the NETest, is ~99% accurate for detecting NET disease.
POLO: Quality-adjusted (QA) progression-free survival (PFS) and patient (pt)-centered outcomes with maintenance olaparib in pts with metastatic pancreatic cancer (mPaC).
Authors: Yoo Hyun Kyoo , Kindler Hedy L. , McCutcheon Susan , McGuinness David , Patel Nikunj , Hettle Robert , Goodbody Rory , Joo Seongjung , Locker Gershon Y. , Golan Talia
Published: May 2020

4626

Background: In the Phase III POLO trial (NCT02184195), maintenance olaparib significantly prolonged PFS vs placebo in pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPaC (median 7.4 vs. 3.8 months). The aim of maintenance treatment is to extend PFS and survival without compromising health-related quality of life due to adverse events. The duration of time spent without symptoms or toxicities (TWiST) and the QA-PFS were assessed in a post hoc analysis of the POLO trial. Methods: Patients were randomized 3:2 to receive maintenance olaparib (tablets; 300 mg bid) or placebo. Restricted mean (RM)-PFS was calculated by estimating the area under the Kaplan–Meier PFS curve between randomization and 29.8 months after randomization (maximum follow-up for the placebo arm in POLO). Patient-centered outcomes were assessed by QA-PFS (derived from the product of the EQ-5D-5L single-index utility score from randomization to disease progression and RM-PFS) and TWiST (RM-PFS minus time with toxicity after randomization). Results: RM-PFS was significantly longer with olaparib, with a between-treatment difference of 4.8 months ( P=0.009; Table). Over this period, no significant or meaningful differences in mean EQ-5D-5L index were observed between treatment groups. The corresponding mean QA-PFS was significantly longer with olaparib vs placebo. TWiST analysis demonstrated a benefit with olaparib over placebo (Table): between-arm difference, 3.8 months ( P=0.039) for the primary analysis (criteria 1: grade ≥2 nausea, vomiting or fatigue). Sensitivity analysis (criteria 1 plus abdominal pain, diarrhea, decreased appetite or constipation) also revealed a trend toward benefit with olaparib (difference: 3.4 months, P=0.062). Conclusions: Consistent with the primary PFS analysis of the POLO trial, RM-PFS and QA-PFS were significantly longer with maintenance olaparib than with placebo. As demonstrated by the findings of the TWiST analyses, the PFS benefit observed with olaparib in pts with a gBRCAm and mPaC persists even when symptoms of toxicity are considered. Clinical trial information: NCT02184195 . [Table: see text]
FOLFIRINOX de-escalation in advanced pancreatic cancer (aPC): A multicenter real-life study.
Authors: Chevalier Hortense , Vienot Angélique , Lièvre Astrid , Edeline Julien , El Hajbi Farid , Peugniez Charlotte , Vernerey Dewi , Meurisse Aurelia , Hammel Pascal , Neuzillet Cindy , Borg Christophe , Turpin Anthony
Published: May 2020

4639

Background: FOLFIRINOX (5FU, irinotecan, and oxaliplatin) is a reference first line (L1) of chemotherapy (CT) in fit patients (Pts) with advanced pancreatic cancer (aPC). Limiting toxicities (in particular, neuropathy) are frequent and maintaining quality of life without a lack of efficacy is a crucial need. Modalities and efficacy of maintenance strategy in aPC remain scarcely studied. Our study describes the French practices of a FOLFIRINOX de-escalation and maintenance in a real-life multicentric cohort. Methods: We performed a retrospective multicentric study in 5 French centers. Pts receiving FOLFIRINOX L1 for aPC were recruited between January 2011 and December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan in patients without tumor progression, after at least 4 cycles of FOLFIRINOX. Maintenance schedules were oral capecitabine or intravenous (IV) 5FU, FOLFOX or FOLFIRI. Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1) and, in case of reintroduction of FOLFIRINOX, second progression free survival (PFS2). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 321 patients included, 147 (46%) received a maintenance therapy. Median age was 60.0 (53-66), 35 (24%) had locally advanced PC and 91 (62%) had metastatic PC. The median number of cycles of FOLFIRINOX was 9.0 (6.0-11.0). Median OS was 16.1 months (95%CI=13.7-20.3). Median PFS1 was 9.4 months (95%CI=8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%), vs fluoropyrimidine (FP) in 52 (35%) and FOLFOX in 25 (17%). Among 118 Pts who received a maintenance CT with FP or FOLFIRI, there was no difference in PFS1 (median: 10.1 vs 9.0, respectively, p=0.33) or OS (median: 16.6 versus 18.7, p=0.86) between the 2 maintenance regimens. After progression under maintenance CT with FOLFIRI or FP, reintroduction of FOLFIRINOX was performed in 20.2% of Pts, with a median PFS2 of 2.8 months (95%CI=2.0-22.3). The rates of G3-4 toxicity were significantly higher during FOLFIRI maintenance CT than with FP (41% vs 22%, p=0.03), especially neuropathy (73% vs 9%). Conclusions: FOLFIRINOX de-escalation in aPC is largely used in France. Fluoropyrimidine maintenance chemotherapy appears to be as effective as FOLFIRI.
Ramucirumab in patients with advanced HCC and elevated alpha-fetoprotein (AFP): Outcomes by treatment-emergent ascites.
Authors: Zhu Andrew X. , Ikeda Masafumi , Galle Peter R. , Yamashita Tatsuya , Llovet Josep , Liang Kun , Wang Chunxiao , Sakaguchi Sachi , Abada Paolo , Widau Ryan C , Kudo Masatoshi
Published: May 2020

4644

Background: REACH and REACH-2 investigated ramucirumab (RAM) vs placebo (PL) in patients (pts) with advanced HCC following sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. Ascites is common in HCC and associated with poorer outcomes. An exploratory analysis of outcomes by treatment-emergent (TE)-ascites was done. Methods: Pts with HCC, Child-Pugh A, ECOG PS ≤1, prior sorafenib, and no clinically meaningful ascites were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or PL Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was done. OS and PFS were evaluated by Kaplan-Meier estimator and Cox models. Prognosis of TE-ascites in OS was evaluated by multivariate Cox models (adjusted for baseline ECOG PS, AFP, macrovascular invasion (MVI), and treatment [trt]). Results: Baseline characteristics were generally balanced between TE-ascites and non-ascites pts; however, more pts with ascites had MVI at baseline. Any-grade ascites was reported at a higher rate in RAM than PL (66 [21%] vs 33 [15%] pts, respectively), with most being low grade. Rate of Gr ≥3 ascites was similar between arms (15 [5%] vs 9 [4%] pts). Median time to onset (43 vs 47 days) and median duration of ascites (13 vs 18 days) were similar in RAM vs PL, with furosemide (22%) and spironolactone (19%) as most common trt and paracentesis (18%) as most common procedure for ascites in both arms. Ascites trended as a prognostic factor for OS after adjustment (with vs without; HR=1.3, 95% CI: 0.99, 1.62). Ascites was more commonly linked with hypoalbuminemia (odds ratio 4.9, 95% CI: 2.5, 9.3), but was not associated with proteinuria or hypertension. TEAEs occurred more frequently in pts with ascites in both arms. The most frequent Gr ≥3 TEAE in pts with ascites was hypertension. One RAM pt discontinued trt due to ascites. RAM trt was beneficial irrespective of presence of ascites (Table), and pts with ascites received more post-discontinuation therapy on RAM than PL (18% vs 6%). Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit in pts who did or did not experience TE-ascites. RAM was well tolerated and no new safety findings were observed. Clinical trial information: NCT011400347; NCT02435433 . [Table: see text]
SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).
Authors: Choueiri Toni K. , Heng Daniel Yick Chin , Lee Jae-Lyun , Cancel Mathilde , Verheijen Remy B , Mellemgaard Anders , Ottesen Lone , Frigault Melanie M. , L'Hernault Anne , Szijgyarto Zsolt , Signoretti Sabina , Albiges Laurence
Published: May 2020

5002

Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]
Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer.
Authors: Srinivasan Ramaprasad , Gurram Sandeep , Al Harthy Munjid , Singer Eric A. , Sidana Abhinav , Shuch Brian M. , Ball Mark Wayne , Friend Julia C. , Mac Lisa , Purcell Erin , Vocke Cathy , Kong Heidi H , Cowen Edward W. , Choyke Peter L. , Malayeri Ashkan A. , Long Lori , Shih Joanna H. , Merino Maria J. , Linehan W. Marston
Published: May 2020

5004

Background: HLRCC is a familial cancer syndrome associated with a type 2 papillary RCC (pRCC) variant. HLRCC is caused by germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH). FH inactivation results in VHL-independent upregulation of hypoxia inducible factor, a reliance on aerobic glycolysis, and activation of the NRF2 pathway, features also shared by some sporadic pRCC tumors. We hypothesized that the metabolic alterations underlying these tumors would be susceptible to targeted therapy with a combination of bevacizumab and erlotinib. Methods: Patients with advanced pRCC were eligible to enroll on this phase II study. To enrich for patients with FH deficiency, those with 1) HLRCC and 2) sporadic pRCC were enrolled into parallel, independent cohorts. All patients received bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily. Patients who had received no more than two agents targeting the VEGFR pathway were included. Patients remained on treatment until unacceptable toxicity or progression. The primary endpoint was overall response rate (ORR); secondary endpoints were progression free survival (PFS) and duration of response. Results: A total of 83 patients with pRCC, including 42 in the HLRCC cohort and 41 in the sporadic cohort were enrolled on study. The majority of patients were IMDC intermediate risk (53/83, 64%) and 27 (33%) had at least one prior treatment. The ORR was 51% (42/83; 95% CI, 40 – 61) in all patients, 64% (27/42; 95% CI, 49 – 77) in the HLRCC cohort, and 37% (15/41; 95% CI, 24 – 52) in the sporadic cohort. The median PFS was 14.2 months (95% CI, 11.4 – 18.6) in all patients, 21.1 months (95% CI, 15.6 – 26.6) in the HLRCC cohort, and 8.7 months (95% CI, 6.4 – 12.6) in the sporadic cohort. The majority of treatment related adverse events (TRAEs) were grade 1 or 2 with the most common being acneiform rash (92%), diarrhea (77%), proteinuria (71%), and dry skin (61%). Grade ≥3 TRAEs occurred in 47% of patients, including hypertension (34%) and proteinuria (13%), with one patient (1.2%) with a grade 5 GI hemorrhage possibly related to bevacizumab. Conclusions: The combination of bevacizumab and erlotinib is well tolerated and is associated with encouraging activity in advanced pRCC, particularly in patients with FH deficient tumors. This is the first and largest prospective study in HLRCC and provides the basis for considering bevacizumab and erlotinib as a preferred option in a patient population that has no widely accepted standard. Clinical trial information: NCT01130519 .
Optimized management of nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma (RCC): A response-based phase II study (OMNIVORE).
Authors: McKay Rana R. , Xie Wanling , McGregor Bradley Alexander , Braun David A. , Wei Xiao X. , Kyriakopoulos Christos , Zakharia Yousef , Maughan Benjamin Louis , Rose Tracy L , Stadler Walter Michael , McDermott David F. , Harshman Lauren C , Choueiri Toni K.
Published: May 2020

5005

Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]
Safety and preliminary efficacy of rogaratinib in combination with atezolizumab in a phase Ib/II study (FORT-2) of first-line treatment in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression.
Authors: Rosenberg Jonathan E. , Gajate Pablo , Morales-Barrera Rafael , Lee Jae-Lyun , Necchi Andrea , Penel Nicolas , Zagonel Vittorina , Sierecki Mitchell Robert , Piciu Ana-Maria , Ellinghaus Peter , Sweis Randy F.
Published: May 2020

5014

Background: Programmed cell-death ligand 1 (PD-L1) overexpression is a mechanism for immune escape in UC. Rogaratinib, an oral pan-FGFR1-4 inhibitor, showed promising efficacy in a Phase I study in pts with solid tumors, including UC, with FGFR1-3 mRNA overexpression (Schuler et al. Lancet Oncol 2019). This Phase Ib/II study is evaluating rogaratinib in combination with atezolizumab, a PD-L1 inhibitor, in pts with FGFR-positive, locally advanced or metastatic UC (NCT03473756). We report results from the Phase Ib study. Methods: Cisplatin-ineligible pts with untreated metastatic UC were eligible if high FGFR1 or 3 mRNA was detected by RNA in situ hybridization of archival tissue (RNAscope). Pts were treated at a starting dose of rogaratinib 800 mg p.o. BID and atezolizumab 1200 mg i.v. on day 1 (21-day cycle). Primary objectives were safety, tolerability, and determination of the recommended Phase II dose. Results: 27 pts were treated (rogaratinib 800 mg + atezolizumab, n = 11; rogaratinib 600 mg + atezolizumab, n = 16); 85% were male, median age was 72 years (range 47-83), 37% had an ECOG PS of 1, and 96% had negative/low PD-L1 expression. Most common treatment-emergent adverse events (TEAEs) were diarrhea (63%), hyperphosphatemia (44%), and urinary tract infection (37%). Dose interruption/reduction due to AEs occurred in 67%/37% of pts; TEAEs lead to discontinuation in 45.5% (800 mg) and 12.5% (600 mg). Most common grade 3/4 TEAEs were increased lipase without pancreatitis (11%), rash, and increased alanine aminotransferase (7% each). Rogaratinib-related unique TEAEs were hyperphosphatemia (44%) and retinal pigment epithelium detachment (4%). The maximum tolerated dose (MTD) was rogaratinib 600 mg BID based on lower overall frequency of AEs. Of 23 evaluable pts (600 mg, n = 13; 800 mg, n = 10), overall 9 (39%) pts had an objective response (RECIST v1.1); 3 (13%) pts had a complete response (600 mg: 2/13 pts), 6 (26%) pts had a partial response (600 mg: 5/13 pts), and 6 (26%) pts had stable disease (600 mg: 4/13 pts). Conclusions: Rogaratinib with atezolizumab showed promising efficacy and safety in cisplatin-ineligible pts with tumor FGFR1 or 3 mRNA-positive UC, with nearly all pts demonstrating low or negative PD-L1 expression. Pts are being enrolled at the MTD of rogaratinib 600 mg BID plus atezolizumab. Clinical trial information: NCT03473756 .
Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.
Authors: Denkert Carsten , Lambertini Chiara , Fasching Peter A. , Pogue-Geile Katherine L. , Mano Max S. , Untch Michael , Wolmark Norman , Huang Chiung-Sheng , Loibl Sibylle , Mamounas Eleftherios P. , Von Minckwitz Gunter , Geyer Charles E. , Boulet Thomas , Song Chunyan , Lewis Phillips Gail , Nowicka Malgorzata , de Haas Sanne , Basik Mark
Published: May 2020

502

Background: The phase 3 KATHERINE study (NCT01772472) compared adjuvant T-DM1 versus H in patients with residual invasive breast cancer after neoadjuvant chemotherapy plus HER2-targeted therapy. Here we report exploratory analyses of the relationship between invasive disease-free survival (IDFS) and biomarkers potentially related to response. Methods: Formalin fixed paraffin-embedded tissue samples were collected before neoadjuvant treatment and/or at surgery. Surgical samples were used for analyses, except when only pre-treatment samples were available (~20% of cases). DNA was derived to identify PIK3CA hotspot mutations and gene expression (RNA) analysis was used to detect HER2, PD-L1, CD8 and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitor signatures. RNA analysis was adjusted for tumor content and expression levels were dichotomized at the median into low (≤) and high (>) groups. The effect of treatment and biomarkers on IDFS was assessed. Results: PIK3CA mutation (mut) status was available from 1363 (91.7%) patients. T-DM1 IDFS benefit was independent of PIK3CA mut status (mut: HR 0.54; 95%CI 0.23–0.90; non-mut: HR 0.48; 95%CI 0.35–0.65) and no impact of PIK3CA mut was observed within either treatment arm. Gene expression data were available from 1059 (71.3%) patients. Similar gene expression levels were observed between treatment arms, but, unlike the surgical samples (n = 815), the pre-treatment samples (n = 244) were not representative of the ITT population. Thus, subsequent analyses were based on surgical samples (H n = 398; T-DM1 n = 417). Consistent treatment benefit with T-DM1 vs H was observed across the single-gene and immune gene-signature subgroups as in the ITT population. High vs low HER2 expression was associated with worse outcome (HR 2.02; 95% CI 1.32–3.11) within the H arm, but not within the T-DM1 arm (HR 1.01; 95% CI 0.56–1.83). High vs low PD-L1 expression was associated with better outcome within the H arm (HR 0.66; 95% CI 0.44–1.00) but not within the T-DM1 arm (HR 1.05; 95% CI 0.59–1.87). Similar trends were observed in the checkpoint inhibitor subgroups. Conclusions: These exploratory analyses provide the first data on the relationship between biomarker expression in residual disease after HER2-targeted therapy and outcomes. PIK3CA mut status did not influence outcomes with H or T-DM1. T-DM1 benefit appeared to be independent of all biomarkers assessed. Clinical trial information: NCT01772472 .
Biomarker analysis and updated clinical follow-up of preoperative ipilimumab (ipi) plus nivolumab (nivo) in stage III urothelial cancer (NABUCCO).
Authors: Van Dijk Nick , Gil Jimenez Alberto , Silina Karina , Hendricksen Kees , Smit Laura , De Feijter Jeantine , van Montfoort Maurits L , Broeks Annegien , Lubeck Yoni , Sikorska Karolina , Boellaard Thierry N. , Kvistborg Pia , Vis Daniel J , Hooijberg Erik , Schumacher Ton , van den Broek Maries , Wessels Lodewyk FA , Blank Christian U. , van Rhijn Bas W.G. , Van Der Heijden Michiel Simon
Published: May 2020

5020

Background: Encouraging pathological complete response (pCR) rates were observed in trials testing neoadjuvant pembrolizumab or atezolizumab in urothelial cancer (UC). In cT3-4N0 tumors, pCR to atezolizumab was only 17% and restricted to tumors showing characteristics of preexisting T cell immunity. In NABUCCO, we aimed to increase response to pre-operative checkpoint blockade, particularly in high risk patients (pts), by combining ipi plus nivo in stage III UC. We previously reported pCR in 46% and downstaging to no remaining invasive disease in 58% (ESMO2019). Here, we present biomarker analyses and updated clinical follow-up (FU) data. Methods: Twenty four stage III (cT3-4aN0 or cT2-4aN1-3) UC pts who were unfit to receive cisplatin-based chemotherapy or refused, were treated with ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. The primary endpoint was feasibility (resection < 12 weeks). Efficacy (pCR), safety and biomarker analysis were secondary endpoints. Whole-exome sequencing (WES) was done on baseline tumor samples and local lymph node (LN) metastases showing no response. RNA-seq and multiplex immunofluorescence (mIF) for immune cell markers were done pre- and post-therapy. Results: After a median FU of 15.6 months, 2 pts relapsed (both non-pCR); 1 of these 2 pts died of metastatic disease. Tumors showing complete response (CR, for biomarker analysis defined as pCR, CIS or pTa) had a significantly higher tumor mutational burden than non-CR tumors. CR to ipi+nivo was independent of baseline CD8 T-cell presence. There was no difference between CR and non-CR tumors in baseline immune gene signatures, such as interferon gamma and T-effector signatures. Surprisingly, exploratory gene expression analysis revealed that non-CR was associated with a baseline B cell immune signature, particularly immunoglobulins and genes involved in B cell receptor signaling. CD20 positive cells (by mIF) and presence of tertiary lymphoid structures (TLS) at baseline were also associated with non-CR. Upon treatment with ipi+nivo, early and mature TLS increased significantly in responding tumors. A subset of pts showed CR in the bladder, but non-CR in a local LN tumor focus. WES revealed that these LN metastases were genetically different from the primary tumor bulk. Conclusions: At 15.6 months follow-up, recurrence after pre-operative ipi+nivo was low. Pathological complete response was not restricted to tumors exhibiting preexisting T cell immunity. Clinical trial information: NCT03387761 .
Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial.
Authors: Ficial Miriam , Jegede Opeyemi , Sant'Angelo Miriam , Moreno Sonia , Braun David A. , Wind-Rotolo Megan , Pignon Jean-Christophe , Catalano Paul J. , Sun Maxine , Van Allen Eliezer Mendel , Freeman Gordon J. , Sharpe Arlene , Hodi F. Stephen , Motzer Robert J. , Wu Catherine J. , Atkins Michael B. , McDermott David F. , Shukla Sachet A. , Choueiri Toni K. , Signoretti Sabina
Published: May 2020

5023

Background: We previously showed that levels of CD8+ tumor infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+TIM3−LAG3−) were associated with response to nivolumab (nivo) in pretreated mccRCC pts (Pignon et al, 2019). Here, we sought to validate these findings in a randomized Phase III trial of nivo versus everolimus (evero) (CM-025) and explore the association of the biomarker with transcriptomic profiles. Methods: Tumor tissues from the CM-025 trial were analyzed (nivo arm: n = 116, evero arm: n = 107). Density/percentage of CD8+ PD1+TIM3−LAG3− TIC was evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by IHC. Linear association with outcomes was assessed using binary logistic (ORR, clinical benefit (CB) defined as CR/PR and PFS≥12 months) and Cox PH (PFS, OS) regression models (1-sided p-values shown). Bulk RNA-seq was performed in a subset of samples (n = 71) and data analyzed using ssGSEA and Gene Signature Scores (GSS). Results: In the nivo arm, density of CD8+ PD1+TIM3−LAG3− TIC (IF biomarker) was associated with ORR (OR = 1.43, p = 0.03) and CB (OR = 1.54, p = 0.02) while a trend was observed with PFS (HR = 0.87, p = 0.06). At an optimized cutoff, nivo treated pts with high IF biomarker (24/116, 20.7%) had higher ORR (45.8% vs 19.6%, p = 0.01) and CB (33.3% vs 14.1%, p = 0.03) and longer median PFS (9.6 vs 3.7 months, p = 0.03) than pts with low IF biomarker. A significant interaction between the IF biomarker and treatment was seen for both PFS and OS (2-sided p = 0.02 and 2-sided p = 0.08, respectively; significance determined as p < 0.15). By bulk RNA-seq, several inflammatory pathways (FDR q < 0.1) and inflammatory GSS (FDR q < 0.05) were enriched in the high IF biomarker group. When combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated clinical outcomes (ORR, CB and PFS) in the nivo arm. In the evero arm, the IF biomarker was neither prognostic nor predictive of any clinical outcome. Conclusions: High levels of CD8+ PD1+TIM3−LAG3− TIC predicted response to nivo (but not to control evero) in mccRCC pts and were associated with activation of inflammatory response. Combination with TC PD-L1 further improved its predictive value, confirming our previous findings (Pignon et al, 2019). Further validation in the setting of first-line anti-PD-1 therapy is ongoing.