bluuebunny/crossref_metadata_2025 huggingface dataset:
Total cost of care differences in National Comprehensive Cancer Center (NCCN) concordant and non-concordant patients with colon cancer.
Authors: Sapkota Ujwal , Cavers William , Reddy Shirisha , Avalos-Reyes Elisea , Johnson Kjel Andrew
Published: June 2022

3624

Background: National Comprehensive Cancer Network (NCCN) colon cancer treatment guidelines have been developed to standardize and improve quality of care. While studies have shown that concordance to these guidelines improves survival, little information exists regarding the impact of concordance and total cost of care (TCOC). This study aimed to evaluate the economic impact of NCCN concordance in patients with colon cancer versus those receiving non-concordant therapies. Methods: This is a retrospective study of patients throughout the United States with colon cancer at a large national Medicaid, Medicare, and commercial insurer from January 1, 2019 - December 31, 2020. NCCN regimen concordance was identified from pharmacy and medical claims and defined as concordant if the entire prescribed treatment regimen matched an NCCN regimen (Level 1 and 2a); patients not receiving an NCCN recommended regimen were deemed to be non-concordant. TCOC and its cost components were contrasted on a matched population of concordant and non-concordant patients with a ratio of 2:1. To eliminate possible selection bias and differences in baseline characteristics that could affect cost, propensity scores were developed using logistic regression and used to match patients on age, comorbidity, socioeconomic status (SES) index and treatment type (chemotherapy and radiation). Results: A total of 937 patients with colon cancer were included (Medicare n = 588; commercial fully insured n = 149; commercial self-insured n = 200). Beginning with and including the first treatment and for up to 180 days after, the TCOC in the concordant group was significantly less among Medicare patients; a reduction of 33% (a difference of $2,986, p < 0.001) in TCOC per member per month (PMPM) was observed. This cost difference was driven primarily by medical chemotherapy spend as concordant patients spent 26% less (a difference of $1,160, p < 0.001). Concordant patients spent 29% less PMPM than non-concordant patients (a difference of $35, p < 0.001) on Evaluation and Management compared to non-concordant patients. There were no significant differences in Inpatient, Emergency Room and Radiation Oncology costs among all patients (p > 0.05). No significant differences were seen in TCOC among commercial fully insured (a difference of $69, p = 0.99) and commercial self-insured (a difference of $5,413, p = 0.07) patients, likely due to smaller sample sizes. Conclusions: In this study, Medicare patients who received NCCN concordant colon cancer regimens spent significantly less in TCOC than patients receiving non-concordant regimens. These savings highlight the importance of evidence-based guidelines in treatment determinations to optimize the value of cancer care. More extensive studies are needed to assess if these findings translate to commercially insured patients and the long-term economic impact of concordance.
A phase II study of stereotactic body radiotherapy (SBRT) combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma (HCC).
Authors: Chen Yixing , Yang Ping , Du Shisuo , Zhou Jian , Huang Cheng , Zhu Wenchao , Hu Yong , Yu Yiyi , Liu Tianshu , Zeng Zhaochong
Published: June 2022

4071

Background: SBRT is an emerging treatment option for oligometastatic cancer disease. Preclinical studies have shown the synergistic effects between the radiotherapy and immunotherapy. Early clinical data also suggested that immunotherapy might augment the local effects of radiotherapy and decrease metastatic recurrence. This study aimed to evaluate the efficacy and safety of SBRT combined with sintilimab (a PD-1 antibody) in patients with recurrent or oligometastatic HCC. Methods: In this single arm, phase II study (NCT03857815), eligibility criteria included Pts with recurrent or oligometastatic HCC (defined as ≤5 metastatic/recurrent lesions), Child-Pugh class A, ECOG PS ≤ 1. Pts received sintilimab 200 mg IV Q3W for up to 12 months, progressive disease, unacceptable toxicity, or withdrawal. SBRT to all lesions was started at cycle 1 day 1. Primary endpoint was progression free survival (PFS) per RECIST 1.1. Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At data cutoff (Dec 28th, 2021), 25 pts with 32 lesions were treated with SBRT + Sintilimab. SBRT was delivered at a median dose of 54 Gy (range 48-60) in 6 fractions (range 6-10) and the median follow-up time was 16.9 months (range 3.9-32.1). In those 25 evaluable pts, median age was 64 years (range 37-77), 24 (96%) were male, 24 (96%) were HBV+, 6 (24%) had extrahepatic metastasis, most pts had prior ≥2 local therapies. The confirmed ORR was 96% (24/25) according to RECIST 1.1 with 18pts CR and 6pts PR. 6-mo and 12-mo PFS rate was 100% and 70% (95%CI, 52.3%-93.6%), respectively.12-mo local control rate was 100%. Median PFS and OS was still not mature. Treatment-related adverse events (TRAEs) occurred in 14 pts (56%). Most common TRAEs were rash (16%), platelet count decreased (12%), myositis (8%). Grade 3 TRAEs (myositis) occurred in 1pt (4%). There were no grade 4-5 TRAEs. TRAEs led to discontinuation in 6 pts (24%). SAE were myocarditis (1pt Grade1), viral hepatitis (1pt Grade 3, treatment-independent) and upper gastrointestinal haemorrhage (1pt Grade 3, PD related). Conclusions: The combination of SBRT with Sintilimab was tolerable and showed an encouraging ORR of 96% in pts with recurrent or oligometastatic HCC. Longer follow up is required to further evaluate the efficacy and safety. Clinical trial information: NCT03857815.
Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.
Authors: Edeline Julien , Merle Philippe , Fang Weijia , Assenat Eric , Pan Hongming , Rimassa Lorenza , Li Zhiwei , Blanc Jean-Frédéric , Yen Chia-Jui , Ross Paul J. , Hu Sheng , Zhang Tao , Tran Albert , Shao Guoliang , Bouattour Mohamed , Chen Yajin , Wu John , Li Vincent , Chica-Duque Sandra , Ren Zhenggang
Published: June 2022

4072

Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]
Immunogenomic characterization of biliary tract cancers: Biomarker enrichment for benefit to immune checkpoint blockade.
Authors: Park Wungki , Keane Fergus , Bandlamudi Chaitanya , Donoghue Mark , Tallón de Lara Paulino , Harding James J. , Khalil Danny , McKinnell Zoe , Sterpi Michelle , Cao Will , El Dika Imane H. , Balachandran Vinod P. , Soares Kevin , Varghese Anna M. , Yu Kenneth H. , Kelsen David Paul , Iacobuzio-Donahue Christine A , Abou-Alfa Ghassan K. , Solit David B. , O'Reilly Eileen Mary
Published: June 2022

4083

Background: Several immunomodulatory molecules (PD-L1, B7H4, and CD276) have been associated with biliary tract cancer (BTC) subgroups, suggesting potential value to immune checkpoint blockade (ICB) in this lethal disease. Phase II monotherapy (pembrolizumab or nivolumab), and combination (atezolizumab and cobimetinib) ICB trials reported low response rates in unselected advanced BTC with a wide range of responses. A recent randomized phase III trial (TOPAZ-1) reported an overall survival (OS) benefit among patients (pts) with advanced BTC treated with chemotherapy and anti-PD-L1 ICB. However, no correlation between PD-L1 expression and OS was noted and biomarker enrichment strategy in BTC for immunotherapy remains a key to optimize OS. Methods: From our comprehensive clinico-genomic database for BTC at Memorial Sloan Kettering (MSK), a retrospective genomic landscape and neoantigen analysis was performed using MSK-IMPACT. Potential immunogenic subgroups were evaluated: homologous recombination deficiency (HRD) defined by pathogenic alterations in BRCA1/2, PALB2, and BAP1, microsatellite stability high (MSI-H) defined by MSIsensor score ≥10, and tumor mutation burden (TMB)>10. Clinical outcomes with anti-PD-1 ICB were evaluated. Results: Among N=1,190 pts with BTC, N=1,346 samples were sequenced between 03/2014 and 01/2022. Key actionable alterations included (%): IDH1, 2 (13, 3), FGFR2 fusions (9), ERBB2 amplification (5), BRAF V600E (2), RNF43 (2), POLE (2), NTRK1 fusion (<1). There were N=230 (17%) patients with putatively more immunogenic BTC (iBTC) identified by HRD [ BRCA1/2 (1, 2.4), PALB2 (1), BAP1 (9)], TMB>10, and MSI-H. Frequency, location (intrahepatic, ICC; extrahepatic, ECC; gallbladder, GBC), TMB, and genomic instability score (GIS) are summarized (Table). Among iBTC subgroup, N=32 pts received ICB. Their median follow up was 29.1 months. Median lines of prior therapy was 3. Median PFS was 5.6 M (95%CI: 1.2-10.1) and OS was 33.4 M (23.1-43.6). Conclusion: A subgroup of BTC pts (iBTC) benefit from ICB. Apart from MSI-H and TMB>10, other genomically-defined subgroups such as HRD may benefit from ICB. Prospective studies are needed to evaluate a better biomarker enrichment strategy beyond PD-L1 and TMB, that can represent other immunogenic aspects of tumor neoantigen and microenvironment. [Table: see text]
Health care resource utilization (HCRU) and costs in patients with biliary tract cancer (BTC) treated with systemic therapy in the United States (US).
Authors: Wang Liya , Singhal Mukul , Eluri Madhulika , Valderrama Adriana , Nepal Bal , Kamble Shital , Grabner Michael , Malhotra Usha , Siegel Abby B. , Swami Shilpi , Javle Milind M.
Published: June 2022

4090

Background: BTC is associated with poor prognosis and limited treatment choices. There is limited evidence on HCRU and costs among BTC patients receiving systemic treatments (ST). This study examined HCRU and total direct cost of care among BTC patients treated with ST to understand the disease burden in management of BTC. Methods: A retrospective cohort study of BTC patients who received first line (1L) ST was conducted, using US private payer Cancer Care Quality Program data and administrative claims from the HealthCore Integrated Research Database between 07/01/2014 - 03/31/2021. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTC diagnosis were excluded. Per patient per month (PPPM) costs in 2020 USD were calculated during 1L, 2L, and 3L treatments associated with HCRU from inpatient, emergency room, and outpatient visits as well as outpatient pharmacy dispensing. Results: Among 298 BTC patients (biliary tract, n=203; gallbladder, n=65; bile duct, n=30; stage IV, n=231; stage III, n=28; stage I/II, n=39) who received ST, mean (SD) age was 61.7 (9) years at 1L treatment initiation, and the majority were female (58%). Following 1L treatment, 44% received 2L treatment, and 16% received 3L treatment. Median follow-up was 7.6 months. Among 201 (67%) patients who had hospitalization in the follow-up period, mean (SD) number of hospitalizations was 2.5 (2), and the average length of stay was 7.0 (5) days. Total PPPM all-cause costs were the lowest during 1L treatment (mean [SD]: $19,589 [$22,603]), and increased as the treatment advanced (2L: $22,617[$19,302]; 3L: $33,534[$40,588]). Similar trend was observed in BTC-related total costs with $16,237 ($22,452) in 1L, $19,083 ($18,670) in 2L and $27,609 ($39,949) in 3L. The table summarizes BTC-related HCRU and PPPM cost during each line of therapy. Conclusions: Study findings suggest significant resource use burden and high total direct medical costs for BTC patients receiving ST. Hospitalizations and outpatient visits represent important HCRU and cost for BTC. These data indicate a need for future newer innovative therapies in the management of BTC.[Table: see text]
Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab for hepatocellular carcinoma (HCC) in BCLC stage c: A prospective, single-arm, phase II trial (TRIPLET study).
Authors: Gu Yang-Kui , Zhang Tian-Qi , Zuo Meng-Xuan , Geng Zhi-Jun , Li Ji-Bin , Huang Zi-Lin , Wu Pei-Hong
Published: June 2022

4106

Background: The combination of anti-angiogenesis and immune checkpoint blockade has been proven to improve clinical outcomes of advanced HCC. We assessed the efficacy and safety of HAIC combined with apatinib and camrelizumab for BCLC stage C HCC. Methods: Consecutive treatment-naive patients with BCLC stage C HCC were enrolled in this phase II trial (NCT04191889). Eligible patients were administrated with HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 2500 mg/m2; q3w), combined with apatinib (250 mg qd) and camrelizumab (200 mg q3w) for 6 cycles, followed by maintenance therapy with apatinib and camrelizumab until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Following an optimal Simon 2-stage design, 26 eligible patients needed to be included in the first stage, of whom at least 11 patients had to achieve objective responses to warrant further investigation in the second stage. Results: In the first stage, confirmed ORR was achieved in 16 and 20 patients per RECIST v1.1 and mRECIST, respectively, therefore enrollment of the second stage continued. From 4/13/2020 to 1/31/2022, 31 eligible patients were enrolled and 29 evaluable for efficacy analyses. The 31 patients were characterized with median age 45 years (range 30-67), men 96.77%, Child-Pugh A 100%, portal vein tumor thrombus Vp 1-2/Vp 3-4 25.81%/45.16%, and extrahepatic metastasis 12.90%. As of 1/31/2022, with a median follow-up of 18.07 months (95% CI 14.10 to 22.04), the confirmed ORR was 70.96% (95% CI, 53.41%-83.91%) with 22 partial responses (PR) per RECIST v1.1,while 87.10% (95% CI, 71.15%-94.87%) with 3 (9.68%) complete responses (CR) and 24 (77.42%) PR per mRECIST. The disease control rate (DCR) was 87.10% (95% CI, 71.15%-94.87%) whether per RECIST v1.1 or mRECIST. The median time to response (TTR) was 2.67 months (interquartile range (IQR), 1.43-2.96) per RECIST v1.1 and 2.03 months (IQR, 1.37-2.80) per mRECIST. The median progression-free survival (PFS) time was 9.37 months (95% CI 7.00 to 11.73) per RECIST v1.1 and 9.63 months (95% CI 5.82 to 13.44) per mRECIST, in particular, the liver-specific median PFS time was 10.80 months (95% CI 5.88 to 15.72) per mRECIST. The 6-month, 12-month, and 18-month overall survival rate were 93.1%, 85.8%, and 65.8%, respectively. Grade ≥3 adverse events (AEs) occurred in 74.19% of the patients, of which the most common AEs were decreased neutrophils (52.17%), decreased lymphocytes (43.38%), and increased ALT and AST (30.43% and 43.48% for each). Conclusions: The triplet treatment of HAIC, apatinib and camrelizumab showed promising clinical benefits and acceptable safety for BCLC Stage C HCC. Further confirmatory randomized controlled trial is about to get underway. Clinical trial information: NCT04191889.
A phase II study combining KN046 (an anti-PD-L1/CTLA-4 bispecific antibody) and lenvatinib in the treatment for advanced unresectable or metastatic hepatocellular carcinoma (HCC): Updated efficacy and safety results.
Authors: Xing Baocai , Da Xu , Zhang Yanqiao , Ma Yue
Published: June 2022

4115

Background: PD-1 inhibitor with Lenvatinib were reported to improve ORR in patients with metastatic HCC. KN046 was a bispecific antibody that target both PD-1/PD-L1 and CTLA-4/B7 immune checkpoints pathway. Preliminary report already showed good efficacy and tolerable safety of the KN046+Lenvatinib regimen. Here we updated the efficacy and safety results with more enrolled patients and longer follow-up duration. Methods: This is an open-label, single-arm, multicenter, phase II trial in pts with unresectable or metastatic HCC. Enrolled patients (pts) with Barcelona Clinic Liver Cancer (BCLC) stage B or C who were not suitable for curative surgery or local therapy had received Lenvatinib 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW<60 kg) orally and KN046 5 mg IV on Day 1 of a 21-day cycle until disease progression or intolerable toxicity or 2-year treatment. Primary endpoints were safety and ORR by RECISTv1.1 per investigators. Results: As data cutoff (January 7, 2022) date, 55 enrolled pts received combination treatment with median duration of 25 weeks. For 52 evaluable pts, ORR was 51.9% (95% CI 37.6-66.0) (RECIST v1.1) and DCR was 86.5% (95% CI 74.2-94.4) (RECIST v1.1). Median PFS was 9.3 months (95% CI 7.0–not estimable [NE]), The median OS and DOR of pts were not reached. The overall incidence of KN046 related treatment-emergent adverse events(TRAEs) was 98.2%, with 27.3% Gr3. The most common Grade ≥ 3 TRAEs included platelet count decreased (7.3% of pts) and aspartate aminotransferase increased (3.6% of pts). The immune related adverse events (irAE) occurred in 14.5% of pts (grade ≥3 5.5%). 3 pts discontinued KN046 treatment due to ≥3 Gr TRAE, which was infusion related reaction, platelet count decreased and interstitial lung disease. 4 (7.2%) pts died from KN046 TRAEs (Hyponatremia, n=1; Interstitial lung disease, n=2; Cause of death unknown, n=1). Conclusions: KN046+Lenvatinib demonstrated a promising efficacy in ORR and PFS and the manageable safety profile in the first-line advanced unresectable or metastatic HCC treatment. These result support the KN046 plus Lenvatinib as a potential new treatment option for this population. Clinical trial information: NCT04542837.
IMMUTACE: A biomarker-orientated phase II, single-arm, open-label AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate-stage hepatocellular carcinoma (HCC; AIO-HEP-0217)—Updated efficacy results.
Authors: Saborowski Anna , Waldschmidt Dirk , Hinrichs Jan , Ettrich Thomas Jens , Martens Uwe Marc , Mekolli Ardian , De Toni Enrico N , Berg Thomas , Geißler Michael , Hausner Guido , Maenz Martin , Ehmer Ursula , Kirstein Marta , Vogel Arndt
Published: June 2022

4116

Background: Immunotherapy based combinations recently revolutionized the treatment of patients (pts) with advanced HCC, but its significance in earlier stages remains to be determined. TACE is commonly used as first line treatment in intermediate HCC, but outcome of patients treated with TACE in real-life cohorts is still poor with a median overall survival (OS) below 20 months. The aim of this study was to determine the safety and efficacy of TACE combined with nivolumab. Methods: This is a phase II trial, that recruited 59 patients at 10 sites in Germany between 06/2018 and 06/2020. Pts received up to two TACE treatments followed by nivolumab (240 mg/ Q2W), initiated on day 2-3 after the first TACE session and continued until progression for a maximum treatment duration of two years. Primary endpoint was ORR (mRECIST; with ORR exceeding 55% (power = 80%; actual beta 0.17) as promising for further investigations). Secondary endpoints include mPFS, mTTFS (median time to failure of strategy), mOS, QoL, and safety/tolerability. Tumor tissue was obtained at baseline and blood samples were collected longitudinally for translational research. Results: 49 pts (14.3% HCV and 8.2% HBV) were enrolled and received at least one dose of nivolumab, median tumor size was 4.5 cm (0.9 – 15 cm) and median number 3 (1 – 12). ORR by mRECIST was 71.4% (CR: 16.3%, PR: 55.1%, SD 4.1%, PD: 14.3%). At a median follow-up of 20 months, mPFS was 7.2 mo (95% CI; 5.3 – 11.2; 40 events), mTTFS was 11.2 mo (95% CI; 7.2, 13.5; 42 events) and mTTSST (median time to subsequent systemic therapy) was 24.9 mo (95% CI; 12.2, - ; 21 events). Median duration of Nivolumab was 8.3 months and mOS was 28.3 mo (95% CI; 20 – not estimable; 23 events). Grade ≥3 treatment-related adverse events occurred in 34.7% of patients. Correlative analysis of efficacy with genetic alterations, gene expression signatures and changes of immune cell populations will be reported soon. Conclusions: The study met its primary endpoint and provides evidence for the efficacy of TACE in combination with nivolumab without new safety signals in pts with intermediate HCC and no prior systemic therapy. Our findings support further evaluation of nivolumab-based combinations for the treatment of intermediate HCC. Disclaimer: This study was supported with drug and funding by Bristol-Myers-Squibb. Clinical trial information: NCT03572582.
Impact of metformin on clinical outcomes in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.
Authors: Khalil Lana , Kang Sandra , McCook-Veal Ashley , Draper Amber , Diab Maria , Shaib Walid Labib , Alese Olatunji B. , El-Rayes Bassel F. , Akce Mehmet
Published: June 2022

4118

Background: Non-alcoholic steatohepatitis (NASH) is an emerging etiology for hepatocellular carcinoma (HCC) and contributes to the increasing incidence of HCC worldwide. Patients with NASH often have risk factors of metabolic syndrome including hypertension, obesity, and type 2 diabetes (T2DM). NASH induced HCC has been shown to be associated with less response to immune check point inhibitors (ICIs) in HCC. Anti-diabetic agent metformin has been shown to be associated with improved outcomes in patients treated with ICIs in melanoma and non-small cell lung cancer. However, the impact of metformin on the efficacy of ICIs is not well defined in HCC. The main purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods: We performed a retrospective analysis of patients with advanced HCC treated with ICIs in first and later-line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were stratified based on their usage of metformin. OS and PFS were analyzed using Cox proportional hazard models and Kaplan-Meier analysis with log-rank test. Results: A total of 111 patients met inclusion criteria, 18 patients in the metformin group and 93 patients in the non-metformin group. Most common cause of HCC was viral hepatitis (52%), followed by NASH (29%), alcohol (8%) and other (11%). Baseline characteristics between the two groups were similar except all patients in the metformin group had a diagnosis of T2DM. ORR was 5.6%. (1 partial response) in the metformin group vs 22.6% (5 complete responses, 16 partial responses) in the non-metformin group. Median OS was 45.9 months in the non-metformin group vs 10.8 months in metformin group (HR 1.99, 95% CI 0.95-4.21, p = 0.064). Median PFS of 6.6 months vs 2.5 months (HR 1.75, 95% CI 0.93-3.29, p = 0.077). Moreover, metformin usage was associated with shorter median OS of 10.8 months (HR 1.96, 95% CI 0.75-5.09, p = 0.16) vs 20.9 months among patients with T2DM. OS was significantly worse in patients with poor ECOG performance status 2-3, MELD score 10-23, higher grade tumor histology, AFP > = 400, and use of IO in later lines of therapy. Conclusions: In this retrospective study metformin use was associated with worse clinical outcomes in advanced HCC patients treated with ICIs.
Efficacy of nivolumab and temozolomide in advanced neuroendocrine neoplasms (NENs) in a phase 2 clinical trial.
Authors: Owen Dwight Hall , Benner Brooke , Wei Lai , Sukrithan Vineeth , Goyal Ashima , Zhou Ye , Suffren Sheryl-Ann , Pilcher Carly , Christenson Gwen , Curtis Nancy , Savardekar Himanshu , Norman Ruthann , Ferguson Sarah , Kleiber Barbara , Wesolowski Robert , Carson William Edgar , Otterson Gregory Alan , Verschraegen Claire F. , Shah Manisha H. , Konda Bhavana
Published: June 2022

4121

Background: Treatment options are limited in patients with metastatic NEN. Temozolomide (TEM) alone and in combination with capecitabine is active in NEN and has been shown to have immunomodulatory impact. Here we present the final results for the NEN cohort of a phase 2 trial of combination nivolumab and TEM in patients with advanced NEN along with observed peripheral immune changes. Methods: NCT03728361 is a non-randomized, two-cohort, open-label phase 2 trial of nivolumab and TEM in patients with metastatic NEN and small cell lung cancer. The NEN cohort enrolled patients with tumors of any WHO grade, location, and line of therapy; all patients had evidence of progression prior to study. Prior immunotherapy was not allowed. Treatment consisted of nivolumab 480 mg IV on day 1 and TEM 150 mg/m2 on days 1-5 of a 28-day cycle. The primary objective was efficacy measured as response rate (RR) by RECIST v1.1. Secondary objectives were progression free survival (PFS) and overall survival (OS), by the method of Kaplan–Meier. The translational objective was to analyze peripheral blood mononuclear cells (PBMCs) collected at screening (baseline) and on cycle 1, day 15 (C1D15) via mass cytometry. Results: The RR was 36% (n=10/28, 95% CI: 18.6%-55.9%), including 10 patients (36%) with PR, 16 (57%) with SD, and 2 (7%) with PD (Table). The disease control rate was 93%. Responses occurred across all WHO grades; 44% of patients with tumors with Ki-67 >20% had PR. There was a significant difference in ORR by primary tumor location (bronchial vs pancreas vs other, p=0.004). There was no significant difference in response by Ki-67% (p=0.872), or in patients treated as first line (31%) or beyond (40%, p=0.706). The median PFS was 8.9 months (95% CI: 3.9 – 11.1 months), and median OS was not reached (95% CI: 20.7 – NR months). Two immune related SAE’s occurred: myocarditis and diarrhea in one patient each; gr4 toxicities included neutropenia (10%) and thrombocytopenia (7%). Profiling of PBMCs revealed no correlation of baseline MDSC levels with clinical benefit, however significant changes within the T cell landscape, including a decrease in CD4+ T cells (59.6% ±13.08 vs. 56.5% ±13.01, p=0.001) and increase in CD8+ T cells (27.9% ±13.36 vs. 31.7% ±14.57, p=0.03) were observed. Conclusions: Combination nivolumab and TEM demonstrated promising efficacy in patients with NENs; median OS has not been reached. Clinical trial information: NCT03728361. [Table: see text]
KRAS wild-type pancreatic ductal adenocarcinoma: Molecular and therapeutic opportunities.
Authors: Desai Aakash , Walden Daniel , Halfdanarson Thorvardur Ragnar , Alberts Steven R , McWilliams Robert R. , Mahipal Amit , Ahn Daniel H. , Babiker Hani M. , Tella Sri Harsha , McGarrah Patrick Walsh , Kizilbash Sani Haider , Adjei Alex A. , Bekaii-Saab Tanios S. , Ma Wen Wee
Published: June 2022

4130

Background: KRAS is mutationally activated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Compared to pts with KRAS mutation, KRAS wild-type (wt) PDAC seem to have better response to therapy and may harbor potentially actionable molecular alterations. Here, we analyze the molecular profile and clinical outcome of a cohort of pts with KRAS wt PDAC. Methods: A retrospective review was conducted on pts with PDAC who underwent CLIA-certified Next Generation Sequencing (NGS) testing at Mayo Clinic between December 1, 2018 and December 1, 2021. Pts with KRAS wt PDAC with available reports were included. Their genomic drivers, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcome data were collected. The study was approved by the institutional IRB. Results: Of the 241 eligible pts, 8% (19) has KRAS wt PDAC. Among those, 2 pts had no mutation identified by the gene/molecular panel used. Of the 17 pts (89%) with identified alterations, mutations found in ³ 2 pts were TP53 (53%), CDKN2A (16%) and CDKN2B/ERBB2/PTEN/MSH3/RNF43/FBXW7/KMT2D/GNAS (11% each). Chromosomal rearrangements were identified in 5 (26%): CADPS2-BRAF, GP2-ERBB2, PTPRK-RSPO3, EML4-NTRK3 and TFG-MET. RNA expression results were available in 12 pts: common overexpression were ERBB2 (27%) and MET/NRAS/MYC/CCDN1/CCNE1/AR (18% each); and the under-expression MGMT (18%). Among the 13 pts with available MSI status via NGS, 2 (11%) were MSI-high (both had high TMB [28.4 and 23.7 m/MB]) while all others were TMB < 10 m/MB. The median age at diagnosis was 61 years (68% males). 8/19 (42%) were Stage IV at diagnosis with 15/19 (79%) pts ultimately diagnosed with metastatic disease. Among metastatic pts, median lines of treatment received was 2.5 (range:0-4). 4 pts received FOLFIRINOX (FFX), 2 gemcitabine/ nab-paclitaxel (GP) and tumor response were comparable to previously reported results. 1 received 1st-line pembrolizumab and remained on therapy at the time of analysis. The median length of follow up from diagnosis was 29 months. A patient with TFG-MET re-arrangement previously progressed on FFX and GP was treated using a MET inhibitor, and achieved significant CA19-9 drop and pancreas tumor shrinkage at 1st restaging, with ongoing response. Conclusions: The molecular profile of KRAS wt PDAC is highly heterogeneous and difficult to generalize. Novel approaches (e.g., basket trials) are needed to develop therapy for this rare PDAC subgroup.
Comparison of systematic inflammatory prognostic scores in patients with advanced pancreatic adenocarcinoma.
Authors: Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Wang Yifan , Allen Michael J , Jang Gun Ho , Zhang Amy , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Grant Robert C. , Knox Jennifer J. , O'Kane Grainne M.
Published: June 2022

4149

Background: Systemic inflammatory scores have been developed as tools to aid clinicians in prognostication and patient (pt) selection for clinical trials. We compared the accuracy of five prognostic scores to predict overall survival (OS) in pts with advanced pancreatic adenocarcinoma (PDAC). Methods: Pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657) from 2015 to 2020 were included. All pts had biopsies for whole genome and RNA sequencing prior to standard first-line chemotherapy in the advanced setting. Prognostic risk was calculated using: neutrophil-to-lymphocyte ratio (NLR; >5 = high), platelet-to-lymphocyte ratio (PLR; > 150 = high), Prognostic Nutritional Index (PNI = albumin + 5 x lymphocytes. PNI < 45 = high risk), Gustave Roussy Immune Score (GRIm-S; NLR>6 = 1 point, albumin <35 = 1 point, LDH > upper limit of normal [ULN] = 1 point. GRIm-S ≥2 = high risk), and Memorial Sloan Kettering Prognostic Score (MPS; NLR >4 and albumin < 40 = high risk). OS was estimated using the Kaplan-Meier method and compared between risk groups (high vs. not-high) for each scoring system using the log-rank test. Cox proportional hazards models were used to analyze the association between each prognostic score and OS, adjusting for baseline clinical and genomic factors. Results: In total, 263 pts with advanced PDAC cancer were included, with median follow up of 32.9 (95% CI 15.9-64.2) months. Median OS in the intention to treat population was 9.3 months (95% CI 8-10.2). PLR and PNI were not prognostic. High risk NLR (N=85, 32%), GRIm-S (N=47, 18%) and MPS (N=46, 17%) identified pts with poor prognosis. The GRIm-S and MPS were most significant: median OS in high vs low risk pts 6.4 vs. 10 months p<0.001 (GRIm-S) and 6.3 vs. 10 months p=0.002 (MPS). On multivariable analyses, high risk NLR, GRIm-Score and MPS were each associated with poor OS after adjusting for baseline clinical and genomic factors (Table). For all models, ECOG ≥1 (N=165, 63%); the basal-like Moffitt RNA subtype (N=49, 20% vs 80% classical) and low HRDetect scores (N=31, 13%) were significantly associated with poor OS. However these scores did not associate with RNA based classifiers or HRD scores and can therefore provide additional prognostic information. Conclusions: Both the GRIm-S and MPS are highly prognostic in PDAC and are scores easily used in the clinical setting and may help in clinical trial selection. Genotypic correlates are being explored.[Table: see text]
Neoadjuvant chemotherapy is associated with improved outcomes in patients with stage 1A and 1B pancreatic cancer undergoing surgery: An NCDB study.
Authors: Rozich Noah , Singh Maharaj , Kriley Isaac , Weese James L. , FACS Aaron Chevinsky , Papenfuss Wesley Allan , Bellini Geoffrey
Published: June 2022

4157

Background: The use of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has shown clear advantages in locally advanced and borderline resectable disease. The benefit in upfront resectable PDAC is debated. Moreover, in early clinical stages IA/IB, potential benefits including improved R0 resection rate, decreased tumor upstaging, and survival, are not clear. We hypothesize that NAC will be associated with improved outcomes and survival compared to adjuvant therapy in patients with clinical stage IA/IB PDAC. Methods: The National Cancer Database (NCDB) PUFs (2004-2017) were used to perform a retrospective review of patients with clinical stage IA or IB PDAC undergoing surgery. Treatment groups were selected based on timing of chemotherapy. Patients receiving chemotherapy or surgery alone were excluded. Results: We identified 6,613 patients with clinical stage IA or IB PDAC who underwent surgery. The neoadjuvant therapy group (NAT) included 1,533 patients who received neoadjuvant or perioperative chemotherapy, and the adjuvant therapy group (AT) contained 5080 patients who received chemotherapy after surgery. Patients in the NAT had higher rates of T1 and T2 disease and lower rates of T3 pathology compared to the AT (pT1: 18.7% vs 7.8%; pT2: 20.1 vs 18.6%; pT3: 59.3% vs 72.1%, p<0.0001). Additionally, the NAT had significantly higher rates of N0 disease and less N1 pathology (pN0: 54.6% vs 37.5%; pN1: 45.4% vs 62.5%, p<0.0001). The R0 resection rate was higher in the NAT (83.2% vs 62.3%, p=0.0197) and there was less lymphovascular invasion (LVI) compared to the AT (34.8% vs 48.1%, p<0.0001). Using Kaplan Meier estimates, the NAT was associated with improved overall survival (OS) compared to the AT (median OS: 33.4 vs 27.5 months, p<0.0001). On multivariable analysis, R0 resection (HR=0.715, CI: 0.619-0.825, p<0.0001), LVI (HR=1.126, 95% CI: 1.038-1.222, p=0.0043) but not receipt of NAC (HR=0.94, 95% CI: 0.852-1.038, p=0.2229) were independent risk factors for OS. Conclusions: NAC is beneficial in patients with stage IA/IB PDAC undergoing surgical resection as it is associated with improved oncologic outcomes including increased R0 resection rate, decreased tumor upstaging, lymph node metastasis, and LVI. Furthermore, patients receiving NAC were found to have improved survival over those getting adjuvant therapy. Based on these results, we recommend all patients diagnosed with PDAC be considered for NAC prior to surgery. [Table: see text]
Association between depth of response (DepOR) and clinical outcomes: Exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER.
Authors: Suárez Cristina , Choueiri Toni K. , Burotto Mauricio , Powles Thomas , Bourlon Maria Teresa , Shah Amishi Yogesh , Tomita Yoshihiko , Bedke Jens , Zhang Joshua , Simsek Burcin , Scheffold Christian , Escudier Bernard , Motzer Robert J. , Apolo Andrea B.
Published: June 2022

4501

Background: Among patients (pts) with untreated aRCC in the CheckMate 9ER trial, superior progression-free survival (PFS; hazard ratio [HR], 0.56) and overall survival (OS; HR, 0.70) were maintained, and objective response and complete response (CR) rates were doubled for nivolumab plus cabozantinib (N+C) vs sunitinib (SUN) with extended 25.4 mo minimum (32.9 mo median) follow-up. This exploratory analysis evaluated the relationship between DepOR and clinical outcomes in CheckMate 9ER. Methods: Eligible pts received N (240 mg) every 2 weeks plus C (40 mg) once daily or SUN (50 mg once daily; 4 weeks of each 6-week cycle). In this analysis, DepOR subgroups were based on best overall response (blinded independent central review [BICR] per RECIST v1.1) and best tumor reduction threshold, as follows: CR; partial response subdivided by a tumor reduction of ≥80%–<100% (PR1); ≥60%–<80% (PR2); or ≥30%–<60% (PR3); stable disease (SD); and progressive disease (PD). PFS (per BICR) and OS by DepOR subgroups were analyzed after a 6-mo post-randomization landmark. Treatment-related adverse events (TRAEs) were assessed in DepOR subgroups. Results: Of 323 and 328 pts randomized to N+C or SUN, 236 and 157 pts were progression-free and alive and 293 and 253 pts were alive at the 6-mo landmark and were categorized by DepOR subgroup. Overall, greater proportions of pts receiving N+C had deeper responses vs SUN (CR, PR1, PR2; Table). Deeper responses with N+C were associated with improved 12-mo PFS rate vs SUN for CR (94.9% vs 82.4%), PR1 (81.3% vs 37.5%), and PR2 (72.1% vs 53.2%). In both arms, increasingly deeper response led to better OS outcome; yet OS rates and medians were comparable between arms for CR, PR1, PR2, and PR3 (Table). No meaningful patterns for overall TRAE rates by DepOR subgroup were identified in either arm. Conclusions: In CheckMate 9ER, more pts receiving N+C achieved deeper responses vs SUN. Deeper responses were generally associated with improved PFS and OS. Clinical trial information: NCT03141177. [Table: see text]
Association between decline of neutrophil-to-eosinophil ratio (NER) at week 6 after ipilimumab plus nivolumab initiation and improved clinical outcomes in metastatic renal cell carcinoma (mRCC).
Authors: Chen Yu-Wei , Tucker Matthew D , Brown Landon Carter , Yasin Hesham Abdallah , Ancell Kristin Kathleen , Armstrong Andrew J. , Beckermann Katy , Davis Nancy B. , Harrison Michael Roger , Kaiser Elizabeth , McAlister Renee , Schaffer Kerry , Wallace Deborah , George Daniel J. , Rathmell Wendy Kimryn , Rini Brian I. , Zhang Tian
Published: June 2022

4527

Background: Low baseline NER has been associated with improved response to immunotherapy in mRCC (PMID:34732251). The current study aimed to investigate the early decline of NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. Methods: Retrospective chart review of ipi/nivo-treated mRCC patients at Vanderbilt-Ingram Cancer Center and Duke Cancer Institute was conducted. Landmark analysis at week 6 after ipi/nivo initiation was performed to assess the association between change in NER and clinical responses [progression-free survival (PFS)/overall survival (OS)]. Results: There were 150 mRCC patients included in the analysis: 78% had clear cell histology, 78% were IMDC intermediate/poor risk, and 74% were male. The median follow-up time was 11.9 months. After ipi/nivo initiation, the median NER decreased from 23.8 (interquartile range: 15.0-57.1) at baseline to 19.8 (10.6-40.8) at week 6; 102 (68%) patients had decreased NER. The NER at week 6 was grouped by percent change (≥ 50% decrease vs <50% decrease vs increase). In multivariable regression analysis after adjustment for age, sex, race, IMDC risk group, baseline NER, histology, prior systemic therapy, and prior nephrectomy (Table), decreased NER ≥ 50% was associated with improved PFS [adjusted hazard ratio (AHR): 0.55, p-value: 0.03] and OS (AHR: 0.38, p-value: 0.02) (Table). Stratified analysis was conducted by baseline NER [≥vs < baseline median NER (23.8)]: decreased NER ≥ 50% was associated with improved PFS (AHR: 0.46, p-value: 0.048) and OS (AHR: 0.29, p-value: 0.01) in the subgroup with high baseline NER. These associations were not observed in the subgroup with low baseline NER (p-value for PFS: 0.25; p-value for OS: 0.61). Conclusions: The decline of NER ≥50% at week 6 after ipi/nivo initiation was associated with improved PFS/OS in mRCC patients with high baseline NER. Prospective studies are warranted to validate NER change as a biomarker to predict response to ICIs in mRCC. [Table: see text]
Sequential immunotherapy in rare variant renal cell carcinomafinal report of UNISoN (ANZUP 1602): Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma.
Authors: Conduit Ciara , Kichenadasse Ganessan , Harris Carole A. , Gurney Howard , Ferguson Tom , Parnis Francis , Goh Jeffrey C. , Morris Michelle Frances , Underhill Craig , Pook David William , Davis Ian D. , Roncolato Felicia , Harrison Michelle L. , Begbie Stephen , Joshua Anthony M. , Link Emma , Hovey Elizabeth J. , Gedye Craig ,   The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2022

4537

Background: Immune checkpoint immunotherapy (ICI) is active against many cancers. Many people are failed by PD1 inhibition alone, but not all patients benefit, nor require combination ICI treatment. UNISoN (NCT03177239) previously reported outcomes in people with non-clear cell renal cell carcinoma (nccRCC) receiving nivolumab (N) monotherapy, and N plus ipilimumab (I) in those whose cancers progressed after N alone. We present the final planned report. Methods: Population, Intervention, Analysis: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1) received N 240mg q2w alone (Part 1). Those with cancers refractory to N at 3 months were offered combination I (1mg/kg) + N (3mg/kg) q3w for up to 4 doses, followed by N 240mg q2w for a maximum total of 12 months of N (Part 2). UNISoN was powered to identify a clinically-relevant objective tumor response rate (OTRR) of 30% (assuming 15% was not relevant) among people receiving I+N in Part 2. Results: 85 pts with a representative spectrum of nccRCC histologies were enrolled and received N. Amongst the total population enrolled to UNISoN Part 1/2, mOS was 24 (16-28) months and 12m OS was 65% (54%-74%); of those proceeding to Part 2, the mOS was 10 (6-17) months only. Overall, 17% (10%-27%; 14/83) and 10% (3%-23%; 4/41) of pts experienced a response from N alone or I+N, respectively. 41 pts refractory to N received I+N. Overall in Part 2, the median time on treatment was 2.1 (95% CI 1.8, 2.8) months, the median number of cycles was 3; median follow-up at final analysis was 22 (16-30) months. In this population, the median PFS was 2.6 (2.2-3.8) months and 12m PFS was 11% (4%-23%). 13% (7%-22%) of patients were free of progression or death at 24 months. The primary endpoint was not met; only 80% of pts failed by N were assessable for response in Part 2. Overall tumor responses from N alone or I+N were more common in pts with papillary histology; pts with chromophobe histology had poor outcomes. No late toxicity safety signals were observed. Conclusions: Some pts with nccRCC benefit from N alone, or addition of I when disease is inadequately controlled by N alone, however most pts have limited benefit from ICI. More effective therapeutic options are needed for the majority of people with rare variant renal cell carcinomas. Novel markers of response are required to more rapidly predict pts who will progress on N. Translational research to identify predictive biomarkers of response is ongoing. Clinical trial information: NCT03177239.
Molecular characterization of the tumor microenvironment in chromophobe renal cell carcinoma (ChRCC) and related oncocytic neoplasms.
Authors: Labaki Chris , Zhang Long , Hou Yue , Bi Kevin , Hobeika Charbel , Bakouny Ziad , Camp Sabrina Yvonne , Priolo Carmen , Khabibullin Damir , Schindler Nicholas , Alchoueiry Michel , Denize Thomas , Saliby Renee Maria , Matar Sayed , Signoretti Sabina , Van Allen Eliezer Mendel , Shukla Sachet A. , Braun David A. , Henske Elizabeth , Choueiri Toni K.
Published: June 2022

4549

Background: ChRCC represents about 5% of all kidney cancer and has a dismal prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. We evaluated the molecular properties of ChRCC and related oncocytic neoplasms to define the tumor immune microenvironment and identify potential therapeutic strategies. Methods: ChRCC, renal oncocytoma (RO) and low-grade oncocytic tumor (LOT) samples with matched normal kidney specimens were evaluated using single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq). T-cell antigenic specificities from scTCR-seq were inferred using a comprehensive database of annotated T-cell receptor sequences (VDJdb). The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Bulk RNA-sequencing (RNA-seq) data of clear cell RCC (ccRCC) and ChRCC were further analyzed using The Cancer Genome Atlas (TCGA) KIRC and KICH cohorts, respectively, with immune cell fractions calculated using CIBERSORTx. Results: After quality-control, 46,817 cells from 5 tumor (ChRCC: n = 3, RO: n = 1 and LOT: n = 1) and 4 normal samples were isolated for scRNA-seq analysis. Renal oncocytic tumors (ChRCC, RO, and LOT) had a low density of CD45+ cells (mean: 739 ± 114 cells/mm2; n = 5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm2; n = 5) (p < 0.05). Across all tumors, CD8+ T-cell clusters displayed a low expression of immune exhaustion markers (i.e. PDCD1 [PD-1], CTLA4, LAG3, HAVCR2 [TIM-3], and TIGIT). Analysis of TCGA bulk RNA-seq data after adjustment for CD8 T-cell fraction showed no difference in the expression of most immune exhaustion markers (i.e. PDCD1, CTLA4, LAG3) in ChRCC compared to normal samples (p > 0.05), contrasting with a substantially higher expression in ccRCC versus normal kidney (p < 0.05). Analysis of the T-cell repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not identify a pattern of clonal expansion, and a considerable proportion of clonotypes were inferred to have specificity for viral antigens (range: 1.3 to 34.4% among all samples; 11.3 to 34.4% after filtering out two samples with a low ( < 300) number of T-cells). Conclusions: Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, a non-exhausted immune phenotype and, a lack of clonally expanded tumor-specific T-cells. These findings may partially explain the molecular basis for the lack of response to ICIs in advanced ChRCC and outline the unique exhaustion phenotype of renal oncocytic tumors.