bluuebunny/crossref_metadata_2025 huggingface dataset:
KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).
Authors: Zhang Ling , Song Jianping , Wang Yiting , Chen Yaoxu
Published: June 2021

3538

Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.
Clinical performance of methylation-based liquid biopsy test COLVERA after optimization of test interpretation rules.
Authors: Vucetic Zivjena , Loayza Naima , Pedersen Susanne Kartin , Tuck Missy , LaPointe Lawrence Charles
Published: June 2021

3546

Background: Clinical guidelines recommend surveillance for patients who complete primary treatment for colorectal cancer (CRC) with the aim of detecting recurrence when amenable to curative intent treatment. Currently recommended surveillance protocols, including imaging and CEA have limitations both in sensitivity and specificity, thus novel methods that detect circulating tumor DNA (ctDNA) have been introduced into clinical practice. COLVERA is a laboratory-developed, real-time PCR test that detects DNA methylation of BCAT1 and IKZF1 genes. These two genes are hypermethylated in 95% of CRC tissue and COLVERA showed improved sensitivity for detection of recurrent disease in comparison to CEA in several clinical populations. The current study evaluated the impact of optimizing the assay’s qualitative reporting method on actionability and clinical performance for recurrence detection in CRC surveillance setting. Methods: Two previously described cohorts of CRC patients (N=322 and N=144) who completed primary treatment and were undergoing surveillance were evaluated. Imaging and blood collections were performed at, or adjacent to, a standard of care visit. cfDNA was extracted from whole blood, bisulphite-treated and assayed in triplicates for BCAT1/IKZF methylation. Previously, any positive replicate of either target gene was reported as COLVERA “detected”. In the current study, COLVERA is “detected” when at least one replicate of IKZF1 or multiple replicates of either IKZF1 and/or BCAT1 are present. Sensitivity, specificity, and diagnostic odds ratio (DOR) for CRC recurrence detection from a single time-point blood sample was determined using radiological imaging as clinical reference standard. Results: In the first cohort (N=322), overall COLVERA test positivity was 6.5% (21/322) with a sensitivity of 59.3% (95% CI: 38.8 - 77.6) and specificity of 98.3% (96.1 - 99.5) for detecting recurrence at a time-point adjacent to imaging, representing improved specificity, from 91.5% (87.7 - 94.4%), with minimal decrease in sensitivity, from 63.0% (42.4 – 80.6). Similarly, in the second cohort (N=144) sensitivity was 62% (47.2 -75.4), compared to 66.0% (57.1 – 69.3) under the prior interpretation method, while specificity was 92.6% (85.3-97), compared to 90.4% (84.7 - 94.7). A high DOR of 84 (26 - 272) (previously 18 (7.6 – 44.4)) indicates that the revised COLVERA interpretation method is clinically more informative and differentiates with greater accuracy patients with and without the disease. Conclusions: This change in the COLVERA interpretation rule resulted in optimized clinical specificity with minimal impact on sensitivity. For an assay intended to aid in surveillance and early recurrence detection, improved accuracy allows the physician to have increased confidence in making actionable decisions based on test result, including further imaging or treatment.
RAMucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic colorectal cancer: Safety results from the phase IIb part of the RAMTAS phase II/III trial of the German AIO (AIO-KRK-0316).
Authors: Kasper Stefan , Goetze Thorsten Oliver , Stintzing Sebastian , Hofheinz Ralf Dieter , Sinn Marianne , Dechow Tobias Nicolaas , Ettrich Thomas Jens , Keitel Verena , Graeven Ullrich , Fischer von Weikersthal Ludwig , Kolov Alexander , Edelmann Thomas , Stein Alexander , Trarbach Tanja , Junge Sabine , Pauligk Claudia , Virchow Isabel , Siveke Jens T , Al-Batran Salah-Eddin , Schuler Martin H.
Published: June 2021

3566

Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.
The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.
Authors: Wang Jingyuan , Millstein Joshua , Loupakis Fotios , Stintzing Sebastian , Arai Hiroyuki , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Zhang Wu , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef
Published: June 2021

3581

Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR]=1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study first-stage.
Authors: Tamberi Stefano , Grassi Elisa , Corbelli Jody , Papiani Giorgio , Barbera Maria aurelia , Zingaretti Chiara , Carli Moretti Chiara , Montroni Isacco , Petracci Elisabetta , Caruso Dora , Nosseir Sofia , Nanni Oriana , Frassineti Giovanni Luca , Di Bartolomeo Maria , Marzola Marina , Bonetti Andrea , Gelsomino Fabio , Pinto Carmine , Tassinari Davide , Ugolini Giampaolo
Published: June 2021

3607

Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study, conducted with support from AstraZeneca, in patient with locally advanced rectal cancer who receive concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is pCR rate after at least 1 cycle of durvalumab. The sample size has been estimated by using the optimal Simon’s two-stage design. If more than 4 complete responses are observed in the first 19 enrolled patients, 36 additional patients will be accrued for a total of 55 evaluable patients. Results: Between November 2019 and July 2020, 20 patients were accrued and 19 were evaluable for study objectives, concluding the first stage of the trial. Baseline characteristics of the first 19 evaluable patients enrolled are listed in the table. All patients received 3 infusions of durvalumab; 18 patients underwent surgery after a median of 13 weeks from CHT/RT end. Five complete pathological responses (ypT0N0) were observed, allowing to proceed to the second stage. About toxicity, four patients had Grade 3-4 adverse events (AE); the most frequent G3-4 AE related to the neoadjuvant therapy were anemia (n=1), diarrhea (n=2) and neuthropenia (n=2). No grade 3 and 4 adverse events related to Durvalumab treatment were observed. Eight patients had G1-2 AE related to durvalumab, the most common being asthenia (n=2) and nausea (n=2). Conclusions: At the end of study’s first stage the preoperative treatment with radiotherapy plus capecitabine followed by durvalumab showed a safe toxicity profile and promising activity in terms of pCR rate. The second part of the trial is ongoing, and the accrual is under completion (44 patients enrolled as of 10 February 2021). Clinical trial information: NCT04083365. [Table: see text]
Neoadjuvant camrelizumab combined with chemotherapy and apatinib for locally advanced thoracic esophageal squamous cell carcinoma (ESCC): A single-arm, open-label, phase Ib study.
Authors: Wang Zhen
Published: June 2021

4047

Background: Neoadjuvant therapy with PD-1 blockade plus chemotherapy has been found to be effective in the first-line treatment of advanced esophageal cancer. However, evidence of PD-1 blockade combined with chemotherapy as neoadjuvant treatment is limited. This study was designed to investigate the safety and efficacy of camrelizumab, a PD-1 blockade combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: A regiment of 2–4 cycles of neoadjuvant camrelizumab (200 mg, intravenous, day 1), nab-paclitaxel (150 mg/m2, intravenous, day 1), nedaplatin (50 mg/m2, intravenous, day 1), and apatinib (250 mg, orally, day 2–4) was given to the treatment-naive patients with resectable locally advanced ESCC. The treatments were repeated every 14 days. In this study, six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment, and then 24 patients received four cycles of neoadjuvant therapy, followed by esophagectomy after 4–8 weeks. The primary end points were safety and feasibility. The secondary end points were the rate of major pathologic response (MPR) and pathologic complete response rate (pCR). Results: A total of 30 patients were enrolled, among them, five patients received two planned cycles of neoadjuvant therapy, and one patient missed the second cycle of therapy due to grade 3 ALT elevations. Further, all other 24 patients received four planned cycles of neoadjuvant therapy. A total of 11 patients (11/30, 36.7%) experienced grade 3 neoadjuvant treatment-related adverse events (TRAEs). No grade 4 and grade 5 TRAEs were reported. The most frequent grade 3 TRAEs was neutropenia (7/30, 23.3%). Twenty-nine patients underwent minimally invasive esophagectomy (McKeown procedure) after neoadjuvant therapy. The reason for not undergoing surgery was due to bone metastasis. There were five treatment-related surgical delays that were caused by adverse reactions (hyperglycemia, arthritis, anemia, leukopenia, capillary endothelial proliferation in oral mucosa). Among the 29 patients undergoing esophagectomy, 15 patients (15/29, 51.7%) achieved MPR, including 7 patients with pCR (7/29, 24.1%). Among the 24 patients who received four cycles of neoadjuvant treatment, there were 7 patients with pCR (7/24, 29.2%), and 14 patients with MPR (14/24, 58.3%). No surgery related mortality was documented. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy plus apatinib is a safe and tolerable treatment for patients with locally advanced ESCC, and the MPR and pCR rate are promising. Clinical trial information: ChiCTR1900023880.
The sequence of chemotherapy and anti-PD-1 antibody influence the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell cancer: A phase II study.
Authors: Zhao Lingdi , Xing Wenqun , Yang Yonghao , Zhang Yong , Ma Baozhen , Fu Xiaomin , Liang Guanghui , Shang Yiman , WANG Zibing , Lin Hongwei , Gao Quanli
Published: June 2021

4051

Background: PD-1 blockade may result in expansion of tumor-specific T cells. However, traditional immunochemotherapy regimens usually designed to use chemotherapy drugs and anti-PD-1 antibody on the same day, which may make chemotherapy drugs kill activated T cells. The purpose of this study was to investigate the rate of pCR of chemotherapy plus anti-PD-1 therapy and the influence of sequence of chemotherapy and anti-PD-1 therapy on pCR in patients with locally advanced esophageal squamous cell cancer. Methods: Thirty esophageal squamous cell cancer patients with T3, T4, or lymph node positive were assigned into experiment group (anti-PD-1 antibody was administrated two days after chemotherapy) and control group ( anti-PD-1 antibody and chemotherapy were administrated on the same day) according to the order of enrollment. There were fifteen patients in each group. The chemotherapeutic regimen was paclitaxel and cisplatin, paclitaxel was given at the dose of 150-175mg/m2 on day 1 and cisplatin was given at the dose of 70-75mg/m2 on day 1. The anti-PD-1 antibody was toripalimab at the fixed dose of 240mg on day 3 or day 1. Operation was performed four to six weeks after the second cycle of chemotherapy combined with toripalimab. Results: From July 2019 to September 2020, a total of 30 patients completed at least one cycle of immunochemotherapy. 11 in the experimental group received operation after two cycles of neoadjuvant chemotherapy plus toripalimab. Thirteen in control groupreceived operation aftertwo cycles of neoadjuvant chemotherapy plus toripalimab. Four patients in experimental group and one in control group got pCR, the rates of pCR in experimental group and control group were 36.4% and 7.7% individually. Although the difference was not significant in statistics, the experimental group had the trend of higher pCR rate(c2= 3.092, p = 0.079). PD-L1 CPS examination before treatment was performed in fourteen patients, it was found that except one patient with PD-L1 CPS was 10, the left thirteen with PD-L1 CPS were all below one. The patient with PD-L1 CPS 10 was in control group and pCR was got in this patient. Except one patient in the experimental group had grade 3 immune-related enteritis, one patient in the control group died from immune-related myocarditis after operation, there were no more immune-related events more than grade 3. Conclusions: Toripalimab was delayed on day 3 when toripalimab plus chemotherapy was taken as neoadjuvant therapy regimen in locally advanced esophageal squamous cell carcinoma might achieve a higher pathological complete response than toripalimab and chemotherapy used on the same day. Clinical trial information: NCT 03985670.
IMbrave150: Exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor).
Authors: Ducreux Michel , Zhu Andrew X. , Cheng Ann-Lii , Galle Peter R. , Ikeda Masafumi , Nicholas Alan , Verret Wendy , Li Lindong , Gaillard Vincent E. , Lencioni Riccardo , Finn Richard S.
Published: June 2021

4071

Background: Based on IMbrave150 (NCT03434379) results, atezo + bev has been approved in > 60 countries for pts with unresectable HCC who have not received prior systemic therapy (Finn RS, NEJM 2020). OS and objective response rate (ORR) improvements with atezo + bev vs sor were maintained with an additional 12 mo of follow up since primary analysis. Updated median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (stratified HR, 0.66; 95% CI: 0.52, 0.85). Updated ORR was 30% with atezo + bev vs 11% with sor by independently-assessed (IRF) RECIST 1.1 (Finn RS, ASCO GI 2021). Here, we report an exploratory analysis examining the association of response by RECIST 1.1 with OS and independent predictors of survival. Methods: Pts in this Ph III study were systemic treatment–naive with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. ORR was determined by IRF RECIST 1.1. Kaplan-Meier analyses of OS by response status were conducted without landmark and with 4- and 6-mo landmarks. Multivariate analysis was conducted using Cox modeling with time-dependent covariate (responder [yes/no]) with backwards elimination. These analyses only included pts treated with atezo + bev. Results: IMbrave150 enrolled 501 pts, including 336 treated with atezo + bev. Median follow-up was 15.6 mo. OS was longer in pts with confirmed response per RECIST 1.1 (responders, CR + PR) vs non-responders by Kaplan-Meier analyses without landmark and with 4- and 6-mo landmarks (Table). By multivariate analysis, in addition to responder (yes/no), 5 of the 10 initially included predictors of OS remained in the final Cox model ( P< 0.10): ECOG PS (0/1), geographic region (Asia excluding Japan/rest of the world), etiology (hepatitis B/hepatitis C/non-viral), macrovascular invasion and/or extrahepatic spread (yes/no), and baseline alpha-fetoprotein ( < 400 ng/mL/≥400 ng/mL). Conclusions: Atezo + bev is the new standard of care for pts with previously untreated, unresectable HCC. Here we showed that in IMbrave150 pts treated with atezo + bev, response by RECIST 1.1 was associated with OS, suggesting that confirmed response is an independent predictor of OS in these pts. Clinical trial information: NCT03434379. [Table: see text]
T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).
Authors: McCoon Patricia , Lee Young S , Kelley Robin Kate , Guthrie Violeta Beleva , Wu Song , Bien Stephanie A , Negro Alejandra , He Philip , Kurland John , Barrett J Carl , Pilataxi Fernanda , Ching Steven , Abou-Alfa Ghassan K.
Published: June 2021

4087

Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]
Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Mazard Thibault , Gomez-Roca Carlos A. , Metges Jean Philippe , Cantarel Coralie , Adenis Antoine , Korakis Iphigenie , Poureau Pierre-guillaume , spalato-Ceruso Mariella , Bourcier Kevin , Kind Michèle , Soubeyran Isabelle , Bessede Alban , Italiano Antoine
Published: June 2021

4096

Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma.
Authors: Bai Li , Sun Meili , Xu Aibing , Bai Yuxian , Wu Jian , Shao Guoliang , Song Lijie , Jin Xiaoping , Song Weifeng , Li Baiyong , Xia Yu , Jiao Shunchang
Published: June 2021

4101

Background: Anti–PD-(L)1 plus anti-CTLA-4 therapies (e.g. nivolumab/ipilimumab, tremelimumab/durvalumab) produce durable immune responses in patients (pts) with advanced hepatocellular carcinoma (HCC). More recent data suggests that the combination of immune checkpoint inhibitors (ICIs) with a multi-kinase inhibitor is efficacious against unresectable HCC (uHCC). AK104 is a humanized IgG1 bispecific antibody that simultaneously binds to PD-1 and CTLA-4. Early data suggests that AK104 possesses encouraging anti-tumor activity in selected tumour types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 antibodies. Lenvatinib is a multi-kinase inhibitor and approved for first-line treatment of uHCC. Here, we report results from a phase 2 study of AK104 plus lenvatinib in pts with uHCC. Methods: In this single-arm, multicenter phase II study (NCT04444167), pts with uHCC, BCLC stage B or C, Child-Pugh class A, who had not previously received systemic treatment received AK104 (6 mg/kg IV q2w or 15 mg/kg IV q3w) and lenvatinib (8 mg [bodyweight < 60 kg] or 12 mg [weight ≥ 60 kg] PO QD). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of February 1 2021, 30 pts (86.7% male, median age 52.5yrs [31-71], 30% was ECOG 1, 93.3% was HBV+) had received the combination therapy of (AK104 6 mg/kg q2w plus lenvatinib). Of 18 pts evaluable for antitumor activity (defined as pts with the opportunity to be followed for at least 2 scans [≥13 weeks]), ORR per RECIST v1.1 was 44.4% (8/18), DCR was 77.8% (8 PRs and 6 SDs including 2 pts who had 28.4% and 29.2% reduction in tumor size from baseline). Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3 TRAEs occurred in 26.7% [8/30], and no G4 TRAEs or TRAEs leading to death). Most common TRAEs (≥15%) were increased AST (36.7%) and ALT (36.7%), decreased platelet count (33.3%), decreased neutrophil count (30.0%), and increased blood bilirubin (26.7%), with the vast majority being grades 1 or 2. Conclusions: AK104 plus lenvatinib as first-line therapy for uHCC has showed promising antitumor activity and an acceptable safety profile. Toxicities were manageable, with no unexpected safety signals. Enrollment for AK104 15 mg/kg q3w plus lenvatinib is currently ongoing, and longer follow-up is needed to further evaluate the durability of response. Clinical trial information: NCT04444167.
Should all pancreatic neuroendocrine tumors (PNET) over 1 cm be resected?
Authors: Hsu Diana , Le Sidney , Chang Alex , Spitzer Austin , Kazantsev George , Peng Peter D , Chang CK , Truong Thach-Giao
Published: June 2021

4108

Background: Pancreatic neuroendocrine tumors (PNET) are a heterogeneous group of tumors that represent 1-2% of all pancreatic neoplasms. Their biologic behaviors are unpredictable with high grade, nodal metastasis, or liver metastasis lending an unfavorable prognosis. Current guidelines recommend resection for functioning tumors and those 2 cm or larger but are less straightforward regarding tumors < 2 cm in size. Previous data show that observation for nonfunctioning tumors < 2 cm can be safe and feasible; however, a significant portion of these patients may have nodal involvement or metastatic disease. Methods: A retrospective review was undertaken to identify patients with pancreatic neuroendocrine tumors treated at Northern California Kaiser Permanente (KP-NCAL) between February 2010 and December 2018. Univariate and multivariate analyses were performed with the log-rank test and Cox regression. Chi-squared test of relevant clinicopathologic factors determined which factors were predictive for overall survival (OS). Results: Mean age was 61 years in our cohort of 354 patients, with 29% over the age of 70. Mean tumor size was 3.43 cm; 32% of tumors were 2 cm or smaller. 51% of the patients had localized disease; 32% of the patients presented with metastatic disease. The pancreatic tail was the most common tumor location (38%), followed by the head of the pancreas (24%). On multivariate survival analysis, stage, location of the tumor, and surgical resection were statistically significant in terms of overall survival ( p<.001). Mean OS for patients with localized and metastatic disease was 93 months versus 37 months ( p<.001). Surgery was utilized in 8.9% of patients with metastatic disease ( p<.001). All patients with PNET smaller than 1 cm in our study group had localized disease only. However, in patients with tumor size between 1 and 2 cm, 11% had nodal or metastatic spread. Conclusions: PNETs are indolent but have malignant potential at any size. In our retrospective study, all of the patients with tumor size < 1 cm had localized disease. For those with PNETs 1-2 cm in size, 11% had nodal or metastatic spread. Based on our findings, we suggest a more aggressive surgical resection size criteria of 1 cm.[Table: see text]
Predictive value of germline ATM mutations in the CCTG PA.7 trial: Gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D) and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Renouf Daniel John , Loree Jonathan M. , Knox Jennifer J. , Kavan Petr , Jonker Derek J. , Welch Stephen , Couture Felix , Lemay Frederic , Tehfe Mustapha , Harb Mohammed , Aucoin Nathalie , Ko Yoo-Joung , Tang Patricia A. , Topham James T. , Jia Shidong , Du Pan , Schaeffer David F. , Gill Sharlene , Tu Dongsheng , O'Callaghan Christopher J.
Published: June 2021

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Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.
A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.
Authors: Leung Chris Poki , Barve Minal A. , Wu Ming-Shiang , Pirollo Kathleen F. , Strauss James F. , Liao Wei-Chih , Yang Shih-Hung , Nunan Robert Alan , Adams Jana , Harford Joe B. , Chang Esther H.
Published: June 2021

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Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]
Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.
Authors: Lee Chung-Han , Voss Martin H , Carlo Maria Isabel , Chen Ying-Bei , Reznik Eduard , Knezevic Andrea , Lefkowitz Robert A , Shapnik Natalie , Tassone Diana , Dadoun Chloe , Shah Neil J. , Owens Colette Ngozi , McHugh Deaglan Joseph , Aggen David Henry , Laccetti Andrew Leonard , Kotecha Ritesh , Feldman Darren R. , Motzer Robert J.
Published: June 2021

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Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. [Table: see text]
Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.
Authors: Suarez Rodriguez Cristina , Larkin James , Patel Poulam M. , Valderrama Begoña P. , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Carter Abigail , Tyson Charlotte , Prendergast Aaron , Mousa Kelly , Powles Thomas
Published: June 2021

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Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached [NR]). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3-NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596.
First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.
Authors: Meza Luis A , Dizman Nazli , Bergerot Paulo Gustavo , Dorff Tanya B. , Lyou Yung , Frankel Paul Henry , Mira Valerie , Llamas Marian , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Salgia Sabrina , Malhotra Jasnoor , Chawla Neal Shiv , Chehrazi-Raffle Alex , Gillece John D , Reining Lauren J , Trent Jeffrey M. , Highlander Sarah K , Pal Sumanta K.
Published: June 2021

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Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.