bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC).
Authors: Shah Manish A. , Almhanna Khaldoun , Iqbal Syma , Thakkar Prashant , Schneider Bryan J. , Yantiss Rhonda , Wu Yiru , Futamura Emma , Port Jeffrey L. , Spinelli Cathy , Sarkar Sandipto , Christos Paul J. , Brar Gagandeep , Betel Doron , Sanfilippo Nicholas J. , Altorki Nasser K.
Published: June 2021

4005

Background: Recent transformative studies in the treatment of EAC support adjuvant nivolumab for patients with residual disease following neoadjuvant chemoradiotherapy (CRT) (Checkmate 577) and pembrolizumab (P) with chemotherapy in untreated metastatic disease (Keynote 590). We hypothesized that pre-operative P combined with CRT can further improve outcomes in patients with locally advanced EAC. Methods: Patients with cT3-4Nx or T2N1 M0 EAC or gastroesophageal junction (GEJ) adenocarcinoma eligible for curative surgery were randomized (1:1) to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + P induction therapy. All patients then received CRT with weekly T/C, RT 41.4Gy in 23 fractions, and P every 3 weeks. Following resection, patients received P for one year. The primary endpoint is rate of major pathologic response (MPR), defined as pathologic complete response or near complete response ( < 10% residual cancer), with 80% power and 0.1 one-sided significance level to detect the difference between a MPR proportion of 30% (historical control) and an alternative hypothesis of 47% (with preoperative P). Tissue was collected for tumor immune microenvironment (TIME) analysis including bulk and single cell RNA(scRNA) expression analysis, DNA sequencing, and flow cytometry. Results: From 8/4/17 to 10/26/20, 40 patients were enrolled: median age 68 [38-81], male 32, esophagus/GEJ type I (n = 16), GEJ II/III (n = 24). CRT was well tolerated, with no grade 3-4 adverse events attributed to P. Notable toxicity included grade 3-4 pneumonitis (13%), anastomotic leak (13%), infection (35%). In 31 evaluable patients to date, the MPR rate was 50.0% (95% CI, 32.7%-67.3%). 1-yr disease free survival was 100% for patients with MPR vs. 31.8% without MPR, p = 0.002. Esophageal/GEJ type I cancers had a significantly higher MPR rate when compared with GEJ type II/III (76.9% vs 37.5%, p = 0.03). scRNA seq on > 100,000 tumor cells revealed EAC/GEJ type I had higher infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors have significantly higher infiltration of activated B cells (p = 0.02). Conclusions: The addition of P to preoperative CRT for EAC is safe and associated with a significantly higher MPR rate compared to historical data. We found MPR to be significantly enriched in EAC/GEJ type I tumors compared with GEJ II/III, associated with important differences in the baseline tumor immune microenvironment. Clinical trial information: NCT02998268.
IDH1 and IDH2 Driven Intrahepatic Cholangiocarcinoma (IHCC): A comprehensive genomic and immune profiling study.
Authors: Makawita Shalini , Borad Mitesh J. , Carapeto Fernando , Kwong Lawrence , Bekaii-Saab Tanios S. , Murugesan Karthikeyan , Ross Jeffrey S. , Danziger Natalie , Israel Mason A. , McGregor Kimberly , Janku Filip , Javle Milind M.
Published: June 2021

4009

Background: IDH1/2 genetic aberrations (GA) occur in 20% of IHCC cases and may be specifically targeted by IDH inhibitors. The genomic and immunologic profile of IHCC with IDH1/2 GA remains undefined. IDH1 mutations impair DNA damage repair (DDR), loss of heterozygosity (LOH) and may represent a biomarker for DDR in these patients. Methods: Comprehensive genomic profiling (CGP) was performed in 3,067 cases of advanced stage IHCC using a hybrid capture-based FDA-approved assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by immunohistochemistry (IHC). Genomic LOH (gLOH) was assessed for samples meeting quality criteria. Densities of tumor associated immune cells and immune-checkpoint markers expressed in epithelial malignant cells and in the tumor microenvironment of 100 surgical samples from 96 patients were evaluated by IHC using digital image analysis of 14 markers (CD3, CD4, CD8, CD68, PD1,PD-L1, B7-H4, B7-H3, IDO1, ICOS, VISTA, OX40, TIM3, LAG3). Tissue microarrays were generated for multiplex immune panel analysis. A p value < 0.05 was considered statistically significant. Results: 426 (14%) of IHCC were IDH1+ and 125 (4%) were IDH2+ (Table) and were mutually exclusive. All IDH1 GA occurred at the R132 locus and included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/ < 1%) and 119Q ( < 1%) and IDH2 GA at R172 (94.4%) and R140 (6.6%). IDH1+ and IDH2+ IHCC had fewer co-occurring targetable GA than IDH1/2 wildtype (WT, IDHwt) cases including FGFR2 rearrangements (RE) (P <.0001), ERBB2 (P =.0009) and BRAF (P =.04). Median gLOH were not significantly different between IDH1+ IDH2+ IHCC vs. IDHwt IHCC (p = 0.37). Potential biomarkers of immune checkpoint inhibition (ICI) response including MSI High, TMB > 10 mut/Mb, and PD-L1 positivity were more frequent in IDHwt IHCC than IDH1+ IHCC. 29/96 (30%) surgical patients were positive for IDH1/2 mutation though mutational status did not confer a statistically significant difference in the 14 immune biomarker panel expression. Conclusions: CGP reveals significant differences in GA between IDH1+, IDH2+ and IDHwt IHCC consistent with IDH1 and IDH2 being driver oncogenes for IHCC. Immune biomarker expression and gLOH did not differ significantly between IDH mutated and WT cases.[Table: see text]
Camrelizumab combined with FLOFOX as neoadjuvant therapy for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma: Updated results of efficacy and safety.
Authors: Liu Ying , Han Guangsen , Li Hongle , Zhao Yuzhou , Li Zhi , Zhuang Jing , Wang Gangcheng , Li Baodong , Wang Jinbang , Li Zhimeng , Xia Qingxin , Zhang Chengjuan , Yu Juan , Li Ke , Xu Shuning , Qiao Lei , Kuang Gaizhen , Li Danyang
Published: June 2021

4036

Background: Although anti-PD-1 antibody in combination with chemotherapy has shown promising antitumor activity in advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), the evidence of neoadjuvant therapy for locally advanced GC/GEJC is limited. Camrelizumab combined FOLFOX as neoadjuvant therapy for resectable locally advanced GC/GEJC was a prospective, single-arm, phase 2 study we conducted. Here, we updated the results of efficacy and safety of this study. Methods: Patients confirmed by endoscopic ultrasonography (EUS) and imaging with clinical stage≥T2 and/or positive lymph nodes were enrolled. They received 4 cycles of camrelizumab (200mg ivgtt on day1, q2w) plus FOLFOX (oxaliplatin 85mg/m2 ivgtt, LV 200mg/m2 ivgtt, 5-Fu 400mg/m2 iv followed by 2.4mg/m2 CIV 46 hours on day 1, q2w) as neoadjuvant therapy. Then patients without disease progression evaluated by imaging underwent gastrectomy of D2 lymph node dissection. The primary endpoint was pCR, the secondary endpoints were R0 resection rate and safety. Results: Between Jul 24 2019 and Nov 30 2020, 49 patients were enrolled. The median age was 57 years (29-72 years). All patients completed 4 cycles treatment. Unfortunately, 2 of them were confirmed PD by imaging. In addition, two patients refused gastrectomy and withdrew from the study. Eventually, 45 patients underwent gastrectomy, of which 3 patients had intraperitoneal metastases during the operation. A total of 42 patients were evaluable, all of them gained R0 resection (100%), 4 patients (10%) achieved pCR and 10 patients (24%) reached TRG1. Among the patients experienced pCR, one of them was Her-2 positive, one was MSI-H, the rest two of them were PD-L1-positive (CPS≥10). The most common ≥grade 3 adverse events (AEs) were neutropenia (35%) and leukopenia (16%). Only 1 patient (2%) experienced grade 3 immune-related AEs of alanine aminotransferase and aspartate aminotransferase increase. No serious AEs resulted in termination of treatment or death. Conclusions: Camrelizumab combined with FOLFOX was an effective and safe neoadjuvant therapy strategy for patients with resectable locally advanced GC/GEJC. Furthermore, the analysis of biomarkers with clinical benefits is undergoing. Clinical trial information: NCT03939962. [Table: see text]
A prospective, phase II, single-arm study of neoadjuvant/conversion therapy with camrelizumab, apatinib, S-1 ± oxaliplatin for locally advanced cT4a/bN+ gastric cancer.
Authors: Li Song , Yu Wenbin , Xie Fei , Liu Zhimin , Lv Weiwei , Shi Duanbo , Yu Dexin , Wei Meng , Wang Jiaqian , Zhao Yongtian , Chen Cheng , Zhao Zhikun , Gao Jing , Sheng Lei , Liu Lian
Published: June 2021

4061

Background: The prognosis of cT4a/bN+ gastric cancer (GC) is poor due to low R0 resection rate and frequent recurrence. We evaluated the feasibility, safety, and efficacy of a combination of immunotherapy, anti-angiogenesis, and chemotherapy for neoadjuvant/conversion treatment of cT4a/bN+ GC. Methods: Patients with T4a/bN+ GC were enrolled to receive camrelizumab (200mg d1), apatinib (250mg d1-14), S-1 (50mg bid d1-10) ± oxaliplatin (85 mg/m2 d1) for at least 2 cycles, followed by re-evaluation and operation. Peri-treatment samples were collected for whole-exome, transcriptome, and T cell receptor (TCR) sequencing. Pathological response (PR) and its relationship with genomic biomarkers are primary endpoints. Results: 25 patients were enrolled, with median age 63 (48-70), 19 male, 11 cT4aN2-3 and 14 cT4bN2-3. The radiological response (RR) rate of the treatments was 33.3% (8/24), and tumor down-staging rate 79.2% (19/24). 24 patients completed re-evaluation, with 3 failed conversion, 2 refused surgery, and 1 postponed surgery for immune-related pneumonia. Among the 18 patients with R0 resection, 3 got complete PR (CPR), 2 major PR (MPR, ≤10% residual cancer cells), and 3 partial PR (11̃49% residual cancer cells), with a PR rate of 44.4% and MPR+ (MPR & CPR) rate of 27.8%. 62.5% patients with PR and 83.3% patients with RR overlapped with each other. At a median of 12.5 (3.4-19.5) months of follow-up, 13 of 17 patients (76.5%) with R0 resection were recurrence-free. No ≥3 toxicity was found. Besides high microsatellite instability, tumor mutation/neoantigen burden (TMB/TNB), mutation signatures (“DNA damage repair” and “DNA mismatch repair”) and related gene mutations (BRCA2, PRKDC, ATM, POLD1, POLE), several novel driver mutations (SSPO, TRPS1, and DOCK2) and copy number variants (DUSP15 loss, FDFT1 gain, and RBBP8NL loss) were related to MPR+ GC. The combination therapy decreased TMB/TNB, facilitated infiltration of active immune cells (CD4+ memory T, CD8+ T, activated and plasmacytoid dendritic cells, and M1 macrophage), and specifically boosted TCR clonality in MPR+ patients. Besides, numbers of mesenchymal stem cells decreased in MPR+ but increased in MPR- GC after the treatment. Conclusions: Combination of camrelizumab, apatinib, S-1 ± oxaliplatin is feasible, safe, and efficient in neoadjuvant/conversion therapy for cT4a/bN+ GC. It may remodel immune microenvironments and induce anti-tumor immune responses. Clinical trial information: NCT03878472. [Table: see text]
Updated results of a phase 1b study of regorafenib (REG) 80 mg/day or 120 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , Kim Richard D. , Harris William Proctor , Sung Max W. , Waldschmidt Dirk , Cabrera Roniel , Garosi Vittorio Luigi , Zebger-Gong Hong , Brennan Barbara J. , Wang Ying A. , Mueller Udo , Ishida Tatiane Cristine , Galle Peter R.
Published: June 2021

4078

Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]
Pemigatinib for previously treated locally advanced/metastatic cholangiocarcinoma (CCA): Update of FIGHT-202.
Authors: Abou-Alfa Ghassan K. , Sahai Vaibhav , Hollebecque Antoine , Vaccaro Gina M. , Melisi Davide , Al-Rajabi Raed Moh'd Taiseer , Paulson Andrew Scott , Borad Mitesh J. , Gallinson David H. , Murphy Adrian Gerard , Oh Do-Youn , Dotan Efrat , Catenacci Daniel , Van Cutsem Eric , Lihou Christine Francis , Zhen Huiling , Féliz Luis , Vogel Arndt
Published: June 2021

4086

Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]
Natural history of patients (pts) with advanced cholangiocarcinoma (CCA) with FGFR2 gene fusion/rearrangement or wild-type (WT) FGFR2.
Authors: Shroff Rachna T. , Rearden Jessica , Li Ai , Moran Susan , Shepherd Stacie Peacock , Lamarca Angela
Published: June 2021

4089

Background: CCA is a rare, heterogeneous malignancy with poor prognosis due to late onset of symptoms and relative resistance to available therapies. FGFR2 fusions are common, occurring in 10–16% of intrahepatic CCA (iCCA). There is increasing awareness of the importance of molecular profiling to inform treatment choices, although real-world data (RWD) are lacking on the natural history of pts with CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. This retrospective, observational, natural history study used a nationwide (US-based) de-identified clinico-genomic database (CGDB) to compare overall survival (OS) in pts with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine CCA CGDB (FH-FMI-CGDB). The data originated from approximately 280 US cancer clinics (̃800 sites of care). Pts were ≥18y of age, had chart-confirmed advanced CCA, comprehensive genomic profiling, and ≥2 visits within the Flatiron Health network since Jan 1, 2011. Primary objective: evaluate OS in pts with FGFR2 fusions/rearrangements and WT FGFR2 from the index date (date of diagnosis of advanced CCA) to date of death from any cause. A key secondary objective was to evaluate the influence of FGFR status on OS after adjusting for potential prognostic variables. Risk-set adjustment was used to account for left truncation for all time-to-event analyses. Results: As of May 2020, 571 pts from the CCA FH-FMI-CGDB met the inclusion criteria; 75 pts with FGFR2 fusions/rearrangements (median age 63y; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 pts FGFR2 WT (median age 65y; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median OS was numerically higher, but not statistically different, for pts with FGFR2 fusions/rearrangements vs FGFR2 WT (12.1m [95% CI 8.5−17.1] vs 7.1m [95% CI 5.7−8.8]; log rank p = 0.184). Median OS was also numerically higher, but not statistically different, for FGFR2 fusions/rearrangements vs FGFR WT in the subset of 437 pts with iCCA (12.1m [95% CI 8.4−17.1] vs 7.8m [95% CI 6.1−10.0]; log rank p = 0.375). FGFR2 status was not a significant factor contributing to OS in univariate, bivariate, or multivariate models after adjusting for potential prognostic covariates. Conclusions: This analysis of RWD did not demonstrate a clear survival advantage for pts with FGFR2 fusions/rearrangements vs FGFR2 WT CCA receiving therapies for advanced disease, although a non-significant trend towards longer OS was observed in pts with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of OS after adjusting for potential prognostic covariates. An additional sub-analysis is ongoing to determine OS from time of initiation of second-line therapy in pts with FGFR2 fusions/rearrangements.
Comparative effectiveness of sorafenib, lenvatinib, and nivolumab as first-line systemic therapy for patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis treated at VA Medical Centers.
Authors: Chapin William Joseph , Hwang Wei-Ting , Karasic Thomas Benjamin , McCarthy Anne Marie , Kaplan David Edward
Published: June 2021

4102

Background: Up to 90% of cases of hepatocellular carcinoma (HCC) in the U.S. occur in patients with cirrhosis. As prognosis in patients with decompensated cirrhosis may be more related to liver function than tumor stage, patients with Child-Pugh (CP) class B and C cirrhosis are often excluded from randomized trials despite representing up to 30% of patients treated with systemic therapy in clinical practice. While prospective data such as the GIDEON registry and CHECKMATE-040 have demonstrated safety of sorafenib and nivolumab in CP B cirrhosis, studies of comparative effectiveness of sorafenib, lenvatinib, and nivolumab are lacking. Methods: We performed a retrospective cohort study of patients with HCC and CP B cirrhosis at U.S. Veterans Affairs Medical Centers who initiated first systemic therapy with sorafenib, lenvatinib, or nivolumab between 9/22/2017 and 2/13/2021. Overall survival (OS) by first systemic therapy was assessed with Kaplan Meier analysis and Cox proportional hazards modeling with pre-specified candidate covariates and a backward elimination approach for variable selection. Missing data were imputed by multiple imputation with chained equations. Results: Among 401 CP B patients undergoing first systemic therapy, 98% were male, 29% had macrovascular invasion (MVI), 35% had extrahepatic spread (EHS), 57%/29%/13% had CP score 7/8/9, 5% had hepatic encephalopathy, 37% had ascites, 63%/2%/36% had HCV/HBV/non-viral cirrhosis, 63% had prior embolization or ablation, and 35% had ECOG performance status of > = 2. Of these patients, 320 received sorafenib, 33 received lenvatinib, and 48 received nivolumab. In univariate analysis, median OS was 4.8 months (95% CI 3.8 – 6.0; 1 year OS 21.8%) in the sorafenib cohort, 6.9 months (95% CI 4.4 – 8.4 months; 1 year OS 27.8%) in the lenvatinib cohort, and 7.7 months (95% CI 3.9 – 9.1 months; 1 year OS 31.7%) in the nivolumab cohort. Covariates with at least one category significantly associated with survival that were retained in the multivariate model included CP score, MELD-Na, BMI, log(AFP), time from diagnosis to systemic treatment, ECOG performance status, Cirrhosis Comorbidity index, and VA complexity level (all p < 0.05); MVI, EHS, and age were retained in the model as pre-specified despite lack of statistical significance. Compared with sorafenib, nivolumab was associated with significantly lower hazard of death (adjusted HR 0.63; 95% CI 0.43 – 0.91; p = 0.015) while hazard of death for lenvatinib treatment was not significantly different (adjusted HR 0.83; 95% CI 0.54 – 1.28, p = 0.41). Conclusions: Among patients with HCC and CP class B cirrhosis undergoing first systemic therapy, nivolumab was associated with significantly lower hazard of death compared to sorafenib after adjusting for important covariates.
Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter prospective universal genetic testing study.
Authors: Uson Junior Pedro Luiz Serrano , Riegert-Johnson Douglas , Boardman Lisa A. , Borad Mitesh J. , Ahn Daniel H. , Sonbol Mohamad Bassam , Faigel Douglas O , Fukami Norio , Pannala Rahul , Kunze Katie , Golafshar Michael A , Esplin Edward D. , Nussbaum Robert Luke , Bekaii-Saab Tanios S. , Samadder Jewel
Published: June 2021

4118

Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]
Genomic profiling of KRAS wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.
Authors: Wei Deng , Li Xiaomo , Zhang Xinsheng , Ma Tonghui , Liu Rong
Published: June 2021

4121

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRASmutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P < 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.
Efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Jin Gang , Guo Shiwei , Zhang Yanqiao , Ma Yue , Guo Xiaodong , Zhou Xiaocui , Yu Qin
Published: June 2021

4138

Background: Pancreatic ductal adenocarcinoma（PDAC）is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Nab-paclitaxel plus gemcitabine has been recommended by international guidelines for first-line treatment of advanced PDAC but chemoresistance is difficult to avoid. Combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated substantial promise for the treatment of several advanced malignancies. A few recent studies have begun to explore the effect of ICIs monotherapy or co in advanced PDAC with few meaningful results. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. The purpose of this study is to evaluate the efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC. Methods: This ongoing phase II trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and never received systemic anti-tumor therapy for advanced or metastatic diseases. KN046 (5mpk, Q2W) plus nab-paclitaxel (125mg/m2, D1, 8, 15, Q4W) and gemcitabine (1000mg/m2, D1, 8, 15, Q4W) were administered 4-6 cycles followed by KN046 (5mpk) maintenance therapy every 2 weeks. Tumour response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed ORR. Secondary endpoints are DCR, DOR, TTP, PFS, OS and safety. Results: As of December 15, 2020, 17 pts were enrolled, median (range) age was 56 (36-75) years, 9 pts ECOG 1, and 7 pts had liver metastases. Median KN046 exposure time was 9.5 wks. 9 pts were included in the efficacy analysis and 17 pts in the safety analysis. In best overall response assessment, there were 55.6% PR (5/9) and 33.3% SD (3/9). ORR was 55.6% (95% CI: 21.2̃86.3), and DCR was 88.9% (95% CI: 51.8̃99.7). The overall incidence of KN046 related treatment-emergent adverse events was 64.7%, with 29.4% were grade 3 TRAE. The most common KN046 related treatment-emergent adverse events (≥10%) were alanine aminotransferase increased (n = 5, 29.4%), nausea (n = 3, 17.6%), rash (n = 3, 17.6%), aspartate aminotransferase increased (n = 2, 11.8%), diarrhoea (n = 2, 11.8%), hyperphosphataemia (n = 2, 11.8%), pyrexia (n = 2, 11.8%), vomiting (n = 2, 11.8%). Conclusions: Combining KN046 with nab-paclitaxel and gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC patients is safe and feasible, and lays the foundation for subsequent clinical trials. Clinical trial information: NCT04324307.
Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.
Authors: Mahalingam Devalingam , Chen Siqi , Xie Ping , Kalyan Aparna , Kircher Sheetal Mehta , Kocherginsky Masha , Xu Jiahui , Maurer Victoria , Viveiros Pedro Antonio Hermida de , Vagia Elena , Wilkinson Grey A , Coffey Matthew C. , Mulcahy Mary Frances , Benson Al Bowen , Zhang Bin
Published: June 2021

4144

Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x1010 TCID50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.
Safety evaluation of combined PD-1+CTLA4 inhibition concurrently to chemoradiotherapy (CRT) in localized muscle invasive bladder carcinoma (MIBC).
Authors: de Ruiter Ben-Max , van Hattum Jons Wouter , De Reijke Theo Maria , Oddens Jorg Reinier , Hulshof Maarten C.C.M. , Bins Adriaan Dirk
Published: June 2021

4531

Background: Neoadjuvant nivolumab (nivo) + ipilimumab (ipi) prior to radical cystectomy showed efficacy in localized MIBC. The safety of PD-1 and PDL-1+CTLA4 inhibition concurrent with CRT in localized MIBC has not been assessed. We present the first clinical trial data on concurrent 3 doses of q4w nivo 480mg (cohort1) and concurrent 4 doses of q3w nivo 3mg/kg + ipi 1kg/mg (nivo3+ipi1, cohort2) in combination with Mitomycin C/Capecitabin (MMC/Cape) CRT. Methods: We report the first 2 cohorts of a phase 1b, EC approved, study with nivo only or nivo3+ipi1 added to MMC/Cape CRT. CRT consists of MMC i.v. on day 1 with Cape 750mg/m2 on days of radiotherapy. Radiotherapy schedule comprises a 20x2Gy whole bladder irradiation with a simultaneous tumorboost of 20x0.75Gy. Patients with MIBC, T2-4N0-1, ECOG performance status <2 were included. A dose escalation scheme, with a staggered enrollment is used. The first 10 patients received nivo 480mg on week 1, 5, 9. Cohort2 of 10 patients received nivo3+ ipi1 at week 1, 4, 7 and 10. Relevant severe Adverse Events (AEs) were registered as Dose Limiting Toxicity (DLT) when they occurred within 6 weeks after start of treatment. Clinical efficacy is evaluated by cystoscopy and CT at week 12 and 24. Results: Both cohorts enrolled 10 patients. Median age was 68 [IQR 61-75] and 70 [IQR 66-75] years in cohort1 and 2, respectively. In cohort1 no patients experienced DLT. No dose reductions were applied. In cohort2, 2 patients experienced DLT, 1 trombocytopenia (grade 4) and 1 asystole (grade 5). 50% of patients did not receive all 4 q3w nivo3+ipi1 infusions, due to AEs. Table 1 reports an overview of AEs. In cohort2 6 SAE’s occurred in 3 patients. Median follow up is 71 [IQR 59-86] and 30 weeks [IQR 12-45] in cohort1 and 2, respectively. 1year OS and DFS is 100% in cohort1. Conclusions: Concurrent 3 doses nivo 480mg q4w added to MMC/Cape based CRT is feasible with a favorable toxicity profile and shows promising efficacy in MIBC patients. An escalated regimen with 4 doses nivo 3mg/kg + ipi 1mg/kg q3w concurrent to CRT shows acceptable toxicity. Cohort3 with ipi 3mg/kg and nivo 1mg/kg is enrolling. Clinical trial information: NCT03844256. [Table: see text]
Response and outcomes to immune checkpoint inhibitors (ICI) in advanced urothelial cancer (aUC) based on prior intravesical BCG.
Authors: Talukder Rafee , Makrakis Dimitrios , Castellano Daniel , Koshkin Vadim S , Alva Ajjai Shivaram , Stewart Tyler F. , Santos Victor Sacristan , Jain Jayanshu , Morales-Barrera Rafael , Grant Michael , Nelson Ariel Ann , Shreck Evan , Sankin Alexander , Zakopoulou Roubini , Rodriguez-Vida Alejo , Liu Sandy , Fröbe Ana , Di Lorenzo Giuseppe , Grivas Petros , Khaki Ali Raza
Published: June 2021

4537

Background: Little is known regarding response and outcomes to ICI for patients (pts) with aUC who were previously treated with BCG for non-muscle invasive bladder cancer. We hypothesized that prior intravesical BCG would not be associated with changes in objective response or survival in pts with aUC treated with ICI. Methods: We performed a retrospective cohort study across 25 institutions. Demographic, intravesical BCG history, treatment and outcomes data were collected for pts with aUC who received ICI. Pts with aUC treated with ICIs were included, pts with pure non-UC, those treated with combination or on clinical trials, pts with multiple ICI treatment lines and those with upper tract UC were excluded. Pts were stratified to prior exposure versus no exposure to BCG. We compared overall response rate (ORR) using logistic regression; and progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards. All analyses were performed in the overall population and further stratified by treatment line (first-line [1L] vs salvage [2+L]) and multivariable models. The stratified analysis was also adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p<0.05 was significant. Results: 1026 aUC pts treated with ICI were identified; 614 pts, 617 pts, and 641 pts were included in ORR, OS and PFS analyses, respectively. Overall, mean age at CPI initiation was 70, 76% were men, 70% were current or former smokers, 75% White, 29% with mixed histology, and 24% had prior exposure to BCG. ORR to ICI in pts with or without prior exposure to BCG was similar, 27% and 28% respectively (OR=0.93 [95% CI 0.61-1.42], p=0.73). Median OS (mOS) for pts with vs without prior BCG exposure was 9 vs 10 mo (HR=1.13 [95% CI 0.88-1.44], p=0.35). Median PFS (mPFS) was 4 months (mo) in both groups (HR=1.02 [95% CI 0.82-1.27], p=0.83). ORR, PFS and OS analyses stratified by ICI treatment line (1L vs 2+L) are listed in the table. Conclusions: In this multi-institutional retrospective analysis, prior intravesical BCG was not associated with objective response or survival in pts with aUC treated with ICI. Limitations of this study include retrospective nature, lack of randomization and possible confounding, but it does provide important preliminary data that selection for ICI treatment should not be impacted by prior exposure to BCG. Further clinical and molecular biomarker exploration is needed to refine patient selection for ICI in aUC.[Table: see text]
Integrating peripheral biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Choueiri Toni K. , Donahue Amber C , Rini Brian I. , Powles Thomas , Haanen John B. A. G. , Larkin James , Mu Xinmeng Jasmine , Pu Jie , Thomaidou Despina , Di Pietro Alessandra , Robbins Paul B. , Motzer Robert J.
Published: June 2021

4547

Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients (pts) with aRCC demonstrated prolonged progression-free survival (PFS) and a higher objective response rate with A + Ax vs S. We report the association of blood-based biomarkers with differential responses to treatment. Methods: Biomarkers in pretreatment (pre-tx) and on-treatment (on-tx) blood samples from 886 enrolled pts were correlated with clinical outcomes and molecular profiling data from corresponding tumor samples. Analyses include blood counts of unique populations, T-cell receptor sequencing, circulating cytokines, and serum proteomics by mass spectrometry MALDI-TOF. Results: At baseline, higher pre-tx monocyte counts were associated with shorter PFS in the A + Ax arm (Table). In the S arm, higher pre-tx levels of multiple T-cell–related metrics, including the percent of productively rearranged peripheral T cells, were associated with longer PFS but had no association in the A + Ax arm (Table). Higher pre-tx neutrophil counts were associated with shorter PFS in both arms, but neutrophil-to-lymphocyte ratio (NLR) was only associated with PFS for the S arm (Table). On-therapy biomarkers showed differential post-tx changes in T-cell numbers and clones at C2D1. Tx-specific differences were also seen in non–T-cell populations such as monocytes and neutrophils at multiple time points through C3D1. Serum levels of pre- and on-tx VEGF, CRP, and several interleukins showed differential associations with PFS (eg, higher pre-tx VEGF was associated with shorter PFS in only the S arm) (Table). Specific genomic alterations in tumor tissues were associated with differences in several pre- and on-tx angiokines & cytokines. Conclusions: Response to treatment with first-line A + Ax or S was associated with immune fitness and tx-specific immunomodulation. We identified peripheral biomarkers in pts with aRCC associated with the presence of impactful genomic alterations and differential clinical outcomes. Clinical trial information: NCT02684006. [Table: see text]
Ipilimumab + nivolumab in people with rare variant renal cell carcinoma refractory to nivolumab alone: Part 2 of UNISON (ANZUP 1602) nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma.
Authors: Gedye Craig , Pook David William , Krieger Laurence Eliot Miles , Harris Carole A. , Goh Jeffrey C. , Kichenadasse Ganessan , Gurney Howard , Underhill Craig , Parnis Francis , Joshua Anthony M. , Ferguson Tom , Roncolato Felicia , Harrison Michelle L. , Begbie Stephen , Morris Michelle Frances , Hovey Elizabeth J. , George Mathew , Prithviraj Prashanth , Link Emma , Davis Ian D. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: June 2021

4565

Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.