bluuebunny/crossref_metadata_2025 huggingface dataset:
CB-839, panitumumab, and irinotecan in RAS wildtype (WT) metastatic colorectal cancer (mCRC): Phase I results.
Authors: Ciombor Kristen Keon , Whisenant Jennifer , Cardin Dana Backlund , Goff Laura Williams , Das Satya , Schulte Michael , Cohen Allison , Coffey Robert J. , Ayers Gregory Dan , Krumsick Rachel , Demo Susan , Whiting Sam H. , Manning H. Charles , Berlin Jordan
Published: January 2019

574

Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) are approved in RAS WT mCRC; however, patients (pts) will develop resistance to these agents. Alterations in glutamine (Gln) metabolism play a critical role in cancer cell growth. In cancers such as CRC, EGFR and Gln cooperate to provide signals and fuel for mitogen activated protein kinase-dependent cell growth. Our in vitro data show that Gln abrogates EGFR inhibition, and blockade of Gln transport restores sensitivity. We also observed a greater antitumor response in vivo with EGFR mAb plus CB-839, an inhibitor of a rate-limiting enzyme of Gln metabolism, than either agent alone. We designed a phase I/II study (NCT03263429) to evaluate CB-839 + panitumumab + irinotecan in anti-EGFR refractory RAS WT mCRC. Methods: Dose escalation used a Bayesian continual reassessment method targeting a 25% toxicity probability. CB-839 (600 mg or 800 mg twice daily [BID]) were evaluated with panitumumab (6 mg/kg) and irinotecan (180 mg/m2). Irinotecan was included in phase I to establish a future phase II dose of the triplet. Prior EGFR mAb treatment (tx) was not required for phase I. Dose-limiting toxicity (DLT) was any tx-related non-hematologic ≥Gr 3 toxicity (except fatigue, rash, or elevated liver enzymes) or ≥Gr 4 hematologic toxicity during the first 28 days. Results: Nine pts have been enrolled; 2 were not evaluable for DLT and replaced. Zero DLTs were observed at dose level 1 (n = 3) or 2 (n = 4); 2 more pts are needed to confirm the maximum tolerated dose (MTD). Most frequent toxicities were anemia and hypomagnesemia (88%) and elevated alkaline phosphatase, nausea, and rash (75%), most ≤Gr 2. One of 7 evaluable pts (14%) has an ongoing partial response, and 5 pts had stable disease (SD; 71%). Three pts have been on tx > 6 months, and 3 pts with prior EGFR mAb tx achieved SD. Conclusions: Triplet combination was tolerable at full doses of each drug, and preliminary antitumor activity was observed in a majority of pts. Phase II will begin after phase I completion and will evaluate efficacy of CB-839 (800 mg BID) and panitumumab (6 mg/kg). Imaging studies using investigational PET tracers to evaluate Gln metabolism as a function of tumor response are planned. Clinical trial information: NCT03263429.
Comprehensive landscape of gene amplifications (amps) in tissue and circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC).
Authors: Raghav Kanwal Pratap Singh , Yaeger Rona , Loree Jonathan M. , Dasari Arvind , Morris Van K. , Kee Bryan K. , Raymond Victoria M. , Nagy Rebecca J , Lanman Richard B. , Strickler John H. , Corcoran Ryan Bruce , Overman Michael J. , Kopetz Scott
Published: January 2019

604

Background: Amps, as oncogenic and resistance drivers, have therapeutic implications, but unlike mutations, have been sparsely described in mCRC. Functional account is piecemeal due to vague definitions, limited data on co-occurring alterations and use of primary tissue samples nonrepresentative of tumor heterogeneity. Our aim was to define the amp landscape in mCRC using tissue and ctDNA sequencing. Methods: We performed systematic analyses of copy-number variation in 2 cohorts of mCRC patients (pts) [tissue (TC) (N = 1,134) and ctDNA (BC) (N = 3,218)] who had high sensitivity targeted sequencing with MSK-IMPACT (341-468 genes) or Guardant Health (70-73 genes) panel, respectively. For BC, plasma copy number was adjusted (ApCN) to account for variable tumor DNA shedding using max allele frequency and high amp (HAmp) was defined as > 4 copies (similar to predefined tissue cutoff). Results: 166 (15%) and 405 (13%) pts in TC and BC harbored amp in at least one of 18 genes assessed by both panels (Table). Amp prevalence for individual gene was similar in both cohorts ( r = 0.9; P < .01) with RTK amps ( EGFR, ERBB2, MET, FGFR1/2, PDGFRA) seen in 8% pts. Key RTK amps were enriched in RAS/BRAF wild type (RB WT) compared to mutant (RB MUT) (OR 3.5; P < .01) pts in both cohorts, in contrast to low prevalence RTK and non-RTK amps. Median ApCN was higher for RTKs in RB WT vs MUT cases ( ERBB2: 12 vs 5; P = .02). Using validated EGFRab exposure (EGFRi) ctDNA signature, we found that EGFRi pts had higher prevalence of EGFR, MET, BRAF, KRAS, PIK3CA and FGFR1 amps compared to EGFRab naïve pts. Conclusions: While individually uncommon, amps occur across key oncogenic pathways in mCRC and after adjusting for ctDNA shedding, are seen at similar prevalence in tissue and plasma. Amps in RTKs are seen in 10-12% of RB WT tumors, suggesting clinically relevant roles as oncogenic effectors and targets. After EGFRi, a number of amps emerge, including PIK3CA and FGFR1 amps, not previously implicated in acquired resistance. [Table: see text]
The efficacy of neoadjuvant treatment in locally advanced rectal cancer with dMMR.
Authors: Deng Yanhong , Zhang Jianwei
Published: January 2019

615

Background: The incidence of Mismatch repair gene deficiency (dMMR) was about 15% in colorectal cancer, but mostly in right side colon cancer, while in locally advanced rectal cancer, it is very rare. As is known, adjuvant chemotherapy with 5FU alone was not recommended in stage II colon cancer with dMMR or MSI. However, in locally advanced rectal cancer with dMMR or MSI, the efficacy of neoadjuvant treatment with 5FU was not yet known. Methods: We enrolled patients with locally advanced rectal cancer from three prospective clinical trials, including the FOWARC study (N = 309), the mFOLFOXIRI neoadjuvant chemotherapy trial (N = 106) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). From the 544 patients, 35 (6.4%) patients were dMMR, 133 patients with unknown status of MMR. Among the 35 patients, 10 patients received 5FU concurrent with radiotherapy (group A), nine patients underwent FOLFOX concurrent with radiation (group B), and 12 patients received FOLFOX neoadjuvant chemotherapy alone (group C). Another four patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (group D), including one patient with nivolumab as neoadjuvant treatment after chemotherapy. Results: Totally, 4 (11.4%) patients achieved pathologic complete response, and 13 (37%) patients had tumor downstaging to ypT0-2N0M0 (stage 0-I). In group A, the pCR rate was 10% (1/10), the tumor downstaging rate was 20% (2/10); In group B, the pCR rate was 33.3% (3/9), the tumor downstaging rate was 55.6% (5/9); In group C, the tumor downstaging rate was 41.7% (5/12). In group D, only one patient achieved pCR, and it is the one who received nivolumab as neoadjuvant treatment. Conclusions: The efficacy of neoadjuvant in locally advanced rectal cancer seemed not affected by the MMR status. But further study was needed.
First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA).
Authors: Janjigian Yelena Yuriy , Chou Joanne F. , Simmons Marc , Momtaz Parisa , Sanchez-Vega Francisco , Shcherba Marina , Ku Geoffrey Yuyat , Won Elizabeth , Chong Curtis Robert , Gerdes Hans , Kelsen David Paul , Ilson David H. , Aljallad Kathrena , Segal Michal Fani , Millang Brittanie M , Schultz Nikolaus , Shah Pari M. , Solit David B. , Capanu Marinela , Hechtman Jaclyn Frances
Published: January 2019

62

Background: Trastuzumab stimulates HER2-specific T cell responses and increases tumor PD-L1 expression, and anti-PD-1 antibody can help enhance T cell-specific immunity of trastuzumab. Oxaliplatin can further enhance T-cells by activating dendritic cells. We conducted a phase II trial of pembrolizumab with chemotherapy/trastuzumab. Methods: Patients with previously untreated HER2 IHC 3+ or FISH+ tumors irrespective of PD-L1 status received intravenous P 200 mg flat dose, T 6 mg/kg (after 8 mg/kg load), O 130 mg/m2 every 3 weeks and oral C 850 mg/m2 2 weeks on/1 week off (or 5-FU continuous infusion). The primary endpoint was 6-months PFS; with target accrual of 37 patients. Secondary endpoints included safety, OS, ORR, exploratory biomarker analysis and 89Zr-trastuzumab PET. Results: 100% of the 24 evaluable pts had tumor regression (ranging from -22% to -100%). The RECIST 1.1 ORR was 83% [95%CI: 63%-95%] (17 PR , 3 CRs), median PFS 11.4 [95%CI: 6-15] months. In 31 pts evaluable for toxicity, common ( > 10%) adverse events included Gr 2 fatigue (35%), Gr 2/3 nausea (35%), Gr 2 diarrhea (26%), Gr2 AST/ALT elevation (16%), Gr2 neutropenia (16%). Immune related toxicities observed in 1 pt each: Gr 2 colitis, Gr 3 interstitial nephritis, Gr 3 AST/ALT elevation; and resolved with steroids. Of 21 patients with available material, 6 (29%) expressed PD-L1. Of these 6 patients, 5 had a PR while 1 had a CR. ERBB2 amplification was evident on NGS in 56% of pre-treatment tumors from 25 tested patients, while the remaining were ERBB2- by NGS likely due to tumor heterogeneity or low tumor content. Mutations in TP53 and alterations in KRAS occurred in 68% and 16%, respectively. To identify mechanisms of acquired resistance, patients are biopsied at progression. In 6 paired sample analysis, we identified two patients with loss of ERBB2 amp at progression. Conclusions: Updated survival, correlative studies and 89Zr-trastuzumab PET imaging will be presented. These promising preliminary safety and efficacy results led to initiation of a definitive phase III Keynote 811 trial. Clinical trial information: NCT02954536.
Phase I/II study of panitumumab (PANI) combined with trifluridine/tipiracil (FTD/TPI) in patients (pts) with previously treated RAS wild-type (wt) metastatic colorectal cancer (mCRC): Final results of APOLLON study.
Authors: Komatsu Yoshito , Kato Takeshi , Kagawa Yoshinori , Yoshino Takayuki , Kuboki Yasutoshi , Gamoh Makio , Yasui Hirofumi , Yamazaki Kentaro , Satake Hironaga , Goto Masahiro , Tanioka Hiroaki , Oki Eiji , Kotaka Masahito , Makiyama Akitaka , Denda Tadamichi , Soeda Junpei , Shibuya Kazunori , Iwata Masaru , Oba Koji , Yamaguchi Kensei
Published: January 2019

624

Background: Previous preclinical study reported that a combination of PANI with FTD/TPI demonstrated synergistic antitumor activity (Baba, 2017); however, no clinical study has been reported in this combination yet. Therefore, we conducted a phase I/II study to evaluate the efficacy and safety of this combination in pts with RAS wt mCRC. Here, we report the results of final analysis, including follow-up. Methods: Eligible pts had RAS wt mCRC refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, or angiogenesis inhibitors, and had never been treated with anti-EGFR antibodies, FTD/TPI, or regorafenib (REG).Pts received four-week cycles of PANI (every two weeks) and FTD/TPI (twice daily, days 1 to 5 and 8 to 12). The primary endpoint was frequency of dose-limiting toxicity (DLT) in phase I and progression-free survival (PFS) rate at 6 months (M) in phase II. With a PFS rate at 6 M of 48% deemed promising and 29% judged unacceptable, and assuming a one-sided significance level of 5%, the necessary sample size to achieve a power of 80% was estimated to be 47 pts (target sample size, 52 pts). Results: Since no DLT occurred in phase I, the recommended dose was determined to be 6 mg/kg for PANI and 35 mg/m2 for FTD/TPI. In phase II with a median follow-up of 16.5 M, the PFS rate at 6 M (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and overall survival were 5.8 M (95% CI: 4.5–6.5) and 14.1 M (95% CI: 12.2–19.3), respectively. The response rate and disease control rate were 37.0% and 81.4%, respectively. The most common grade 3 or higher adverse events (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), and dermatitis acneiform (9.1%). Subsequent therapy was given to 39 pts (72.2%), including 25 pts (46.3%) treated with REG. Subgroup analyses stratified by age, PS, and primary lesion will be reported at the time of conference presentation. Conclusions: PANI combined with FTD/TPI showed favorable antitumor activity with an acceptable safety profile for previously treated RAS wt mCRC, although the primary endpoint of PFS rate at 6 M did not meet the prespecified threshold. Clinical trial information: NCT02613221.
Randomized study evaluating trifluridine/tipiracil (TAS-102) versus + trifluridine/tipiracil + bevacizumab as last-line therapy in patients with chemorefractory unresectable metastatic colorectal cancer (mCRC).
Authors: Pfeiffer Per , Yilmaz Mette , Möller Sören , Maltha Line , Krogh Merete , Zitnjak Daniela , Szameitat Caroline Lemb , Hejlesen Finn , Thomsen Karina Gravgaard , Qvortrup Camilla
Published: January 2019

637

Background: Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) is approved for the use in patients with chemorefractory mCRC. Inspired by the encouraging results of a small phase I/II study, C-TASK FORCE, evaluating the combination of FTD/TPI and bevacizumab in chemorefractory mCRC patients (Kuboki et al, 2017), we designed the present randomized trial. Methods: This randomized study enrolled as planned 80 mCRC patients. The main inclusion criteria were: histologically confirmed and chemorefractory mCRC; PD during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, EGFR-inhibitor (RAS wildtype), and bevacizumab was optional; PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m²/dose bid from day 1 to day 5 and from day 8 to day 12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. The primary endpoint was to increase progression-free survival (PFS) from 1.8 months to 3.8 months. Secondary objectives included overall survival (OS) and safety. Results: Eighty patients with chemorefractory mCRC were randomized from September 2017 to August 2018. The median PFS was significantly improved from 2.6 months (arm A) to 5.9 months (arm B) with a hazard ratio (HR) 0.51 (95% CI, 0.28 to 0.92; P < 0.03) and median OS was significantly improved from 7.3 months (arm A) to 10.3 months (arm B) with HR 0.42 (95% CI, 0.18 to 0.99; P < 0.05). After median follow-up for OS of 5.6 months, 57 patients were alive at September 7th, 2018. Therapy was well tolerated with adverse events as expected, patients receiving FTD/TPI + bevacizumab had more grade 3-4 neutropenia (56% in arm B vs 30% in arm A, p = 0.03) and three patients in arm B (vs zero in arm A ) developed febrile neutropenia. SAEs were observed in 13 (arm A) and 11 patients (arm B), respectively. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + bevacizumab, as compared with FTD/TPI monotherapy, was associated with a significant and clinical relevant improvement in PFS and OS with tolerable toxicity. Clinical trial information: 2016-005241-23.
Antitumor activity of margetuximab (M) plus pembrolizumab (P) in patients (pts) with advanced HER2+ (IHC3+) gastric carcinoma (GC).
Authors: Catenacci Daniel V.T. , Lim Kian Huat , Uronis Hope Elizabeth , Kang Yoon-Koo , Ng Matthew C.H. , Gold Philip Jordan , Enzinger Peter C. , Lee Keun Wook , Lacy Jill , Park Se Hoon , Yen Jennifer , Odegaard Justin , Franovic Aleksandra , Baughman Jan E. , Wynter-Horton Aisha , Chen Francine , Moore Paul A. , Wu Tony , Davidson-Moncada Jan Kenneth , Bang Yung-Jue
Published: January 2019

65

Background: Trastuzumab (T) + chemo is standard first-line therapy (tx) for HER2+ gastroesophageal adenocarcinoma (GEA) pts, though progression ensues in 6-8 months. The approved second-line tx is ramucirumab +/- paclitaxel (R+PAC). Pts with GC are less responsive to R+PAC than gastroesophageal junction (GEJ) pts, in particular HER2+ GC, and no anti-HER2 agents are approved in post-T setting. We report results of combination M+P in HER2+ GC pts and describe a biological rationale for this population. M is an anti-HER2 mAb Fc optimized for enhanced binding to activating FcgRIIIa (CD16A) and decreased binding to inhibitory FcgRIIb (CD32B). M demonstrated an enhanced Fc-dependent MoA, including enhanced ADCC. Methods: HER2+, PD-L1-unselected, second-line GEA pts post T progression received M (15 mg/kg) + P (200 mg) Q3wk. Safety, objective response rate (ORR), median overall & progression-free survival (mOS, mPFS), disease control rate (DCR), circulating tumor DNA, & tumor PD-L1 expression were assessed. Results: To date, 66 GEA pts were dosed; 35 (53%) GC and 31 (47%) GEJ. Overall, 12/66 (18.2%) had tx-related adverse events ≥ grade 3; 5 had drug-related SAEs: dehydration, diabetic ketoacidosis, hypotension and pneumonitis, each a single event, and 2 events of autoimmune hepatitis. Eligibility was based on archival HER2 expression; an exploratory endpoint measured retention of HER2 expression post-T by ERBB2 ctDNA. HER2 expression was lost in 23/56 (41.1%) of pts tested post T. HER2 retention was higher in pts with GC versus GEJ (65.8% vs. 44.8%) and in GEA pts with IHC 3+ vs 2+ archival tumors (61.7% vs 47.4%, respectively). Furthermore, GC had higher PD-L1 expression than GEJ, 53.3 vs. 33.3%, respectively. This coincided with more responses in IHC3+ GC pts, ORR 12/29 (41.4%; 95% CI 23.5-61.1), DCR 21/29 (72.4%; 95% CI 52.8-87.3), mPFS 5.5 months (95% CI 2.3-7.6), mOS not reached, with lower bound of 9.1 months for 95% CI. Enrollment of an additional 25 pts enriched for IHC3+ GC is ongoing. Conclusions: Results suggest that M+P, a chemo-free regimen, demonstrates acceptable tolerability and has encouraging preliminary activity in second-line HER2+ GEA, specifically in GC pts who retain ERBB2 amp prior to second-line tx. Clinical trial information: NCT02689284.
FOLFOX rechallenge versus regorafenib in patients with metastatic colorectal cancer refractory to standard chemotherapy: A retrospective analysis.
Authors: Calegari Maria Alessandra , Zurlo Ina Valeria , Di Stefano Brunella , Camarda Floriana , Di Dio Carmela , Garufi Giovanna , Cassano Alessandra , Barone Carlo Antonio , Bria Emilio , Basso Michele , Orlandi Armando
Published: January 2019

669

Background: Nowadays the optimal treatment for mCRC beyond second line is still questioned. During last years, regorafenib and TAS-102 showed to improve survival compared to best supportive care in pts with refractory mCRC. Recently, some retrospective analyses compared the efficacy and safety of regorafenib and TAS-102 reporting no significant differences in survival and response outcomes. In real-world clinical practice, chemotherapy (CT) rechallenge is often considered for refractory mCRC. However, evidences regarding CT rechallenge is limited and no study has previously compared such approach with the recently approved antineoplastic agents in late lines. The aim of this study was to compare the efficacy between CT rechallenge and regorafenib in pts with refractory mCRC. Methods: This is a mono-institutional retrospective study. We compared the efficacy of FOLFOX rechallenge and regorafenib in pts with mCRC refractory to at least 2 lines of standard CT, treated at Fondazione Policlinico Universitario “A. Gemelli”-IRCCS between Jan-10 and Jan-18. The primary endpoint was OS. Secondary endpoints were RR and PFS. Results: One hundred thirty-one pts received regorafenib and 43 FOLFOX rechallenge. OS was significantly higher with FOLFOX rechallenge than it was with regorafenib (13 vs. 6 months; HR 0.67, 95% CI 0.33-0.66; p = 0.0002). PFS was significantly higher in the FOLFOX rechallenge group compared to the regorafenib group (5 vs. 3 months; HR 0.64, 95% CI 0.46-0.89; p = 0.0073). Accordingly, RR was better in pts receiving FOLFOX rechallenge compared to regorafenib (25 vs. 3%; Chi-square p < 0.0001). Conclusions: Our study, although retrospective and small-sized, compared for the first time to our knowledge the efficacy of CT rechallenge to regorafenib in refractory mCRC. In our analysis, CT rechallenge with FOLFOX proved to be superior compared to regorafenib, with a survival and response benefit in pretreated mCRC. The survival benefit observed for rechallenge might be explained by the significantly higher tumor shrinkage achieved with CT rechallenge compared to regorafenib. Our results warrant further confirmation in wider and/or prospective analyses.
Exploratory analysis of the effect of FTD/TPI in patients treated in RECOURSE by prognostic factors.
Authors: Tabernero Josep , Sobrero Alberto F. , Borg Christophe , Ohtsu Atsushi , Mayer Robert J. , Vidot Loïck , Moreno Vera Shanti Ricardo , Van Cutsem Eric
Published: January 2019

677

Background: The Phase III RECOURSE trial, in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies, demonstrated that trifluridine/tipiracil (FTD/TPI) significantly extended overall survival (OS) and progression-free survival (PFS) versus placebo in all subgroups, regardless of age, geographical origin, or KRAS status, with acceptable safety. Literature reports have shown optimal benefit for pts with low tumor burden (< 3 metastatic sites), indolent disease (≥ 18 mo since diagnosis of first metastasis), ECOG PS 0-1, and no liver metastasis when treated in late line mCRC. Methods: This exploratory post hoc analysis of RECOURSE (all ECOG 0-1) compared pts on FTD/TPI or placebo with good prognostic characteristics (GPC; low tumor burden and indolent disease) and poor prognostic characteristics (PPC; high tumor burden and/or aggressive disease). These subgroups were then analyzed by liver metastasis at baseline, ECOG PS, KRAS status and age. Results: Baseline characteristics were generally similar between the two groups. GPC placebo pts performed better than the PPC placebo pts, but worse than the GPC pts treated with FTD/TPI. GPC pts treated with FTD/TPI showed median OS of 9.3 mo versus 5.3 mo in PPC pts (HR 0.46; 95% CI: 0.37, 0.57; p < 0.0001); there was a similar effect for PFS. GPC pts had significantly better mOS and mPFS regardless of age (≥ 65 vs. < 65 y), ECOG PS (0–1), KRAS status (mutant vs. wildtype), and liver metastasis (y/n). No liver metastasis was the best prognostic factor: mOS in such pts treated with FTD/TPI was 16.4 mo and 7.6 mo in the GPC (n = 97) and PPC (n = 35) groups, respectively (HR 0.42; 95% CI: 0.24, 0.74; p < 0.0019); there was a similar effect for PFS. Pts with ECOG PS 0 at baseline remained PS 0-1 at discontinuation in 96% of the GPC group. Conclusions: Low tumor burden and indolent disease indicate good prognosis in late line mCRC. Pts with no liver metastasis have the best prognosis and are likely to have longer OS. GPCs might explain the percentage of long-term responders on FTD/TPI in RECOURSE. Maintenance of ECOG PS 0–1 during treatment is crucial in the continuum of care, allowing pts to benefit from further treatment options. Clinical trial information: NCT01607957.
KRAS amplification and mutation are independent events in gastroesophageal adenocarcinomas (GEA).
Authors: Madison Russell , Chao Joseph , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig , Klempner Samuel Jacob
Published: January 2019

70

Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV versus KRASa GEA (1.9% vs. 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV versus KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.4%) versus KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (3.0%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT versus KRASSV versus KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.
Synchronous brain metastasis and impact of primary tumor side in colorectal cancers.
Authors: Muzaffar Mahvish , Naqash Abdul Rafeh
Published: January 2019

712

Background: 25% of patients with colorectal cancer(CRC) present with synchronous metastatic disease. The incidence of brain metastasis (BM) in CRC is very low (1.2–3.2%) and tend to occur later in the disease course. Synchronous BM(SBM) in CRC is very rare. We sought to explore the impact of primary tumor characteristics on SBM. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on primary colorectal cancer cases diagnosed during 2010-2015 with brain metastasis at diagnosis were identified. Patients with unlabeled primary site and autopsy alone cases were excluded. Demographic and colorectal cancer characteristics including age, gender, race, tumor grade and primary tumor side were analyzed. Logistic regression model was used to test the association between survival and side of cancer. Results: A total of 475 cases met the inclusion criteria. The mean age was 64.04 yrs. (range 28-95). Majority of the patients (80%) were white, 12% black and others (8%), Male: Female ratio was 1:1.58% patients had primary tumor on left side (splenic flexure, sigmoid, rectosigmoid and rectal) and 42% had right sided (ascending colon, hepatic flexure, cecum, transverse colon) primary tumor. The median overall survival was 5 months with 1-year survival of 26% in the whole cohort. The 1-year overall survival was 21% for patients with right sided primary tumor versus 30% for patients with SBM and left sided primary tumor(p = 0.03). The median disease specific survival was 5 months for right side and 7 months for Left sided tumor with SBM. The regression model showed that higher grade (RR 14, p = 0.003)) and right sided primary tumor (RR 4.2, p = 0.04) were associated with worse outcome among patients with SBM in colorectal cancer. Conclusions: Synchronous brain metastasis is very rare in colorectal cancer. Tumor side seems to be prognostic even in this aggressive disease subset. This differential outcome further indicates that sidedness should be considered in goals of care and treatment discussion.
A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2 positive advanced gastric cancer (Ni-HIGH study).
Authors: Takahari Daisuke , Wakatsuki Takeru , Ishizuka Naoki , Fukuda Naoki , Shoji Hirokazu , Hara Hiroki , Minashi Keiko , Boku Narikazu , Yamaguchi Kensei
Published: January 2019

TPS177

Background: Trastuzumab (Tmab) with cisplatin and fluoropyrimidines improved the overall survival (OS) of patients (pts) with HER2 (+) advanced gastric cancer (AGC). Nivolumab (Nivo) is an anti-programmed cell death-1 (PD-1) antibody that demonstrated a survival benefit as third line or later of AGC. To date, most trials investigating anti-PD-1 antibody for 1st line treatment focus on HER2 (-) AGC. In HER2(+) breast cancer mouse model, combining Tmab with anti-PD-1 antibody was reported to enhance ADCC activity of Tmab, and show greater tumor regression. In our data, the PD-L1 expression was observed in 44% of tumor cells and 70% of immune cells in human HER2(+) AGC. Based on these data, we have plannedthis phase Ib investigator-initiated trial to investigate the safety and tolerabirity of Nivo plus Tmab and either S-1 or capecitabine (Cape) plus Oxaliplatin (Ox) for pts with HER2(+) AGC. Methods: Histopathologically confirmed HER2(+) AGC with mesurable lesions, aged > 20 years, chemo-naïve pts are enrolled in this study. Pts receive Nivo (360 mg/body; day 1) plus Tmab (course1, 8 mg/kg; course 2 onward, 6 mg/kg; day 1) and either S-1 (40 mg/m2 bid d1-14; cohort 1) or Cape (1000 mg/m2 bid d1-14; cohort 2) plus Ox (130 mg/m2; day 1) every three weeks until desease progression or unacceptable toxicity. In the primary part, six pts for each cohort will be assessed for tolerability.To estimate the objective response rate (ORR) in the analysis-set, on our hypothesis that a true response rate is 80%, 20 pts are required for the 90% C.I. to be ± 20%. Therefore the expansion part for each cohort will be 12-15 pts. Primary endpoint is safety. Secondary endpoint is tolerability and exploratory endpoints include ORR, disease control rate, progression free survival and OS. Collaborative biomarker analysis includes whole exome sequences, RNA sequences, gut microbiome, and IHC using biopsy specimens. In addition, T-cell repartry, circulating tumor DNA and exomes will be also analyzed using blood obtained during treatment. This study just has been initiated at four sites in Japan. Clinical trial information: UMIN000034222.
Multicenter prospective randomized controlled trial of comparing laparoscopic proximal gastrectomy and laparoscopic total gastrectomy for upper third early gastric cancer (KLASS-05).
Authors: Park Do Joong , Kim Hyung-Ho , Han Sang Uk , Hyung Woo Jin , Hwang Sun-Hwi , Hur Hoon , Yang Han-Kwang , Lee Hyuk-Joon , Kim Hyoung-Il , Kim Young Woo , Kong Seong-Ho , Lee Han Hong , Park Youngkyu , Lee In Seob , Kim Beom Su , Lee Young-Joon , Park Ji-Ho , Suh Yun-Suhk , Ahn Sang-Hoon
Published: January 2019

TPS184

Background: Proximal gastrectomy (PG) is rarely performed for upper third early gastric cancer (EGC) because of postoperative reflux esophagitis. Recently, PG with double tract reconstruction was introduced and reported to have a reflux of approximately the same frequency as total gastrectomy (TG) with esophagojejunostomy. PG has several theoretical advantages over TG but has not yet been proven in randomized controlled trial. This study aimed to provide scientific evidence of laparoscopic PG with double tract reconstruction as a standard procedure for proximal EGC. Methods: The present trial is multicenter, prospective, randomized, controlled trial with superiority design. A total of 138 patients with upper third cT1N0M0 gastric adenocarcinoma are randomized to laparoscopic PG with double tract reconstruction and laparoscopic TG with esophagojejunostomy. Patients are enrolled for two years and followed up for two years. Primary co-endpoints are hemoglobin change and vitamin B12 cumulative supplement quantity after 2 years of operation. We used the alpha-split method to set the hemoglobin to 4% and vitamin B12 to 1% for alpha. The sample size needed was 62 patients for each arm. Accounting for 10% follow-up loss, the enrollment of 69 patients in each group was required. Secondary endpoints are prevalence rate of postoperative reflux esophagitis, morbidity and mortality, quality of life 2-year after operations, relapse-free survival, and overall survival. Nineteen investigators from 10 institutes participated in this trial. The first patient was enrolled on October 27, 2016 and we completed the patient enrollment on September 17, 2018. Clinical trial information: NCT02892643.
A randomized phase II study of cabiralizumab (cabira) + nivolumab (nivo) ± chemotherapy (chemo) in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Wang-Gillam Andrea , O'Reilly Eileen Mary , Bendell Johanna C. , Wainberg Zev A. , Borazanci Erkut Hasan , Bahary Nathan , O'Hara Mark H. , Beatty Gregory Lawrence , Pant Shubham , Cohen Deirdre Jill , Leong Stephen , Beg Muhammad Shaalan , Yu Kenneth H. , Evans T.R. Jeffry , Seufferlein Thomas , Okusaka Takuji , Phillips Penny , Liu Xuan , Perna Serena K , Le Dung T.
Published: January 2019

TPS465

Background: Treatment options for PDAC are limited; thus, new therapies that can improve outcomes and extend survival are needed. PDAC is associated with high infiltration by tumor-associated macrophages (TAMs) that inhibit antitumor T-cell activity. Blocking colony-stimulating factor 1 receptor (CSF-1R) signaling—which supports the recruitment, differentiation, and maintenance of immunosupressive macrophages in tumors—may lead to depletion of TAMs and upregulation of T-cell checkpoints. Cabira, a humanized IgG4 monoclonal antibody, binds to CSF-1R and blocks its signaling, a key determinant of TAM activation and survival. By reducing TAMs and promoting a proinflammatory microenvironment, cabira may stimulate T-cell responses, thereby sensitizing PDAC to therapy with nivo (anti‒PD-1). In a phase 1a/b study cabira + nivo was tolerable and showed evidence of on-target tumor immune modulation and durable clinical benefit in heavily pretreated patients (pts) with advanced PDAC (Wainberg et al. J Immunother Cancer. 2017 [abst O42]; Carleton et al. J Clin Oncol. 2018 [abst 3020]). Here we describe a randomized, open-label, phase 2 study evaluating the safety and efficacy of cabira + nivo ± chemo in advanced PDAC. Methods: Pts aged ≥18 y with locally advanced/metastatic PDAC that progressed on/after first-line chemo (gemcitabine [gem] or 5-fluorouracil [5-FU] based) will be enrolled. Pts with active/suspected autoimmune disease, uncontrolled/significant cardiovascular disease, or prior exposure to select immune cell–modulating antibodies are not eligible. Depending on prior chemo received, pts will be randomized to 1 of 4 arms (n≈40 each): cabira + nivo; cabira + nivo + gem/nab-paclitaxel; cabira + nivo + oxaliplatin/5-FU/leucovorin; or investigator’s choice of standard-of-care chemo. Endpoints include median progression-free survival (primary), overall survival rate, objective response rate, median duration of response, pharmacokinetics, and safety. In a completed preliminary safety cohort, 12 pts were treated with cabira + nivo + chemo and monitored for 4 wk; competitive enrollment is open, with 32 pts enrolled. (NCT03336216, NCT02526017) Clinical trial information: NCT03336216.
MORPHEUS: A phase Ib/II study platform evaluating the safety and clinical efficacy of cancer immunotherapy (CIT)–based combinations in gastrointestinal (GI) cancers.
Authors: Desai Jayesh , Kortmansky Jeremy S. , Segal Neil Howard , Fakih Marwan , Oh Do-Youn , Kim Kyu-Pyo , Rahma Osama E. , Ko Andrew H. , Chung Hyun Cheol , Alsina Maria , Yeh Kun-Huei , Li Shi , Al-Sakaff Nedal Jaffer Abdulla , Patel Jilpa , Barak Hila , Wang Jun , Zhang Xiaosong , Bleul Conrad , Cha Edward , Lee Jeeyun
Published: January 2019

TPS467

Background: CIT has significant survival benefits across multiple tumor types, but durable response is experienced by only subsets of patients (pts). To extend clinical benefit to more pts, efficacious CIT combinations (combos) targeting multiple cancer immune escape mechanisms need to be identified. The MORPHEUS platform includes multiple ph Ib/II trials designed to identify early signals of safety and efficacy of CIT combos. Using a randomized trial design, multiple treatment (tx) arms are compared with a single control arm in each pt cohort. We present three GI-specific MORPHEUS trials, each assessing CIT combos that could concurrently enhance multiple aspects of the cancer immune response. Methods: The MORPHEUS trials described here are global, open-label, randomized, Ph Ib/II trials enrolling pts with pancreatic ductal adenocarcinoma (PDAC), gastric or gastroesophageal junction cancers or colorectal cancer (CRC). New arms with novel CIT combos (table) are opened as new txs become available, and arms with minimal efficacy or unacceptable toxicity are closed. Studies include multiple cohorts for pts receiving different lines of tx (1L and 2L PDAC and gastric; 3L CRC). Pts with loss of clinical benefit or unacceptable toxicity may be eligible to enroll in a different CIT combo arm. Primary endpoints include safety and investigator-assessed ORR (RECIST v1.1); secondary endpoints: PFS, OS, DCR and DOR. Clinical trial information: NCT03193190, NCT03281369, NCT03555149. [Table: see text]
FOENIX-101: A phase II trial of TAS-120 in patients with intrahepatic cholangiocarcinoma harboring FGFR2 gene rearrangements.
Authors: Goyal Lipika , Bahleda Rastilav , Furuse Junji , Valle Juan W. , Moehler Markus Hermann , Oh Do-Youn , Chang Heung-Moon , Kelley Robin Kate , Javle Milind M. , Borad Mitesh J. , Chen Li-Tzong , Uboha Nataliya Volodymyrivna , Klumpen Heinz-Josef , O'Dwyer Peter J. , Li Daneng , Morizane Chigusa , Huang Jerry , Bridgewater John A.
Published: January 2019

TPS468

Background: Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from the intrahepatic bile duct. Standard treatment of unresectable, recurrent, or metastatic iCCA is with cytotoxic chemotherapy. FGFR2 gene fusions have been identified as oncogenic drivers in 10–20% of iCCA tumors, but no targeted agents have been established to date. TAS-120 is an investigational irreversible FGFR1–4 inhibitor in development as a once-daily oral treatment for iCCA. Based on initial studies in multiple tumor types expressing FGFR abnormalities, iCCA was identified as a tumor type with potential susceptibility to FGFR inhibition and high unmet need. A phase I portion of the trial with an iCCA expansion cohort demonstrated tolerability and preliminary evidence of clinical efficacy with TAS-120 as a continuous, once-daily oral treatment in patients with iCCA. The most common AEs in the phase I portion of the trial were hyperphosphatemia, a mechanism-based on-target side effect, cutaneous AEs, and gastrointestinal AEs. The phase I portion of the study is continuing to enroll, and final results are anticipated in early 2019. Based on preliminary findings, a phase II portion of the study (FOENIX-101; clinicaltrials.gov registration NCT02052778) has been initiated. Methods: The phase II portion of the trial is a global, single-arm study of TAS-120 in patients with iCCA harboring FGFR2 gene rearrangements. The study will enroll approximately 100 adult patients with locally advanced or metastatic iCCA that progressed after ≥ 1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy. Screening for FGFR2 gene rearrangements will be performed at a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life. Clinical trial information: NCT02052778.
Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).
Authors: Hammel Pascal , Berardi Rossana , Van Cutsem Eric , Feliu Jaime , Greil Richard , Wasan Harpreet Singh , Metges Jean-Philippe , Nygren Peter , Osterlund Pia J. , Parner Vibeke , Seufferlein Thomas , Gupta Anu , Salesse Sophie , Biswasbaldwin Nigel , Ibrahim Ayman , Youssoufian Hagop , El-Hariry Iman , Hidalgo Manuel
Published: January 2019

TPS471

Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. An HR in OS of 0.725 is being targeted representing a conservative estimate based on the P2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.
A randomized clinical trial of chemotherapy with gemcitabine/cisplatin/nabpaclitaxel with or without the AXL inhibitor bemcentinib (BGB324) for patients with advanced pancreatic cancer.
Authors: Beg Muhammad Shaalan , Lowy Andrew M. , O'Dwyer Peter J. , Jameson Gayle S. , Borazanci Erkut Hasan , Patel Hitendra , Massey Clare , Schoelermann Julia , Lorens James , Fattah Farjana , Crane Kimberli , Williams Erin Fenske , Clark Jatan , Von Hoff Daniel D. , Brekken Rolf A.
Published: January 2019

TPS473

Background: The Axl pathway coordinately mediates immune evasion and drug resistance in pancreatic cancer. Systemic Axl inhibition can enhance the efficacy of cancer therapy by blocking tumor cell proliferation, survival and drug resistance associated with epithelial-mesenchymal transition (EMT), and targeting innate immune suppression in the tumor microenvironment. Bemcentinib (BGB324) is a first in class, selective oral inhibitor of Axl. Our group has shown that bemcentinib therapy, in combination with gemcitabine, improved survival in multiple preclinical models of pancreatic cancer. Methods: This is a multicenter, randomized, phase 1b/2 clinical trial of nab-paclitaxel/gemcitabine/cisplatin with or without bemcentinib. Patients with metastatic pancreatic cancer, good performance status and preserved liver, kidney and hematologic function are eligible. The treatment schedule is as follows: Bemcentinib 100 or 200 mg daily, nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 intravenously on D1, 8 every 21 days. 3 -12 patients will be recruited in part 1 following a modified 3+3 dose finding scheme. Part 2 of the study is a 1:1 randomized phase 2 design enrolling 62 patients. The primary objective is to determine complete response rate. Secondary end points are overall response rate, PFS and adverse events. A parallel biomarker study will accompany the trial analyzing blood and tissue samples to determine the effect of chemotherapy and bemcentinib on 1) Axl pathway activity in tumor tissue, 2) changes in immune landscape including upregulation of immune cytokines, and immune cell infiltration into the tumor, 3) apoptosis and decreased proliferation of tumor and 4) to identify predictive biomarkers of response. Clinical trial information: NCT03649321.
SYNERGY-AI: Artificial intelligence based precision oncology clinical trial matching and registry.
Authors: Kurnaz Selin , Loaiza-Bonilla Arturo , Freedman Jason Lawrence , Arango Belisario Augusto , Johnston Kristin , Bonilla-Reyes Paula Andrea , Culcuoglu Cagatay M ,   SYNERGY-AI Precision Oncology Group
Published: January 2019

TPS717

Background: Precision oncology encompasses the implementation of high level of evidence disease-specific and biomarker-driven diagnostic and treatment recommendations for optimized cancer care. Artificial Intelligence (AI), telemedicine and value-based care may optimize clinical trial enrollment (CTE) and overall cost-benefit. This ongoing, international registry for cancer pts evaluates the feasibility and clinical utility of an AI-based precision oncology clinical trial matching tool, powered by a virtual tumor boards (VTB) program, and its clinical impact on pts with advanced cancer to facilitate CTE, as well as the financial impact, and potential outcomes of the intervention. Methods: The SYNERGY-AI Registry is an international prospective, observational cohort study of eligible adult and pediatric pts with advanced solid and hematological malignancies, for whom the decision to consider CTE has already been made by their primary providers (PP). Using a proprietary application programming interface (API) linked to existing electronic health records (EHR) platforms, individual clinical data is extracted, analyzed and matched to a parametric database of existing institutional and non-institutional CTs. Machine learning algorithms allow for dynamic matching based on CT allocation and availability for optimized matching. Patients voluntarily enroll into registry, which is non-interventional with no protocol-mandated tests/procedures—all treatment decisions are made at the discretion of PP in consultation with their pts, based on the AI CT matching report, and VTB support. CTE will be assessed on variables including biomarkers, barriers to enrollment. Study duration anticipated as ~36 mo (~24-mo enrollment followed by 12 mo of data collection, to occur every 3 mo). The primary analysis will be performed 12 mo after last pt enrolled. The impact time to initiation of CTE on PFS and OS will be estimated by Kaplan-Meier and Cox multivariable survival analysis. Enrollment is ongoing, with a target of ≥ 1500 patients. Key inclusion criteria: Pts with solid and hematological malignancies; cancer-related biomarkers. Key exclusion criteria: ECOG PS > 2; abnormal organ function; hospice enrollment Clinical trial information: NCT03452774.