Citations

Purpose FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. Patients and Methods Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. Results Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS. Conclusion CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Treatment with cisplatin and gemcitabine demonstrates a survival benefit in patients with advanced biliary tract cancer (ABTC). However, the weekly administration can add significant toxicities that may prohibit prolonged treatment. Based on previous studies, we implemented a modified biweekly regimen of GC in an attempt to optimize the prescribed regimen with an improved toxicity profile, added convenience to patients while maintaining efficacy. Patients with ABTC were treated with fixed dose rate (FDR) gemcitabine (1,000 mg/m2/min) and cisplatin 20 mg/m2 on days 1 and 15 of every 28‐day cycle. Patients received treatment until time of progression, death, or discontinuation due to intolerance. Collected data included demographics, clinico‐pathologic features, toxicities, and survival. Kaplan‐Meier curves were used to calculate the median overall survival (OS) and progression free survival (PFS). The study included 107 evaluable pts with unresectable ABTC who received the biweekly regimen. Sites of tumor included gallbladder (21.5%), ampullary (3.7%), and bile duct (74.8%). Median number of cycles was 6 (1–27). Median PFS was 8.34 (6.74, 9.23) months and median OS was 10.32 (9.10, 11.43) months. Most common grade ≥3 adverse events included neutropenia (11%), fatigue (10%), and thrombocytopenia (6.4%). Biweekly FDR GC in ABTC is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in prior clinical trials. Minimal toxicities were observed despite a prolonged course for many patients. Further prospective trials should consider evaluating the role of biweekly GC regimen in ABTC, including a potentially more favorable platform in novel experimental strategies.

Abstract The emergence of targeted therapies for the treatment of metastatic colorectal cancer (mCRC) has considerably improved survival, but has also resulted in a dilemma of identifying the optimal sequence and combination of various agents in the mCRC treatment landscape. A number of cytotoxic agents, including irinotecan, oxaliplatin, 5-fluorouracil, capecitabine, and TAS-102, are available for treatment of mCRC. Additionally, whereas patients harboring rat sarcoma viral oncogene homolog (RAS)–wild type mCRC can be treated with the anti-epidermal growth factor receptor antibodies cetuximab and panitumumab or antiangiogenic agents (bevacizumab, ziv-aflibercept, and ramucirumab), patients with RAS-mutant mCRC are limited to antiangiogenic agents as biologic options. Regorafenib, a multikinase inhibitor, can be used in both RAS subgroups. As such, the recommended sequence of therapies that should be received by each subgroup must also be considered separately. This review provides an overview of recent clinical data for approved and investigational targeted therapies that have been studied across different mCRC treatment lines and patient subgroups. It also examines emerging trends in the treatment landscape for mCRC, including treatment with immune checkpoint inhibitors and the utilization of genomic profiling. Implications for Practice Currently, there are no established guidelines for optimal sequencing of cytotoxic or targeted agents in metastatic colorectal cancer (mCRC). This review provides a snapshot of the current mCRC treatment paradigm and examines the latest clinical data that support the utilization of several targeted agents alone or in combination with backbone chemotherapy across different lines of treatment and patient populations, highlighting recommendations for their usage. Recent advances in the treatment landscape are also summarized, including genomic profiling and preliminary results with immune checkpoint inhibitors.

Objectives Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. Methods Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. Results Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76–2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09–2.87). Conclusions Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.

Genotype, particularly Ras status, greatly affects prognosis and treatment of liver metastasis in colon cancer patients. This pilot aimed to apply word frequency analysis and a naive Bayes classifier on radiology reports to extract distinguishing imaging descriptors of wild-type colon cancer patients and those with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. In this institutional-review-board-approved study, we compiled a SNaPshot mutation analysis dataset from 457 colon adenocarcinoma patients. From this cohort of patients, we analyzed radiology reports of 299 patients (> 32,000 reports) who either were wild-type (147 patients) or had a KRAS (152 patients) mutation. Our algorithm determined word frequency within the wild-type and mutant radiology reports and used a naive Bayes classifier to determine the probability of a given word belonging to either group. The classifier determined that words with a greater than 50% chance of being in the KRAS mutation group and which had the highest absolute probability difference compared to the wild-type group included: “several”, “innumerable”, “confluent”, and “numerous” (p < 0.01). In contrast, words with a greater than 50% chance of being in the wild type group and with the highest absolute probability difference included: “few”, “discrete”, and “[no] recurrent” (p = 0.03). Words used in radiology reports, which have direct implications on disease course, tumor burden, and therapy, appear with differing frequency in patients with KRAS mutations versus wild-type colon adenocarcinoma. Moreover, likely characteristic imaging traits of mutant tumors make probabilistic word analysis useful in identifying unique characteristics and disease course, with applications ranging from radiology and pathology reports to clinical notes.

BACKGROUNDThere are limited therapeutic options for treatment‐refractory pancreatic ductal adenocarcinoma (PDAC), with a paucity of data to support the best option after progression on gemcitabine‐based regimens. The authors performed a meta‐analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan formulations to a fluoropyrimidine (FP) after first‐line treatment progression in patients with PDAC.METHODSDifferent databases, including PubMed, EMBASE, and Cochrane, were searched to identify randomized controlled trials comparing FP monotherapy versus FP combination therapy that included either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in patients with PDAC who progressed after first‐line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared with FP. Outcomes of interest included overall survival (OS) and progression‐free survival (PFS).RESULTSFive studies with 895 patients were identified. Patients randomized to receive FPIRI/FPOX had a significantly improved PFS and a trend toward improved OS compared with those who received FP monotherapy. When comparing FPIRI with FP, there was an improvement in both PFS (hazard ratio, 0.64; 95% confidence interval, 0.47‐0.87; P = .005) and OS (hazard ratio, 0.70; 95% confidence interval, 0.55‐0.89; P = .004) in patients who received the combination. Conversely, FPOX produced only a modest improvement in PFS with no improvement in OS.CONCLUSIONSCombination chemotherapy with OX or various IRI formulations appears to improve PFS compared with single‐agent FP. FPIRI, but not FPOX, appears to confer an OS advantage. The combination of FP with irinotecan formulations appears to be the appropriate next line of treatment upon progression after gemcitabine‐based chemotherapy regimens. Cancer 2017;123:4680‐4686. © 2017 American Cancer Society.

Abstract Introduction: 5-fluorouracil (5-FU)-based chemoradiation (CRT) is a standard neoadjuvant treatment strategy for the treatment of locally-advanced rectal adenocarcinomas (LARC). MEK-1/2 inhibition has been shown to radiosensitize Ras mutant tumors in preclinical models, including colorectal cancer. In this phase 1 trial, we are testing MEK-1/2 inhibition in combination with neoadjuvant CRT for LARC. Methods: This trial is a standard 3+3 design testing 3 dose levels of the MEK-1/2 inhibitor trametinib in combination with CRT: 0.5 mg, 1.0 mg, and 2.0 mg daily, followed by an expansion cohort. All patients first receive a one week lead-in dosing of trametinib monotherapy, and undergo a tumor biopsy at the end of that week to assess pharmacodynamic inhibition by immunohistochemistry (IHC). Then, patients receive standard CRT (5-FU 225 mg/m2 per day by continuous infusion during radiotherapy, and 50.4 Gy in 28 fractions, 5 days/ week) in combination with trametinib (5 days/week). Patients have total mesorectal excision (TME) 6-10 weeks after completion of CRT. Results: 17 patients have been enrolled to date, with current enrollment occurring on the trametinib 2 mg expansion cohort (total 18 patients planned). Of these, 15 patients (10 males, 5 females) have toxicity and surgical response data available. Median age is 53 years (range 35-74 years), and 6 patients have Stage II disease, while 9 patients with Stage III disease. There have been no grade 4-5 toxicities. One dose-limiting toxicity (DLT) of diarrhea occurred in the 2mg dose cohort, attributed mainly to 5FU CRT, but led to trametinib discontinuation. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient and was held for 3 days for 2 patients. All patients completed TME, and 3 patients had wound infection at 2 weeks after TME, while 2 patients had perineal wound infection at 4 weeks after TME. Three out of 9 (33%) patients at the 2mg dose cohort had a pathologic complete response (pCR), and 2/9 (22%) patients had a near pCR. Adjuvant chemotherapy was given to 10 patients, 4 patients did not receive (3 refused), and 1 patient is pending. Correlative research studies have been performed in the first 12 patients enrolled. Examination of phospho-ERK levels using Vectra quantitative immunohistochemistry in pre-treatment versus post-lead-in trametinib tumor tissue reveals dose-dependent decreases in p-ERK expression in both tumor and stromal tissue as trametinib is increased from 0.5 to 2.0 mg (range 18-46% absolute reduction), with maximal reduction observed in the 2 mg cohort. Additionally, we have performed whole exome sequencing of a custom panel of 279 cancer associated genes (IGNITE platform) in tumor and normal tissue, and have identified high frequency mutations in KRAS, BRAF, and TP53, as well as additional lower frequency mutations in every tumor. One patient was noted to have microsatellite instability. Finally, we will present data correlating degree of change in p-ERK staining, mutational analysis, and mismatch repair status with pathologic response. Conclusions: The combination of trametinib with 5-FU-based CRT for LARC is feasible with promising signs of clinical activity and tolerability. Initial analysis of tumor tissue confirms dose-dependent pharmacodynamic inhibition of ERK-1/2 within 5 days of starting trametinib. Citation Format: Terence M. Williams, Christina Wu, Lai Wei, Emily Chan, Ryan Robb, Sameek Roychowdhury, Amy Webb, Cynthia Timmers, Tanios Bekaii-Saab, Evan Wuthrick. A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for locally-advanced rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT088. doi:10.1158/1538-7445.AM2017-CT088

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.