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The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA

Background In the intent-to-treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation. Materials and Methods Tumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR. Results In both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation. Conclusion Treatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. NCT01170663. Implications for Practice Ramucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first-line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.

Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1-14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.

Background The Janus kinase/signal transducer and activator of transcription (JAK‐STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. Methods In this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). Results The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 (OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. Conclusions Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.

671 Background: N is a multiple angiokinase inhibitor (including VEGFR, PDGFR and FGFR). A randomised Phase III study, LUME-Colon 1 (NCT02149108), evaluated the efficacy and safety of N in pts with refractory mCRC after failure of standard therapies. LUME-Colon 1 showed a statistically significant improvement in PFS (HR [95% CI] 0.58 [0.49–0.69]; p < 0.0001) but no difference in OS (HR [95% CI]: 1.01 [0.86–1.19]; p = 0.8659). Here, we report the HRQoL outcomes. Methods: 768 pts with mCRC adenocarcinoma refractory to standard chemotherapy were randomised 1:1 to receive either N (200 mg bid) + BSC or P (bid) + BSC in 21-day courses until disease progression or undue toxicity. HRQoL was assessed every 21 days using the EORTC QLQ-C30 instrument; the main endpoints of interest were the differences in mean scores up to median follow-up time (treatment difference, TD) for physical functioning (PF) and global health status/QoL (QL) scales using a longitudinal model, with 95% CIs and associated p-values adjusted for baseline stratification factors. Time to deterioration (TTD) of scores and status change ( ≥ 10 point change from baseline) were also assessed. Results: Compliance with questionnaire completion was high ( > 85% in first 12 cycles). Mean baseline (N vs P) PF (80 vs 80) and QL (65 vs 65) scale scores were balanced between treatment arms. The mean TD favoured N vs P for PF scale scores (TD 2.66 [95% CI: 0.97–4.34]; p = 0.0020) and QL scale scores (TD 1.61 [95% CI: −0.04–3.27]; p = 0.0555). TTD of PF (HR 0.84; 95% CI: 0.69–1.03; p = 0.0904) and QL (HR 0.90; 95% CI: 0.75–1.08; p = 0.2674) scores were not significantly different between treatment groups, although the percentage of patients with improved PF (17.2% vs 11.8%; p = 0.0462) and QL scores (30.3% vs 21.6%: p = 0.0102) were both significantly higher for N vs P. Conclusions: In LUME-Colon 1, patient reported outcomes confirmed that overall HRQoL was not impaired by treatment with N. There was evidence for improvement of PF and QL with N vs P, corresponding to the significant increase in PFS observed. Clinical trial information: NCT02149108.

663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Gastric cancer is the third-leading cause of cancer-related deaths worldwide. Outcomes of current treatment regimens remain unsatisfactory, particularly in pts with advanced gastric cancer. TAK-264 is a novel drug conjugate consisting of a human monoclonal antibody that specifically targets GCC, which is expressed in approximately 70% of gastric cancers, linked to the potent microtubule disrupting agent monomethyl auristatin E. In the first-in-human Phase 1 study ([NCT01577758][1]) evaluating the safety of TAK-264, preliminary signals of clinical activity were reported in pts with gastric, gastroesophageal, and pancreatic carcinoma. The primary objective of this Phase 2 open-label, non-randomized, multicenter study ([NCT02202759][2]) was to evaluate the overall response rate (ORR; complete response + partial response) of adult pts with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction. Here we report the findings from the Interim Analysis (IA). Pts aged ?18 years with histologically-confirmed metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction, who were GCC-positive as demonstrated by immunohistochemistry with an H score ?10 and who had received ?1 prior therapy were eligible for inclusion. TAK-264 1.8 mg/kg was administered as a single 30-minute intravenous infusion on day 1 of a 21-day cycle until disease progression or unacceptable toxicity occurred. Pts were evaluated for a response every 2 cycles. At data cut-off (October 1, 2015), 37 pts had been enrolled (81% male), of which 36 (97%) pts were response-evaluable. The median age at baseline was 63 years (range, 31-81) and the median time from the initial diagnosis was 19.7 months (range, 5-76). Pts had received a median of 3 prior therapies (range, 1-7). Of the 36 pts in the response-evaluable population, the ORR was 6% (2 pts) and stable disease was observed in 15 (42%) pts. Progressive disease was experienced by 19 (53%) pts. All pts received at least one dose of TAK-264 and were included in the safety population. Common adverse events (AEs) observed in ?15% of pts included nausea (49%), fatigue (30%), decreased appetite and asthenia (each 27%), constipation and vomiting (each 22%), peripheral edema (19%), and diarrhea and anemia (each 16%). Diarrhea and neutropenia were the most prevalent Grade ?3 AEs, (each 5%). Other Grade ?3 gastrointestinal AEs included dysphagia, nausea and decreased appetite (each 1%). Results from the current IA suggest that few pts with GCC-positive metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction experienced limited clinical benefit with TAK-264 treatment. The correlation between GCC levels and clinical outcomes is being explored. Based on the IA, these data do not support continuation of the study. Citation Format: Khaldoun Almhanna, Maria Luisa Limon Miron, David Wright, Antonio Cubillo Gracian, Richard Hubner, Jean-Luc Van Laethem, Carolina Muriel Lopez, Maria Alsina, Federico Longo Munoz, Johanna Bendell, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic. Phase II trial of TAK-264 in previously treated patients (pts) with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expression guanylyl cyclase C (GCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT107. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01577758&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02202759&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom