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Purpose: Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study., Patients and Methods: Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1)., Results: Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events., Conclusion: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted., Competing Interests: Heinz-Josef LenzHonoraria: Merck Serono, Roche, Bayer, Boehringer Ingelheim, Isofol Medical, GlaxoSmithKlineConsulting or Advisory Role: Merck Serono, Roche, Bayer, Bristol Myers Squibb, GlaxoSmithKlineTravel, Accommodations, Expenses: Merck Serono, Bayer Eric Van CutsemConsulting or Advisory Role: Bayer, Lilly, Roche, Servier, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, IncyteResearch Funding: Amgen, Bayer, Boehringer Ingelheim, Lilly, Novartis, Roche, Celgene, Ipsen, Merck, Merck KGaA, Servier, Bristol Myers Squibb Ka Yeung Mark WongConsulting or Advisory Role: Baxalta, Ipsen, Novartis, Roche, MSD OncologySpeakers' Bureau: Sirtex Medical, MSD OncologyTravel, Accommodations, Expenses: MSD Oncology, Novartis Alain HendliszConsulting or Advisory Role: Bayer, MSD Oncology, Sirtex MedicalResearch Funding: Sanofi/Aventis, Lilly, Servier/Pfizer, Amgen Massimo AgliettaConsulting or Advisory Role: Bristol Myers SquibbResearch Funding: AstraZeneca, PharmaMarTravel, Accommodations, Expenses: Merck, Tesaro, Bristol Myers Squibb Pilar García-AlfonsoConsulting or Advisory Role: Roche, Amgen, Merck Serono, Sanofi, ServierSpeakers' Bureau: Roche, Merck Serono, Amgen, Sanofi, ServierTravel, Accommodations, Expenses: Roche, Merck Serono Bart NeynsHonoraria: Bristol Myers Squibb, Novartis, Roche, Merck Sharp & DohmeConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Roche, Merck Sharp & Dohme, Amgen, Pfizer/EMD SeronoSpeakers' Bureau: NovartisResearch Funding: Pfizer, NovartisTravel, Accommodations, Expenses: Bristol Myers Squibb, Novartis, Roche, Merck Sharp & Dohme, Amgen Dana B. CardinHonoraria: OncLive/MJH Life SciencesConsulting or Advisory Role: Rafael PharmaceuticalsResearch Funding: Incyte, Celgene, EMD Serono, Bristol Myers Squibb, Array BioPharma, Advaxis, Lilly, Rafael Pharmaceuticals, Corcept Therapeutics Tomislav DragovichResearch Funding: Halozyme, Bristol Myers Squibb, Medivir, Kyowa Hakko Kirin, ARMO BioSciences, Berg Pharma, Rgenix, HolyStone Therapeutics, Novocure Sandzhar AbdullaevEmployment: Bristol Myers SquibbStock and Other Ownership Interests: Bristol Myers Squibb Joseph GricarEmployment: Bristol Myers SquibbStock and Other Ownership Interests: Bristol Myers Squibb Jean-Marie LedeineEmployment: Bristol Myers SquibbStock and Other Ownership Interests: Bristol Myers Squibb Michael James OvermanConsulting or Advisory Role: 3D Medicines, Bristol Myers Squibb, Roche/Genentech, Gritstone Oncology, MedImmune, Merck, Novartis, Promega, Spectrum Pharmaceuticals, Array BioPharma, Janssen, PfizerResearch Funding: Bristol Myers Squibb, Merck, Roche, MedImmune Sara LonardiConsulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSDSpeakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, AmgenResearch Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Purpose: To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer., Patients and Methods: Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here., Results: Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014)., Conclusion: Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Purpose: To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin., Patients and Methods: This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL)., Results: Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P

Purpose: In a previous cohort study, we proposed that responsiveness of metastatic colorectal cancer (mCRC) to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies has a genetic basis, being associated with increased EGFR gene copy number (GCN) as measured by fluorescence in situ hybridization (FISH) in individual tumors. The present study was aimed at assessing the predictive role of EGFR GCN, in terms of clinical outcome, in patients treated with panitumumab., Patients and Methods: Patients with mCRC refractory to standard therapies were a subset of patients from a phase III trial of panitumumab plus best supportive care (BSC; n = 58) versus BSC alone (n = 34) who were selected on the basis of availability of tumor samples adequate for FISH., Results: In patients treated with panitumumab, a mean EGFR GCN of less than 2.5/nucleus or less than 40% of tumor cells displaying chromosome 7 polysomy within the tumor predicted for shorter progression-free survival (PFS; P = .039 and P = .029, respectively) and overall survival (P = .015 and P = .014, respectively). None of the treated patients with mean EGFR GCN of less than 2.47/nucleus or less than 43% of tumor cells displaying chromosome 7 polysomy obtained objective response compared with six of 20 and six of 19 patients with values greater than these cutoff limits, respectively (P = .0009 and P = .0007, respectively). Evaluation of BSC-treated patients showed no correlation between EGFR GCN or chromosome 7 polysomy status and PFS., Conclusion: In a larger and more homogeneous series than in previous studies, present exploratory data suggest that mCRC patients with tumors distinguishable by FISH analysis of EGFR as homogenously disomic or with low chromosome 7 polysomy have a reduced likelihood of response to panitumumab.

Purpose: The combination of cisplatin, epirubicin, and leucovorin preceding fluorouracil (PELF) includes three novel agents compared with the standard combination of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric carcinoma. We report the results of a prospective randomized comparison of the two combinations in previously untreated patients., Patients and Methods: One hundred thirty assessable patients were entered onto the trial; 52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental treatment was chosen. Approximately 90% of patients had measurable tumor masses., Results: The overall response rates (complete responses [CRs] and partial responses [PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a statistically significant advantage for the experimental treatment (P = .001). Time to progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2 months), and survival durations (median, 5.6 and 8.1 months) were not significantly different between the FAM and PELF regimens, respectively. The PELF combination was more toxic compared with FAM, but generally tolerable., Conclusion: This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses. Due to tolerability, it is not recommended for routine clinical use. However, it should be considered, among other second-generation chemotherapy combinations, in future randomized studies aimed to improve the therapeutic outcome in gastric carcinoma.