BackgroundCopanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms.Patients and methodsThis phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis.ResultsThirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2–138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0–874) and 70 days (range 0–897), respectively; median duration of response was 390 days (range 0–825) and 166 days (range 0–786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression.ConclusionIntravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing.This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

BackgroundFibroblast growth factor receptor (FGFR2) has been proposed as a target in gastric cancer. However, appropriate methods to select patients for anti-FGFR2 therapies have not yet been established.MethodsWe used in situ techniques to investigate FGFR2 mRNA expression and gene amplification in a large cohort of 1036 Japanese gastric cancer patients. FGFR2 mRNA expression was determined by RNAscope. FGFR2 gene amplification was determined by dual-color in situ hybridization (DISH).ResultsWe successfully analyzed 578 and 718 samples by DISH and RNAscope, respectively; 2% (12/578) showed strong FGFR2 gene amplification (FGFR2:CEN10 >10); moderate FGFR2 gene amplification (FGFR2:CEN10 <10; ≥2) was detected in 8% (47/578); and high FGFR2 mRNA expression of score 4 (>10 dots/cell and >10% of positive cells with dot clusters under a 20× objective) was seen in 4% (29/718). For 468 samples, both mRNA and DISH data were available. FGFR2 mRNA expression levels were associated with gene amplification; FGFR2 mRNA levels were highest in the highly amplified samples (n = 12). All highly amplified samples showed very strong FGFR2 mRNA expression (dense clusters of the signal visible under a 1× objective). Patients with very strong FGFR2 mRNA expression showed more homogeneous FGFR2 mRNA expression compared to patients with lower FGFGR2 mRNA expression. Gastric cancer patients with tumors that had an FGFR2 mRNA expression score of 4 had shorter RFS compared with score 0–3 patients.ConclusionRNAscope and DISH are suitable methods to evaluate FGFR2 status in gastric cancer. Formalin-fixed paraffin-embedded (FFPE) tissue slides allowed evaluation of the intratumor heterogeneity of these FGFR2 biomarkers.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-017-0758-x) contains supplementary material, which is available to authorized users.

(Table). Rates of second neoplasms and grade 3-5 infections were similar in G and R arms for CHOP and CVP but not for B. In all chemo groups, SAEs were more frequent with G than R, and AEs causing treatment discontinuation and fatal AEs were similar. Reductions in T-cell counts were more pronounced and prolonged in the B group than CHOP or CVP groups. Conclusions:In treatment-naive FL pts, PFS was superior with Gchemo relative to R-chemo with consistent effects across chemo regimens. Some differences were seen in safety profiles between chemo regimens, but comparisons may be confounded by the lack of randomisation.

672 Background: In the randomized phase 3 CONCUR trial (NCT01584830), regorafenib significantly improved overall survival (OS) and progression-free survival (PFS) vs placebo (PBO) in Asian patients (n = 136 regorafenib; n = 68 PBO) with treatment-refractory mCRC (HR [95% CI]: OS 0.55 [0.40‒0.77]; PFS 0.31 (0.22‒0.44]). Protein biomarker data from the phase 3 CORRECT trial of mostly Western patients with mCRC identified TIE-1 as a potential predictor of clinical response to regorafenib; however, this association was not significant in multivariable analyses. We present an exploratory protein biomarker analysis of patients in CONCUR. Methods: Sixteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in plasma samples collected at study entry from 121/204 (59%) patients (n = 83 regorafenib; n = 38 PBO). Potential predictive and prognostic effects were evaluated. Results: The biomarker cohort was representative of the overall study population in major baseline demographic factors, OS (HR 0.61; 95% CI 0.40‒0.93), and PFS (HR 0.25; 95% CI 0.16‒0.39). Elevated levels of ANG-2 (HR 2.46; p = 0.0016) and VEGF-A (HR 1.38; p = 0.03) were associated with poor OS prognosis; however, no significant association with treatment OS benefit for regorafenib vs PBO was observed for either marker (ANG-2: HR 0.76; p = 0.3307; VEGF-A: HR 0.83; p = 0.20). Elevated levels of five plasma proteins were associated with poor PFS prognosis: ANG-2 (HR 1.73; p = 0.0085), VEGF-A (HR 1.30; p = 0.0308), IL-8 (HR 1.67; p = 0.0014), VWF (HR 2.39; p = 0.0029), and IGF-BP2 (HR 1.71; p = 0.0384). Elevated levels of IL-8 (HR 0.70; p = 0.019), VWF (HR 0.53; p = 0.0312), and IGF-BP2 (HR 0.60; p = 0.0336) showed a modest interaction with regorafenib PFS; however, these results did not reach statistical significance after adjustment for multiple testing (p = 0.0045). Conclusions: None of the plasma proteins analyzed were predictive of regorafenib clinical benefit as measured by both OS and PFS in Asian patients with mCRC. These results, as well as those in CORRECT, suggest that rationally selected protein markers are not suitable to predict treatment benefit of regorafenib. Clinical trial information: NCT01584830.

Introduction: Previous studies indicate that follicular lymphoma patients who have progression of disease (POD) within 24 months (ie POD24) of receiving frontline chemoimmunotherapy have worse overall survival and thus constitute a high-risk population (Casulo et al. J Clin Oncol 33:2516-2522, 2015; Jurinovic et al., Blood 128:1112-1120, 2016). We have previously reported in the CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma that treatment with the pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor copanlisib resulted in durable responses with a manageable safety profile (Dreyling et al., J Clin Oncol 35:3898-3905, 2017). We explore here the outcomes for the subset of patients with rapid POD from the CHRONOS-1 study. Methods: Patients with histologically confirmed indolent B-cell non-Hodgkin lymphoma and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab (R) and an alkylating agent or regimen. Copanlisib was administered at a fixed dose of 60 mg via 1-hour I.V. infusion on days 1, 8 and 15 of a 28-day cycle. Treatment continued until progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate after ≥4 cycles as assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007). Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were reported using MedDRA (version 19.1). This exploratory analysis was based on patient's first-line treatment. Results: A total of 140 patients were treated and evaluable for POD based on first-line treatment; the principal histologies were follicular lymphoma (FL; n=102) and marginal zone lymphoma (n=23). First-line treatments in 140 evaluable patients included: 34% R-CHOP, 23% R-other, 21% R-CVP, 18% chemotherapy, and 2% patients R only. For FL patients, 87 of 102 (85%) received some form of R-chemotherapy as first-line treatment. A total of 93 patients (66.4%) progressed in less than 24 months and were deemed the POD<24 group for this analysis; the remaining 47 patients (33.6%) were classified as POD>24. The median time from 1st line treatment to first POD was 11.0 months in the POD<24 and 35.3 months in the POD>24 group. The median number of lines of prior therapy for both groups was 3. The median time to progression for the most recent line of therapy prior to start of copanlisib treatment was also shorter for the POD<24 group (7.0 months; 65.6% refractory) than for the POD>24 group (15.7 months; 48.9% refractory). At the time of data cutoff (February 2018), the median duration of copanlisib treatment was 6.0 months (range 0.2-44.2) for the POD<24 group and 5.0 months (range 0.4-32.2) for POD>24. Whereas the fraction of patients with complete responses (CR) were identical in both groups (17%) [Table], the ORR was 58.1% in the POD<24 group and 68.1% in the POD>24 group. In FL patients the ORR was similar in both groups, but the percent of patients with CR was higher in the POD<24 group (22.1%) compared to the POD>24 group (17.7%). The overall median DOR was 14.9 months and 14.1 months, respectively. Median PFS was 11.3 months in the POD<24 group and 17.6 months in the POD>24 group; approximately 50% censored events in each group. Median OS was 42.6 months in the POD<24 group but had not yet been reached in the POD>24 group. The median duration of safety follow-up was 6.7 months in the POD<24 group and 6.1 months in the POD>24 group. All-grade treatment-emergent adverse events (AEs) were similar in both groups, with grade (G) 3/4 events 48.4%/33.3% in the POD<24 group and 66.0%/21.3% in the POD>24 group. Serious AEs considered treatment-related occurred in 29.3% of patients (15.0% G3/7.1% G4). There were 3 treatment-related G5 events, 2 (2.2%) in the POD<24 group and 1 (2.1%) in the POD>24 group. Conclusions: Two-thirds of patients treated with copanlisib in the CHRONOS-1 study were considered high-risk based on POD in less than 24 months after first-line therapy, yet the efficacy of copanlisib in both groups was similar. These results suggest that copanlisib treatment should be explored as treatment for patients failing to achieve durable responses in the first-line setting. Disclosures Leppa: Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding. Follows:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Lenz:Gilead: Consultancy, Honoraria; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau. Demeter:Amgen: Consultancy; BMS: Consultancy; Novartis: Consultancy; Aramis Pharma: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Angelini: Consultancy. Rodrigues:Bayer: Employment. Wirtz:Bayer: Employment. Hiemeyer:Bayer: Employment. Liu:Bayer: Employment. Koechert:Bayer: Employment. Garcia-Vargas:Bayer: Employment. Childs:Bayer: Employment. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Dreyling:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees.