Jorge Riera-Knorrenschild

Phase III Comparison of Preoperative Chemotherapy Compared With Chemoradiotherapy in Patients With Locally Advanced Adenocarcinoma of the Esophagogastric Junction

PURPOSE Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown. PATIENTS AND METHODS Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual. RESULTS The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26). CONCLUSION Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.

Lapatinib versus lapatinib plus capecitabine as second-line treatment in HER-2-overexpressing metastatic gastro-esophageal cancer (GC): A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

112 Background: HER2 amplification is present in a subgroup of gastroesophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-EGFR and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1-21 plus capecitabine (CAP) 2000mg/m² on days 1-14 of a 21-day cycle or LAP 1500 mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary endpoint was the objective response rate (ORR) as assessed by the investigator using RECIST 1.1 criteria. We aimed to include 38 pts per arm to show a response rate of >20% in either of the two arms. Resu...

Abstract B61: Exploratory analyses of the randomized phase 2 IMPACT study: Patients with response to prior induction chemotherapy have improved outcome when treated with the TLR-9 agonist MGN1703

Background: The international randomized (2:1) double-blind placebo-controlled phase 2 IMPACT trial recruited patients with metastatic colorectal cancer (mCRC) and disease control after induction with 1st-line chemotherapy +/- bevacizumab. The trial aimed to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent Toll-Like Receptor 9 (TLR9) agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after 4.5 to 6 months of induction therapy. Methods: After randomization of 59 patients (43 MGN1703, 16 placebo) the trial was prematurely closed. The final analysis showed superiority of MGN1703 over placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p=0.041) and 0.56 (p=0.070) by local investigator assessment or independent radiological review, respectively. Some delayed and long term responses were observed, 3 still ongoing in excess of 36 months. Exploratory PFS analyses of pretreatment characteristics identified patients with objective response (HR=0.39, p=0.0051), normalized CEA (HR=0.07, p Results: Despite a median follow up of 17.7 months at the time of final study analysis, the OS data were not mature with only 35% and 50% of patients in the MGN1703 arm and placebo arm with an event, respectively. The power of the following OS analyses is therefore limited and will require confirmation when a large majority of events has been observed. The HR for the whole study ITT population was 0.63 (median 22.6 vs. 15.1 months for MGN1703 vs. placebo; p=NS). The subgroup of patients who were randomized into the study after achieving a RECIST response to prior induction therapy had HR of 0.40 (median 24.5 vs. 15.1 months; p=NS). Patients randomized in the study with stable disease had instead no benefit (HR 1.57; p=NS). The HR for OS of patients with presence of activated NKT cells and normalized CEA level after induction therapy was 0.43 and 0.69, respectively. Overall these results appear in line with the evidence from PFS subgroup analyses suggesting that responders may benefit the most from switch maintenance treatment with MGN1703. Recent literature provides a rationale for such finding, as a large series showed that presence of high density of lymphocyte infiltration in CRC metastases strongly predicts responses to chemotherapy (Halama et al, Cancer Res 2011; 71:5670-5677). A good response to chemotherapy may thus be a surrogate marker for increased immunogenicity of the tumor and allow identifying patients with an immune system that may be able to control tumor progression when broadly activated by MGN1703. Based on this hypothesis, the phase 3 IMPALA study has recently started recruitment in several European countries. Patients who achieved an objective response to their 1st-line induction therapy for mCRC are randomized to either continue local standard treatment or start switch maintenance with MGN1703. CEA and activated NKT values at baseline are stratification factors and will be also assessed prospectively. Conclusions: The exploratory PFS and OS subgroup data from the IMPACT study support the hypothesis that is possible to identify patients more likely to benefit from an immunomodulatory treatment following active induction chemotherapy. This information has been used to design the phase 3 IMPALA study currently recruiting patients. Citation Format: Werner Scheithauer, Jorge Riera-Knorrenschild, Hans-Georg Kopp, Frank Mayer, Hendrik Kroening, Dieter Nitsche, Jan Kuhlmann, Reinhard Ziebermayr, Johannes Andel, Dirk Arnold, Alfredo Zurlo, Burghardt Wittig, Hans-Joachim Schmoll. Exploratory analyses of the randomized phase 2 IMPACT study: Patients with response to prior induction chemotherapy have improved outcome when treated with the TLR-9 agonist MGN1703. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B61.

629PLAPATINIB VERSUS LAPATINIB PLUS CAPECITABINE AS SECOND-LINE TREATMENT IN HER2-OVEREXPRESSING METASTATIC GASTRO-ESOPHAGEAL CANCER (GC): A RANDOMIZED PHASE II TRIAL OF THE ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE (AIO)

ABSTRACT Aim: Her2 amplification is present in a subgroup of gastroesophageal cancers (GCs). Her2 inhibition with Trastuzumab has shown to improve clinical outcomes in metastatic disease. Lapatinib ditosylate (LAP), a dual anti EGFR and anti Her2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in Her2 positive breast cancer. We aimed to study the activity of LAP in HER2 amplified GC. Methods: Patients (pts) with Her2 positive (FISH ratio ≥2.0 or IHC3+ if ratio was between 1.8 and 20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP + CAP, 19 to LAP mono). Pts received a median of three treatment cycles. 10 pts in the LAP + CAP group (56%) and 7 pts in the LAP mono group (37%) had received prior Trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP + CAP arm, achieved an objective response. Therefore, the study was closed prematurely. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP + CAP group (p = 0.07). The other secondary efficacy endpoints (progression-free [median 41 and 47 days] and overall survival [median values not yet mature]) were comparable in the two treatment groups. Rates of diarrhea (all grades) were higher with LAP + CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, while other adverse events were mostly similar between the groups (18[100%] vs. 17[90%]). Slightly more pts in the LAP-CAP group experienced serious adverse events (44 vs. 32%). Conclusions: Lapatinib showed insufficient activity, especially as monotherapy, in HER2 amplified pretreated advanced GC. This led to premature study termination. The safety profile of LAP or LAP + CAP was as expected with some more toxicity in the combination arm. Disclosure: P.C. Thuss-Patience: Research support by GSK; F. Lordick: GSK. All other authors have declared no conflicts of interest.