The 1-year and median overall survivals (mOS) of advanced gastroesophageal adenocarcinomas (GEA) are ~50% and <12 months. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally-sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion platform type-II design with a survival primary endpoint. Of 68 patients by intention-to-treat, 1-year survival was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided p=0.0024). First-line response rate (74%), disease control rate (99%), and median progression free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. Significance This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial. Research.

IMPORTANCE Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ՆT3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and UGT1A1 genotype-directed irinotecan) to optimize efficacy while limiting toxic effects may have value. OBJECTIVE To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. INTERVENTIONS Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m 2 over 46 hours; oxaliplatin, 85 mg/m 2 ; irinotecan, 180 mg/m 2 for UGT1A1 genotype 6/6, 135 mg/m 2 for UGT1A1 genotype 6/7, or 90 mg/m 2 for UGT1A1 genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive for ERBB2 also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). MAIN OUTCOMES AND MEASURES Margin-negative resection rate and PRG. RESULTS A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10

Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come.

Purpose Preclinical data supports combining AKT-inhibitors with human epidermal growth factor receptor-2 (HER2) targeted therapies to overcome resistance to treatment. This Phase 1 study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the maximum tolerated dose (MTD). Experimental Design The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30–60 mg every other day and lapatinib 1000–1500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except Cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2+ breast cancer. Results Twenty-three participants enrolled in the dose escalation cohort. Dose limiting toxicities (DLTs) were hyponatremia, fatigue, rash, hypocalcaemia and mucositis. Common toxicities included diarrhea, nausea and rash. The MTD was reached at MK-2206 45 mg po qoDay and lapatinib 1500 mg po qDay. Two participants maintained stable disease for >4 months, including a colorectal cancer participant with substantial CEA decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for >6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206. Conclusions MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Anti-tumor activity was promising and supports evaluation of AKT inhibitors combined with HER2 targeted therapies.