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In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents., HER2+ breast cancer patients can often develop resistance to trastuzumab and therefore potential combination therapies need to be explored. Here, the authors report the results of a multi-center randomized phase II clinical trial evaluating the pathological and molecular responses associated with trastuzumab and/or lapatinib in combination with chemotherapy in HER2+ breast cancer patients.

Background: Improving outcomes for patients with HER2+ CNS metastases remains an unmet clinical need. Lapatinib (L) plus capecitabine (C) yields a 20% objective response rate (ORR) in the CNS in patients with previously treated HER2+ breast cancer brain metastases (Lin N, Clin Cancer Res 2009). Everolimus (E), an oral inhibitor of the mammalian target of rapamycin (mTOR), penetrates into the CNS in murine xenograft models (Meikle L, J Neurosci 2008). TRIO-US B09 is an investigator-initiated trial evaluating the safety and clinical activity of the novel combination of L+C+E for the treatment of patients with HER2+ breast cancer brain metastases. Methods: Patients with trastuzumab-pretreated, HER2+ metastatic breast cancer (MBC) with progression of disease (PD) in the brain and a measurable brain lesion participated. Patients were excluded if they had a prior mTOR inhibitor or an ECOG PS>2. Prior L and/or C, and prior surgery and/or radiation to the brain were allowed. The primary endpoint was CNS ORR at 12 weeks (cycle 3) by RECIST 1.1. Secondary endpoints included safety, progression-free survival, overall survival and extra-CNS ORR. To test the safety of the combination of L+C+E, a 3+3 dose escalation phase was conducted (starting doses: L 1000 mg QD, E 5 mg QD, C: 750 mg/m2 BID d1-14). Treatment was given Q21 days. Patients were evaluated for dose limiting toxicities during C1. Tumor imaging was conducted every 3 cycles. MRI of the brain was performed every 2 cycles through cycle 6 and then every 3 cycles. Neurological symptom assessment was conducted on day 1 of every cycle. Study participants continued to receive treatment until PD, unacceptable toxicity or withdrawal of consent for 12 mos. Results: Nineteen patients were enrolled at 11 sites in the US and treated with at least one dose of study drug. Of 18 patients with data available, median age was 58.5 (45-68), median number of systemic therapies for MBC was 2 (0-6), and 94.4% had prior radiation and/or surgical resection of brain metastases. 10 patients participated in the dose escalation phase of the study. The maximum tolerated doses were determined to be L 1000 mg QD, E 10 mg QD + C 1000 mg/m2BID days 1-14; however, given tolerability concerns, dose expansion proceeded with Cohort 2 dose for C (750 mg/m2 BID d1-14). Of 17 eligible patients with imaging results available to date, 2 (12%) had a partial response in the CNS at week 12, one of whom continues on study (currently in cycle 13). Stable disease was observed in 7 patients. The most common grade 3/4 adverse events (AE) (CTCAE v4.0) related to E and/or L in 18 treated patients were anorexia (5.5%), dehydration (5.5%), diarrhea (17%), fatigue (5.5%), fever (5.5%) hyperglycemia (5.5%), hypokalemia (11%), and oral mucositis (17%). Conclusions: This is the first report of this regimen for patients with HER2+ MBC to the brain. This regimen is generally well-tolerated and shows promising activity in the CNS of heavily pretreated patients. Final efficacy and toxicity analyses for all 19 patients will be presented. Citation Format: Hurvitz SA, Martinez DA, Singh R, Taguchi J, Chan D, Dichmann R, Castrellon A, Barstis J, Hu E, Berkowitz J, Mani A, DiCarlo B, Smalberg I, Hobbs E, Slamon DJ. Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of patients with HER2-positive metastatic breast cancer with progression in the CNS after trastuzumab (TRIO-US B-09) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-07.

Background:Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease.Methods:Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1–14) in 21-d cycles. The primary endpoint was the 12-week CNS objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), best CNS ORR and extra-CNS ORR.Results:A total of 19 participants were enrolled and treated with ⩾1 dose of the study drug. The median age was 58.5 years, the median number of therapies for metastatic breast cancer was 2.5 (0–11). Pretrial, 74% of participants had received prior lapatinib, capecitabine or both. A total of 63% had received previous CNS radiation or surgical resection and CNS radiation. The maximum tolerated doses were lapatinib at 1000 mg, everolimus at 10 mg, and capecitabine at 1000 mg/m2. Phase II proceeded with capecitabine at 750 mg/m2due to better tolerability. The most common grade 3/4 adverse events were mucositis (16%), diarrhea, fatigue, and hypokalemia (11% each). Of 11 participants evaluable for 12-week CNS ORR, 3 (27%) had partial response and 7 (64%) had stable disease. The best CNS ORR in eligible participants was 28% (5/18). The median PFS and OS were 6.2 and 24.2 months, respectively.Conclusions:This novel triplet combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants. Larger studies are warranted to further evaluate this regimen.Trial registration:ClinicalTrials.gov: NCT01783756. Registered 05 February 2013, https://clinicaltrials.gov/ct2/show/NCT01783756

BACKGROUND: Neoadjuvant trastuzumab (H) improves pathologic complete response (pCR) rates in HER2+ breast cancer (BC) vs. chemotherapy alone. Lapatinib (Ty) plus H exhibits synergy in vitro and efficacy in metastatic BC. This study evaluates the clinical and molecular effects as well as safety of neoadjuvant TC plus H and/or Ty in HER2+ BC. METHODS: This is an open-label, randomized phase II study in which pts with Stg I-III BC are assigned to 1 of 3 arms: Arm 1: TCH, Arm 2: TCTy, and Arm 3: TCH-Ty. Planned accrual is 140 pts. To test the safety of TCH-Ty, the 1st 20 pts are all assigned to TCH-Ty. The next 120 pts are randomized (40:40:40) to 1 of the 3 arms. Data from the first 20 pts is being presented. These pts received a run-in cycle of Ty (1000 mg/d on days 1-21) + H (8 mg/kg iv), followed by 6 cycles of q3-wkly TCHTy (T: 75 mg/m2, C: AUC 5 or 6, H: 6 mg/kg, Ty: 1000 mg/d on d1-21). The 1st 6 pts were part of a dose escalation evaluation of C. Biopsies are taken at baseline, after the run-in cycle with H and/or Ty, and at the time of definitive BC surgery. The primary endpoint is pCR rate defined as the absence of viable tumor cells in the breast and axillary lymph nodes. Safety evaluation, molecular effects, clinical response, and cardiac events were secondary endpoints. RESULTS: The first 20 pts were assigned to TCH-Ty. No DLTs were observed in the dose escalation phase and pts 6-20 received carboplatin AUC 6. The median age was 50 years (range, 38-66 years). Nineteen pts had invasive ductal and 1 pt had invasive lobular carcinoma. Nine tumors (45%) were ER+/PR+, 3 (15%) were ER+/PR-, and 8 (40%) were ER-/PR-. At presentation, 8 pts had Stg IIA, 7 :IIB, 2: IIIA, and 3:IIIB disease. As of April 2010, 17 of the first 20 pts have completed the study (14 completed all protocol specified therapy and 3 discontinued due to adverse event). Six of these 14 pts (43%) achieved pCR. One additional pt who discontinued the study after 3 cycles of chemotherapy achieved pCR. No heart failure or decline in LVEF >10% from baseline was observed. All pts experienced diarrhea (2 episodes of Grade 3 and no episodes of Grade 4). There were no deaths. The most common Grade 1/2 and all Grades 3/4 AEs are listed in the table below. CONCLUSIONS: Preoperative combination therapy with TCH-Ty is an effective regimen with manageable toxicity in HER2+ non-metastatic BC. This is the first report of this 4-drug combination in early BC. Further study in a phase III trial is ongoing. Updated efficacy and toxicity data from the 1st 20 pts who received all 4 drugs will be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-12.

Adenocarcinoma of the stomach is the most common gastrointestinal cancer in the world and the second leading cause of cancer death worldwide (Jemal et al, 2009). Although there is significant geographic variation in this disease, recent trends in incidence have suggested that gastro-oesophageal junction (GEJ) adenocarcinomas are among the fastest growing malignancies in the Western world (Blot and McLaughlin, 1999). Furthermore, despite significant evidence that adenocarcinomas of the GEJ have distinct epidemiologic and pathologic features; they are often grouped with distal gastric cancers in clinical studies (Marsman et al, 2005). Therefore, novel investigational approaches are needed for this subset of upper gastrointestinal tract cancers in order to improve outcomes. In patients with metastatic gastric and oesophageal adenocarcinomas, the median overall survival (OS) ranges between 7 and 10 months. Most studies in oesophageal and gastric cancers have included fluoropyrimidines and platinums as the backbone of these therapies, with some regimens containing a third chemotherapeutic agent. A randomised phase III trial demonstrated that the combination of fluorouracil and oxaliplatin was at least equivalent to if not better than fluorouracil and cisplatin with an improved toxicity profile (Al-Batran et al, 2008). In addition, the REAL-2 trial demonstrated that the triplet regimens, which contained oxaliplatin in place of cisplatin showed similar efficacy. In these trials, the median OS times were 10.7 and 11.2 months, respectively (Cunningham et al, 2008). The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is part of the human EGFR (HER) family. As in many epithelial malignancies, oesophageal and gastric cancer studies have shown significant variability in overexpression of EGFR with rates ranging between 17% and 90% (Takehana et al, 2003; Hanawa et al, 2006; Pinto et al, 2007). Many of these studies have shown that overexpression of the EGFR is correlated with a worse prognosis (Ozawa et al, 1989; Wang et al, 2007). Therefore, it has been speculated that EGFR blockade may be an effective therapeutic strategy in this disease. This phase II trial was designed to expand on two previous trials that investigated the role of EGFR tyrosine kinase inhibitors in upper GI adenocarcinomas (Dragovich et al, 2006; Ferry et al, 2007). Both these single-agent trials demonstrated that there was modest activity in patients with tumours that were derived from the oesophagus and GEJ with no objective responses seen in patients with distal stomach cancer. The current trial was designed to determine the efficacy and toxicity of FOLFOX and erlotinib specifically in patients with oesophagus and GEJ adenocarcinoma with a particular emphasis on possible surrogate biomarkers.

BACKGROUND: The BCIRG006 study (Slamon, et al. N Engl J Med 2011) demonstrated similar efficacy and superior safety of adjuvant docetaxel, carboplatin, and trastuzumab (TCH) over an anthracycline regimen in HER2+ BC. Dual HER2-blockade with lapatinib (Ty) and H demonstrated synergism preclinically and significant activity in the metastatic and neoadjuvant settings (Blackwell, et al. J Clin Oncol 2012; Baselga, et al. Lancet 2012). This study evaluates the clinical and molecular effects of neoadjuvant TC plus H and/or Ty in HER2+ BC. METHODS: This is an open-label, randomized phase II study in which pts with stage I-III, operable BC were assigned to 1 of 3 arms: Arm 1-TCH, Arm 2-TCTy, and Arm 3-TCHTy. To test the safety of TCHTy, the first 20 pts received TCHTy. The remaining pts were randomized (1:1:1) to the 3 arms. Pts received a run-in cycle of Ty (1000 mg/d days 1-21) and/or H (8 mg/kg iv), followed by 6 cycles of q3-wkly TC (T: 75 mg/m2, C: AUC 5 or 6) plus H (6 mg/kg) and/or Ty (1000 mg/d d1-21). The first 6 pts were part of a dose-escalation evaluation of C and received AUC5. The remaining pts received C at AUC6. Biopsies were taken at baseline, post run-in cycle, and at surgery. The primary endpoint was pCR rate in each arm (defined as the absence of viable tumor cells in both the breast and axillary lymph nodes). Safety evaluation, molecular effects, and cardiac events were secondary endpoints. RESULTS: From October 2008 to December 2012, 130 pts were enrolled at 13 centers in the US. Two pts withdrew from study prior to starting any Tx (1 ineligible, 1 withdrew consent) and are excluded from analyses. As of May 2013, complete data was available for 106 pts: 32 in Arm 1, 27 in Arm 2 and 47 in Arm 3. Of these, 16 patients came off study tx prior to surgery (6 in Arm 2, 10 Arm 3) but are included in the ITT analyses. Median age was 48 years (range 27-76). Hormone receptors were both negative (HR-) in 43 pts (41%) and were ER and/or PR positive (HR+) in 63 (59%). At presentation, 5 (5%) pts had clinical stage I, 71 (67%) stage II and 30 (28%) stage III BC. The overall pCR was 42% (45/106), including 43% (13/30) in Arm 1, 25% (7/28) in Arm 2 and 52% (25/48) in Arm 3 (Chi-squared test P = 0.069). Using a pair-wise comparison, pCR is significantly lower in Arm 2 than in Arm 3 (p = 0.021) but no difference was detected between Arms 1 and 2 (p = 0.14) or 1 and 3 (p = 0.45) The pCR in HR+ and HR- tumors were 33% HR+ vs 58% HR- for Arm 1, 13% HR+ vs 42% HR- for Arm 2, and 41% HR+ vs 68% HR- for Arm 3. There were no deaths and no episodes of CHF reported. LVEF decreased >10% from baseline and below the lower limits of normal in 5 pts (1 pt in Arm 1, 3 in Arm 2, 1 in Arm 3). The most common gr >3 AEs in Arms 1/2/3 respectively were pain (10%, 25%, 17%), diarrhea (3%, 11%, 27%), neutropenia (7%, 11%, 13%), anemia (10%, 11%, 4%) hypokalemia (7%, 7%, 8%), and infection (7%, 11%, 6%). CONCLUSIONS: To our knowledge, this is the first report of this 4–drug combination in the neoadjuvant setting. Final efficacy, safety and molecular analyses from all 128 pts will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-02.

Background: PD 0332991 is a potent, oral, small molecule inhibitor of CDK 4/6 kinase. Preclinical studies identified that human luminal ER+ breast cancer cell lines were uniquely sensitive to G0/G1 arrest and growth inhibition by PD 0332991 and this appears to be related to an intact Rb pathway in this subtype (Finn, SABCS 2008, abstract 5064). These studies also identified the ability of PD 0332991 to act synergistically with anti-hormonal treatment in vitro and to restore sensitivity to hormonal treatment in models of acquired resistance. Based on these observations, a phase I/II randomized study of PD 0332991 in combination with letrozole versus letrozole alone as first-line treatment of metastatic ER+ breast cancer was launched.Methods: Post-menopausal women with ER+, HER2-negative breast cancer were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, no brain metastases, and adequate organ function. The phase I part of the study was conducted to assess the safety and tolerability of the combination including dose-limiting toxicities (DLTs). Enrollment in phase I is planned for up to 12 patients. The starting dose was PD 0332991 125 mg daily for 3 weeks followed by 1 week off (Schedule 3/1) and letrozole 2.5 mg daily. Cycle 1 consisted of PD 0332991 administered for 2 weeks alone followed by 1 week off. Subsequent cycles consisted of PD 0332991 on Schedule 3/1 and letrozole administered continuously. Pharmacokinetic samples were collected to assess the potential for a drug–drug interaction (DDI). Archival tumor tissue was required for biomarker evaluation. The tumor assessments were performed every 8 weeks.Results: Nine patients have currently been enrolled and treated; median duration of treatment was 3 months (range Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5069.