Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform.

BACKGROUND: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). METHODS: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety. RESULTS: In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred. CONCLUSION: Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial.

IMPORTANCE: Confirmation of long-term comparability between subcutaneous and intravenous trastuzumab is essential. OBJECTIVE: To evaluate efficacy and safety of subcutaneous trastuzumab compared with that of intravenous trastuzumab for patients with ERBB2 (HER2)-positive early breast cancer after 6 years' follow-up in the HannaH (Enhanced Treatment With Neoadjuvant Herceptin) trial. DESIGN, SETTING, AND PARTICIPANTS: Open-label, prospective, multicenter, international, neoadjuvant-adjuvant, randomized, phase 3 noninferiority clinical trial (primary end points: pathologic complete response and serum trough concentration predose cycle 8) conducted for 596 patients with ERBB2-positive early breast cancer enrolled from October 19, 2009, to December 1, 2010. INTERVENTIONS: Eligible patients received 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of fluorouracil, 500 mg/m2, epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) with either fixed-dose subcutaneous trastuzumab, 600 mg, or intravenous trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in the neoadjuvant setting. Patients received an additional 10 cycles of subcutaneous trastuzumab or intravenous trastuzumab (according to their initial randomization) after surgery in the adjuvant setting to complete 1 year of anti-ERBB2 therapy. MAIN OUTCOMES AND MEASURES: Event-free and overall survival rates were calculated using the Kaplan-Meier method. Hazard ratios were estimated by Cox proportional hazards regression. Adverse events and serious adverse events were graded per standard criteria. RESULTS: In total, 294 women (mean [SD] age, 50.3 [11.1] years) treated with subcutaneous trastuzumab and 297 women (mean [SD] age, 49.5 [10.8] years) treated with intravenous trastuzumab were included in respective intention-to-treat populations. Six-year event-free survival rates (65% in both study groups; hazard ratio, 0.98; 95% CI, 0.74-1.29) and overall survival rates (84% in both study groups; hazard ratio, 0.94; 95% CI, 0.61-1.45) were similar between the subcutaneous and intravenous trastuzumab groups. Patients achieving a total pathologic complete response had longer event-free survival and higher 6-year overall survival rates than those with residual disease. Incidence of adverse events (290 of 297 [97.6%] vs 282 of 298 [94.6%]), grade 3 or higher adverse events (158 of 297 [53.2%] vs 160 of 298 [53.7%]), cardiac events (44 of 297 [14.8%] vs 42 of 298 [14.1%]), and serious adverse events (65 of 297 [21.9%] vs 45 of 298 [15.1%]) was comparable between the subcutaneous and intravenous trastuzumab treatment groups. CONCLUSIONS AND RELEVANCE: This final analysis of the HannaH trial further confirms the comparable efficacy and safety of subcutaneous and intravenous trastuzumab and highlights the suitability of subcutaneous trastuzumab as an alternative route of administration for patients with ERBB2-positive early breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00950300.

Autoimmunity and Benefit from Trastuzumab Treatment in Breast Cancer: Results from the HERA Trial.

BACKGROUND/AIM: This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant trastuzumab-based therapy. PATIENTS AND METHODS: HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated. RESULTS: A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival). CONCLUSION: No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.

Adjuvant Subcutaneous Trastuzumab for HER2-Positive Early Breast Cancer: Subgroup Analyses of Safety and Active Medical Conditions by Body Weight in the SafeHer Phase III Study.

BACKGROUND: This SafeHer subgroup analysis assessed the safety of fixed-dose subcutaneous trastuzumab (H SC) as an adjuvant therapy in HER2-positive early breast cancer (EBC) by body weight. PATIENTS AND METHODS: Patients with HER2-positive EBC not previously treated with anti-HER2 therapy received H SC 600 mg (every 3 weeks for 18 cycles), with neoadjuvant or adjuvant chemotherapy or without adjuvant chemotherapy. Adverse events (AEs) were assessed throughout treatment and at final follow-up (28 ±5 days after last treatment). Subgroups were categorized by body weight, Asian origin, and chemotherapy administration. All analyses were descriptive. RESULTS: Of 2,577 patients enrolled, 2,573 received ≥1 dose of study medication and were included in this safety analysis. Median body weight at baseline was 67.0 kg (range 33.6-150.0 kg). Any-grade AEs occurred in 88.7% (2,282/2,573) of the overall population, versus 87.1% (590/677) of the lowest bodyweight quartile (≤59 kg), 90.0% (561/623) of the highest quartile (>77 kg), and 86.5% (327/378) of the Asian population. Grade ≥3 AEs occurred in 23.2% (596/2,573) of the overall population, 17.9% (121/677) of the lowest bodyweight quartile, 26.8% (167/623) of the highest quartile, and 15.3% (58/378) of the Asian population. The highest bodyweight quartile had the highest incidence of medical conditions at baseline (highest quartile, 75.6%; lowest quartile, 56.1%). CONCLUSION: These data support the use of fixed-dose H SC as an adjuvant therapy in HER2-positive EBC and confirm the comparable safety profile of H SC in patients with low body weight or of Asian origin versus the overall population in SafeHer. ClinicalTrials.gov: NCT01566721. IMPLICATIONS FOR PRACTICE: The safety profile of fixed-dose subcutaneous trastuzumab (H SC) was comparable between patients in the lowest bodyweight subgroup and the overall patient population, and also between patients of Asian origin (of whom a higher proportion often fall within the lower bodyweight quartiles) and the overall population. The safety data from this SafeHer subgroup analysis therefore support the use of fixed-dose H SC 600 mg administered every 3 weeks as an adjuvant therapy for patients with HER2-positive early breast cancer across different bodyweight subgroups and in the Asian patient population.

Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer.

BACKGROUND: Trastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). METHODS: The ROP Study was a single-arm, multicenter, international continuation trial of H in patients who had previously completed a global Roche-sponsored trial with H therapy, had stable disease, and were receiving H at the end of the lead-in trial. Patients with chronic heart failure during the lead-in trial could be included following a risk-benefit analysis. The primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer at the end of the lead-in study, and to follow the long-term outcomes and long-term overall safety in these patients. RESULTS: Twenty-five of 69 patients enrolled in the ROP Study received long-term H therapy (19 breast cancer and 6 gastric/GEJ cancer). The median duration of H treatment for patients with breast cancer was 8 years 7 months, and 5 years 2 months for patients with gastric/GEJ cancer. The cardiac status of the patients remained stable over time, with no serious cardiac adverse events or marked changes in left ventricular ejection fraction (LVEF). The median overall worst LVEF measurement was 57.0%, and no patients experienced an LVEF of < 45% (range 47-63%). There were no serious adverse events related to study treatment. CONCLUSIONS: These results suggest that H has an acceptable safety profile and was well tolerated in patients who received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). Further investigation and reporting of long-term H therapy would be valuable. TRIAL REGISTRATION: This study was retrospectively registered on March 24, 2016 with Clinicaltrials.gov, number NCT02721641 .

Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy.

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers' increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.

BACKGROUND: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. METHODS: HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). FINDINGS: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. INTERPRETATION: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. FUNDING: F Hoffmann-La Roche (Roche).

Quality of life in the trastuzumab for gastric cancer trial.

BACKGROUND: The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2-positive advanced gastric or gastroesophageal junction cancer. We report health-related quality of life (HRQoL) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) results from this trial. PATIENTS AND METHODS: Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ-C30 and QLQ-STO22. Q-TWiST methodology was applied retrospectively using the clinical data and utility coefficients. RESULTS: Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ-C30 and QLQ-STO22 scores, including QLQ-C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q-TWiST by 2.42 months compared with chemotherapy alone. CONCLUSION: Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality-adjusted survival in patients with HER2-positive gastric or gastroesophageal junction cancer.

Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated.

PURPOSE Pharmacokinetics (PKs) and safety results from phase II/III trials suggest that, if high trastuzumab serum concentrations are reached early during treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, patients will gain clinical benefit, and the synergistic effects of trastuzumab and chemotherapy will be maximized. This phase I/II study evaluated the PKs, efficacy, and safety of a novel, intensive loading regimen of trastuzumab in women with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS An intensive loading regimen of trastuzumab was given (6 mg/kg intravenously on days 1, 8, and 15 followed by 6 mg/kg every 3 weeks from day 22) to women age 18 years or older with HER2-positive MBC who may have received previous surgery, radiotherapy, and/or chemotherapy. Study medication was continued until disease progression or withdrawal occurred. Results All eligible women (N = 72) received at least one dose of trastuzumab. Median estimated trough concentration of trastuzumab at the end of 3 weeks of the intensive loading regimen (total of 18 mg/kg of trastuzumab administered) of cycle 1 was 119 mg/L, which is higher than steady-state trough concentrations with a conventional weekly or every-3-week regimen (64.9 or 47.3 mg/L, respectively). No new or unexpected adverse events or increased cardiotoxicity were reported during the study. In patients with measurable disease (n = 47), response rate was 23.4%. Median time to progression was 7.7 months (in all patients). CONCLUSION An intensive loading regimen of trastuzumab achieved higher-than-steady-state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.