Project description:The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody-drug conjugate, T-DM1, are internationally agreed standards of care for advanced HER2 positive breast cancer, where available. However, until recently, options for patients for third-line therapy and beyond were of modest efficacy or limited by toxicity. In 2019, the results of trials of two exciting new agents for this space were presented. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, combines the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a new standard of care after T-DM1, in combination with capecitabine and trastuzumab. The antibody-drug conjugate, trastuzumab deruxtecan, demonstrated remarkable efficacy in heavily pre-treated patients and received accelerated approval in the United States, whilst confirmatory Phase 3 trials are completed. This review will discuss the available data for the post-T-DM1 setting, focusing on tyrosine kinase inhibitors including tucatinib.
Project description:On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.
Project description:Importance:Treatment options for patients with disease progression after treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) are limited. Tucatinib is an oral, potent, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor (TKI) being developed as a novel treatment for ERBB2/HER2-positive breast cancer. Objective:To determine the maximum tolerated dosage of tucatinib in combination with T-DM1 in the treatment of patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Design, Setting, and Participants:In this phase 1b open-label, multicenter, clinical trial, 57 participants enrolled between January 22, 2014, and June 22, 2015, were 18 years of age or older with ERBB2/HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Data were analyzed between January and March 2018. Interventions:Tucatinib 300 mg or 350 mg administered orally twice per day for 21 days and T-DM1 3.6 mg/kg administered intravenously once every 21 days. Main Outcomes and Measures:Safety assessments, pharmacokinetics, and response were assessed using RECIST 1.1 every 2 cycles for 6 cycles, followed by every 3 cycles. Results:Fifty-seven T-DM1-naive patients (median [IQR] 51 [44.0-63.0] years of age) who had undergone a median of 2 earlier HER2 therapies (range, 1-3) were treated. The tucatinib maximum tolerated dosage was determined to be 300 mg administered twice per day with dose-limiting toxic reactions seen at 350 mg twice per day. Pharmacokinetic analysis showed that there was no drug-drug interaction with T-DM1. Adverse events seen among the 50 patients treated at the maximum tolerated dosage regardless of causality included nausea (36 patients; 72%), diarrhea (30 patients; 60%), fatigue (28 patients; 56%), epistaxis (22 patients; 44%), headache (22 patients; 44%), vomiting (21 patients; 42%), constipation (21 patients; 42%), and decreased appetite (20 patients; 40%); the majority of adverse events were grade 1 or 2. Tucatinib-related toxic reactions that were grade 3 and above included thrombocytopenia (7 patients; 14%) and hepatic transaminitis (6 patients; 12%). Conclusions and Relevance:In this study, tucatinib in combination with T-DM1 appeared to have acceptable toxicity and to show preliminary antitumor activity among heavily pretreated patients with ERBB2/HER2-positive metastatic breast cancer with and without brain metastases. Trial Registration:ClinicalTrials.gov Identifier: NCT01983501.
Project description:BackgroundThis study was aimed at estimating the appropriate price of tucatinib plus trastuzumab and capecitabine (TXC), as third-line treatment, in HER2+ breast cancer (BC) patients from the Italian National Health System (NHS) perspective.MethodsA partitioned survival model with three mutually exclusive health states (i.e., progression-free survival (PFS), progressive disease (PD), and death) was used to estimate the price of tucatinib vs trastuzumab emtansine (TDM-1), considering a willingness to pay (WTP) of 60,000 EUR. Data from the HER2CLIMB trial, the Italian population, and the literature were used as input. The model also estimated the total costs and the life-years (LY) of TXC and TDM1. Deterministic and probabilistic (PSA) sensitivity analyses were conducted to evaluate the robustness of the model.ResultsIn the base case scenario, the appropriate price of tucatinib was 4828.44 EUR per cycle. The TXC resulted in +0.28 LYs and +16,628 EUR compared with TDM-1. Results were mainly sensitive to therapy intensity variation. In PSA analysis, TXC resulted cost-effective in 53% of the simulations. Assuming a WTP ranging 20,000-80,000 EUR, the tucatinib price ranged from 4090.60 to 5197.41 EUR.ConclusionsThis study estimated the appropriate price for tucatinib according to different WTP in order to help healthcare decision makers to better understand the treatment value.
Project description:On December 19, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc., Whitehouse Station, NJ) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Approval was based on Cancer Immunotherapy Trials Network protocol 9, also known as KEYNOTE-017 (NCT02267603), a multicenter, nonrandomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. The major efficacy outcome measures were overall response rate (ORR) and response duration assessed by blinded independent central review per RECIST 1.1. The ORR was 56% (95% confidence interval: 41, 70) with a complete response rate of 24%. The median response duration was not reached. Among the 28 patients with responses, 96% had response durations of greater than 6 months and 54% had response durations of greater than 12 months. The most common adverse reactions of pembrolizumab reported in at least 20% of patients who received pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. IMPLICATIONS FOR PRACTICE: This report presents key information on the basis for the Food and Drug Administration's accelerated approval of pembrolizumab for the treatment of recurrent locally advanced or metastatic Merkel cell carcinoma, including efficacy and safety information. This approval provides patients and physicians with an additional treatment option for this aggressive and life-threatening carcinoma.
Project description:PurposeIn PERTAIN's primary analysis (31 months' median follow-up), adding pertuzumab to trastuzumab and an aromatase inhibitor (AI) with/without chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (M/LABC). A potentially enhanced treatment effect was observed in patients with no induction chemotherapy. We present the final analysis (>6 years' median follow-up).Patients and methodsPatients (N = 258) were randomized 1:1 to pertuzumab (loading/maintenance: 840/420 mg) plus trastuzumab (loading/maintenance: 8/6 mg/kg) every 3 weeks and an AI (1 mg anastrozole or 2.5 mg letrozole daily; Arm A), or trastuzumab and an AI (Arm B). Induction chemotherapy was at investigator discretion. Primary endpoint: PFS. Key secondary endpoints: overall survival (OS) and safety.ResultsMedian PFS was 20.6 versus 15.8 months in Arms A and B, respectively (stratified HR, 0.67; P = 0.006). Median OS was 60.2 versus 57.2 months (stratified HR, 1.05; P = 0.78). Pertuzumab treatment effect was potentially enhanced in patients with no induction chemotherapy (26.6 vs. 12.5 months). Any-grade adverse events (AE) occurred in 122 patients per arm (96.1% vs. 98.4%); grade ≥ 3 AEs in 72 (56.7%) and 51 (41.1%); serious AEs in 46 (36.2%) and 28 (22.6%).ConclusionsThe PFS benefit of pertuzumab was maintained and OS was similar between arms at final analysis. Adding pertuzumab may enhance activity in patients who do not require first-line chemotherapy for M/LABC. No new safety concerns were reported. These data provide additional evidence of the role of first-line pertuzumab and trastuzumab in HER2-positive M/LABC.
Project description:Synergism in action of tucatinib and trastumab is reported in breast cancer management. However, its molecular basis is yet to be determined. In this context we attempted to provide an explanation at the molecular level by performing in silico experimentation and coupling its result with already available published observations. Our study will provide basis for planning further experimental study for unravelling the truth.
Project description:BackgroundTucatinib is an oral human epidermal growth factor receptor 2 (HER2)-directed therapy approved in combination with trastuzumab and capecitabine for use in patients with previously treated HER2+ metastatic breast cancer (MBC) with/without brain metastases (BM). To inform clinical decision-making, it is important to understand tucatinib use in real-world clinical practice. We describe patient characteristics, treatment patterns, and clinical outcomes for tucatinib treatment in the real-world setting.MethodsThis retrospective cohort study included patients diagnosed with HER2+ MBC (January 2017-December 2022) who received tucatinib treatment in a nationwide, de-identified electronic health record-derived metastatic breast cancer database. Patient demographics and clinical characteristics were described at baseline (prior to tucatinib initiation). Key outcomes included real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS).ResultsOf 3,449 patients with HER2+ MBC, 216 received tucatinib treatment (n=153 with BM; n=63 without BM) and met inclusion criteria. Median (range) age of patients was 56 (28-84) years, 57.9% were White, and 68.5% had Eastern Cooperative Oncology Group performance status ≤1. Median (IQR) follow-up from start of tucatinib treatment was 12 (6-18) months. Among all patients who received tucatinib treatment, median (95% CI) rwTTD was 6.5 (5.4-8.8) months with 39.8% and 21.4% remaining on treatment at 12 and 24 months, respectively. Median (95% CI) rwTTNT was 8.7 (6.8-10.7) months. Patients who received the approved tucatinib triplet combination after ≥1 HER2-directed regimen in the metastatic setting had a similar median (95% CI) rwTTD (any line: 8.1 [5.7-9.5] months; second-line (2L) and third-line (3L): 9.4 [6.3-14.1] months) and rwTTNT (any line: 8.8 [7.1-11.8] months; 2L and 3L: 9.8 [6.8-14.1] months) to the overall population. Overall, median (95% CI) rwOS was 26.6 (20.2-not reached [NR]) months, with similar findings for patients who received the tucatinib triplet (26.1 [18.8-NR] months) and was NR in the subgroup limited to the 2L/3L population.ConclusionTucatinib treatment in the real-world setting was associated with a similar median rwTTD, rwTTNT, and rwOS as in the pivotal HER2CLIMB trial, with particular effectiveness in patients in the 2L/3L setting. These results highlight the importance of earlier use of tucatinib in HER2+ MBC.
Project description:BackgroundSeveral human epidermal growth factor receptor 2 (HER2)-targeted regimens (anti-HER2 target agent combined chemotherapy) have been introduced for the treatment of HER2-positive locally advanced or metastatic breast cancer progressed after trastuzumab. We therefore conducted a network meta-analysis to compare and rank HER2-targeted regimens in this population after trastuzumab therapy.MethodsThe electronic databases of PubMed, EmBase, Cochrane Central Register of Controlled Trials, and the websites of http://clinicaltrials.gov/ (US NIH) were systematically searched for published and unpublished randomized controlled trials (RCTs) from their inception to October, 2020. Nine treatment regimens were eligible to be included in this analysis. The primary outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were grade ≥3 adverse events.ResultsA total of 2,104 citations were identified and 12 RCTs comprising 3,769 patients were selected for final analysis. For HER2 positive unresectable, locally advanced or metastatic patients progressed after trastuzumab therapy pyrotinib plus capecitabine ranked the highest surface under the cumulative ranking area (SUCRA) in PFS, ORR and its SUCRA in OS was higher than Trastuzumab emtansine (T-DM1). T-DM1 plus atezolizumab, pyrotinib plus capecitabine, and pertuzumab plus trastuzumab plus capecitabine had comparable SUCRA in OS (76.1% vs. 74.5% vs. 71.2%). Six of included studies reported any grade ≥3 adverse events, the prevalence of any grade ≥3 adverse events in lapatinib plus capecitabine (353/683), T-DM1 (213/558), trastuzumab plus capecitabine (130/218), pertuzumab plus trastuzumab plus capecitabine (118/228), pyrotinib plus capecitabine (220/384), T-DM1 plus atezolizumab (43/132) and capecitabine (24/94) were 51.7%, 38.2%, 59.6%, 51.8%, 57.3%, 32.6% and 25.5%, respectively. Specific adverse event characteristics related to different HER2-targeted regimens need to be well known ahead and managed during the therapy.ConclusionsThe results indicated that for HER2 positive breast cancer with previous trastuzumab therapy pyrotinib plus capecitabine was probably more efficacious in PFS and ORR. T-DM1 plus atezolizumab, pyrotinib plus capecitabine and pertuzumab plus trastuzumab plus capecitabine have comparable effect on OS improvement and all of them were likely better than T-DM1. The risk of grade ≥3 adverse events for specific treatment regimens were also provided.
Project description:PurposeAndrogen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab.MethodsEligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety.ResultsOverall, 103 women were enrolled [median age 60 years (range 34-83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0-3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs.ConclusionsEnzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. CLINICALTRIALS.Gov numberNCT02091960.