Lung toxicity induced by anti-HER2 antibody - drug conjugates for breast cancer.

Human epidermal growth factor receptor 2 (HER2) serves as both a prognostic indicator and a therapeutic target for breast cancer. Therefore, anti-HER2 therapy plays a crucial role in the treatment of HER2-positive cancer. Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody, a chemical linker and a payload, wherein their aim is to reduce the toxicity associated with chemotherapy drugs by utilizing specific antibodies. Among the anti-HER2 ADCs currently approved for clinical use, trastuzumab emtansine(T-DM1) and trastuzumab deruxtecan (T-Dxd) have demonstrated remarkable efficacy in treating HER2-positive breast cancer. However, it is essential to emphasize the occurrence of lung toxicity during the treatment process, which can be life-threatening. In this review, we provide an overview of the new epidemiological features associated with interstitial lung disease (ILD) related to anti-HER2 ADCs in breast cancer. We also summarize the potential pathogenesis and explore the diagnosis and treatment strategies within this field.

Adjuvant Trastuzumab Emtansine Versus Paclitaxel and Trastuzumab in Stage I HER2-Positive Breast Cancer: The ATEMPT Trial.

This ASO perspective reviews the findings of a randomized, phase II clinical trial evaluating adjuvant trastuzumab emtansine (T-DM1) compared with paclitaxel and trastuzumab (TH) in stage I human epidermal growth factor receptor 2-positive breast cancer, as reported recently by the ATEMPT trial investigators. Patients treated with T-DM1 had better disease-free survival but did not have fewer treatment toxicities. The T-DM1-treated group had higher rates of treatment discontinuations, therefore long-term follow-up will be required to evaluate survival differences between T-DM1 and TH.

Safety profile of trastuzumab-emtansine (T-DM1) with concurrent radiation therapy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings. MATERIALS AND METHODS: This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT. RESULTS: After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low. CONCLUSION: Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.

HER2-targeted antibody-drug conjugates for breast cancer: ancestry and dose adjustment for thrombocytopenia.

BACKGROUND: Thrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding. METHODS: Subjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p < 0.01 in a proportional hazards model for the sub-distributions of 4 (primary and competing) endpoints. Covariates examined as potential confounders were age, metastatic disease, specific HER2-targeted drug, and prior drug switching for toxicity. RESULTS: Among 181 subjects, 48 reported Asian ancestry. Incidence of dose adjustment for thrombocytopenia was higher in patients with Asian ancestry and among patients switched to T-DXd after experiencing thrombocytopenia on T-DM1. Independent of specific drug and prior drug switching, Asian ancestry was associated with dose adjustment for thrombocytopenia (hazards ratio 2.95, 95% confidence interval 1.41-6.18) but not with competing endpoints. Among participants of Asian ancestry, the ancestral origin was usually China or the Philippines (where Chinese ancestry is common). CONCLUSIONS: The association between Asian ancestry and thrombocytopenia on HER2-targeted therapy is independent of age, metastatic disease, drug, and history of similar toxicity. This association may have a genetic basis linked to Chinese ancestry.

High risks adverse events associated with trastuzumab emtansine and trastuzumab deruxtecan for the treatment of HER2-positive/mutated malignancies: a pharmacovigilance study based on the FAERS database.

BACKGROUND: T-DM1 and T-DXd are two promising antibody-drug conjugates for treating advanced HER2-positive breast cancer and HER2-mutated lung cancer. Understanding the differences in the adverse events (AEs) profile of both drugs may help clinicians make an appropriate treatment decision. RESEARCH DESIGN AND METHODS: All data obtained from the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q3 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the AE signals of T-DM1 and T-DXd for comparison. RESULTS: A total of 2,113 and 1,269 AE reports associated with T-DM1 and T-Dxd, respectively, were retrieved from FAERS database, in which, respondents were mostly elderly women. Their statistical differences (p < 0.001), poses high incidence of thrombocytopenia, including cardiotoxicity (p < 0.05) for T-DM1, while myelosuppression, interstitial lung disease (ILD), and pneumonitis for T-DXd. Splenomegaly, nodular regenerative hyperplasia, hepatic cirrhosis, portal hypertension, neuropathy peripheral, and spider nevus, are particular to T-DM1. Similarly, febrile neutropenia, pneumocystis jirovecii pneumonia, neutrophil count decreased, and KL-6 increased, are unique to T-DXd. CONCLUSIONS: T-DXd is more likely to induce ILD/pneumonia and myelosuppression than T-DM1, whereas T-DM1 has higher risk of hepatotoxicity, cardiotoxicity, and thrombocytopenia than T-DXd. T-DM1-related hepatotoxicity may need redefinition. Clinicians may need to balance the benefits and risks of antibody-drug conjugates treatment for certain patients.

Acute skin radiation toxicity seen with concurrent T-DM1: A single institutional report of 35 patients.

Trastuzumab emtansine (T-DM1) is a novel therapeutic for HER2+ breast cancer patients with residual disease after neoadjuvant chemotherapy. Concurrent radiotherapy (RT) is offered to a subset of patients based on results from the KATHERINE trial which showed a favorable safety profile. With emerging therapies that necessitate concurrent RT, we must closely follow rates of skin toxicity. Our first 35 patients who underwent concurrent T-DM1 treatment with breast/chest wall (CW) ± nodal irradiation are reported. Most patients (22/35) had grade 2+ toxicity and 3 patients had grade 3 toxicities. We add our experience with radiation dermatitis and concurrent T-DM1 to contribute to existing reports.

ASTEFANIA: adjuvant ado-trastuzumab emtansine and atezolizumab for high-risk, HER2-positive breast cancer.

There is a strong rationale for combining HER2-targeted therapies with cancer immunotherapy to increase efficacy in breast cancer, particularly in the early-stage setting, where the immune system has not been weakened by heavy pretreatment. ASTEFANIA aims to evaluate the efficacy of adjuvant atezolizumab in combination with ado-trastuzumab emtansine in patients with high-risk, HER2-positive early breast cancer and residual disease following HER2-based neoadjuvant therapy. Eligible patients will be randomized to receive ado-trastuzumab emtansine in combination with either atezolizumab or placebo for 14 cycles within 12 weeks of primary surgery. The primary outcome is invasive disease-free survival and secondary outcomes include additional efficacy end points, safety and pharmacokinetics. The study plans to enroll 1700 patients across 32 counties. Clinical Trial Registration: NCT04873362 (ClinicalTrials.gov).

Incidence and risk of severe adverse events associated with trastuzumab emtansine (T-DM1) in the treatment of breast cancer: an up-to-date systematic review and meta-analysis of randomized controlled clinical trials.

OBJECTIVES: We performed an up-to-date meta-analysis to quantify the overall incidence and risk of severe adverse events (AEs) associated with T-DM1 in patients with breast cancer. METHODS: Pubmed, Embase, and oncology conference proceedings were searched for relevant studies. Data were extracted to calculate the summary incidence rate and relative risk (RR) of grade ≥3 AEs. RESULTS: A total of 5,045 patients from 7 RCTs were included in the meta-analysis. The use of T-DM1 was associated with an increased risk of severe thrombocytopenia (RR 10.66, 95% CI 3.23-35.18, P < 0.001), anemia (RR 1.68, 95% CI 1.15-2.44, P = 0.007), elevated ALT (RR 2.67, 95% CI 1.60-4.47, P < 0.001), and AST (RR 3.76, 95% CI 1.45-9.78, P = 0.007). In addition, the use of T-DM1 can increase the risk of severe hypertension (RR 1.59, 95% CI 1.03-2.45, P = 0.037) and peripheral sensory neuropathy (RR 8.13, 95% CI 1.89-35.03, P = 0.005). CONCLUSIONS: Treatment with T-DM1 increases the risk of severe hematologic toxicities, hepatotoxicity, hypertension, and peripheral sensory neuropathy in patients with breast cancer, while the overall incidence of these AEs is low.

Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer.

BACKGROUND: KAMILLA is a single-arm safety study of trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC; NCT01702571). We report the final analysis of cohort 2 (Asia) within the context of published cohort 1 (Global) findings. METHODS: Patients had HER2-positive, locally advanced, or metastatic BC progressing after chemotherapy and anti-HER2 therapy or ≤6 months after adjuvant therapy. The primary objective was to further evaluate T-DM1 (3.6 mg/kg, administered intravenously every 3 weeks) safety/tolerability, including the following adverse events of primary interest (AEPIs): grade ≥3 AEPIs (hepatic events, allergic reactions, thrombocytopenia, hemorrhage events), all grade ≥3 treatment-related AEs, and all-grade pneumonitis. RESULTS: KAMILLA enrolled 2185 patients (cohort 1, n = 2003; cohort 2, n = 182) as of 31 July 2019. Of these, 2002 and 181 per cohort were treated and included in the safety population. Approximately 70% of patients had two or more previous treatment lines in the metastatic setting. Median T-DM1 exposure was 5.6 and 5.0 months per cohort; median follow-up was 20.6 and 15.1 months. The overall AEPI rate was higher in cohort 2 (93/181; 51.4%) versus cohort 1 (462/2002; 23.1%), mostly driven by a higher grade ≥3 thrombocytopenia rate in cohort 2. In cohort 2, grade ≥3 thrombocytopenia was not associated with grade ≥3 hemorrhagic events and most (128/138) fully resolved. Grade ≥3 treatment-related AEPI rates were 18.4% (cohort 1) and 48.6% (cohort 2), the latter mainly due to thrombocytopenia. Any-grade pneumonitis rates were 1.0% and 2.2%. No new safety signals were identified. Median (95% confidence interval) progression-free survival was 6.8 months (5.8-7.6 months) and 5.7 months (5.5-7.0 months) in cohorts 1 and 2, respectively; median overall survival was 27.2 months (25.5-28.7 months) and 29.5 months (21.1 months to non-estimable). In both cohorts, median progression-free survival and overall survival decreased with increasing prior therapy lines. CONCLUSIONS: Cohort 2 results aligned with previous findings in Asian patients, supporting the manageable safety profile and use of T-DM1 in advanced BC.

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer].

As a newly emerged class of anticancer bioagents in the most precise and selectively targeted way, antibody-drug conjugate (ADC) combines the cancer-targeting abilities of monoclonal antibodies with the cytotoxicity potency of payload, delivering highly cytotoxic drug into tumors via 'targeted chemotherapy'. ADC has revolutionized the treatment landscape of human epidermal growth factor receptor 2 positive and triple negative subtypes in breast cancer. Three ADCs have been approved by U. S. Food and Drug Administration with breast cancer indications, including trastuzumab emtansine (T-DM1; also approved in China), trastuzumab deruxtecan (T-DXd, DS-8201) and sacituzumab govitecan (IMMU-132; also approved in China). Antibodies, cytotoxic drug, linker, and conjugation process are implicated in ADC profile, resulting in unique adverse drug reactions and toxicity heterogeneity within ADC class. For example, more attention should be paid to the management of thrombocytopenia, hepatotoxicity, and reductions in left ventricular ejection fraction (LVEF) in patients treated with trastuzumab emtansine; clinical physicians should pay attention to the risk of neutropenia, interstitial lung disease/pneumonitis, and reductions in LVEF when treated with trastuzumab deruxtecan; sacituzumab govitecan most frequently caused neutropenia, anemia and diarrhea requiring close monitor. ADC has generally favorable safety profiles, and dose modifications and/or symptomatic supporting treatment are effective in terms of toxicity management. This consensus aims at providing guidance for clinical oncologists of early detection, regular assessment, timely management and follow-up monitor of ADC-associated adverse reactions/events.

Noncirrhotic Portal Hypertension after Trastuzumab Emtansine in HER2-positive Breast Cancer as Determined by Deep Learning-measured Spleen Volume at CT.

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.

Trastuzumab emtansine increases the risk of stereotactic radiosurgery-induced radionecrosis in HER2 + breast cancer.

INTRODUCTION: In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS). METHODS: Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA). RESULTS: 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2 year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2 Gy fractions (EQD2) > 90 Gy2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2 years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8 months. CONCLUSION: T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Incidence of adverse events with therapies targeting HER2-positive metastatic breast cancer: a literature review.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.

BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).

Efficacy and safety of trastuzumab emtansine in older patients with HER2-positive advanced breast cancer: a real-world study.

INTRODUCTION: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate and its survival advantage has been shown in advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, clinical trials underrepresent patients ⩾65 years of age, leading to a lack of information in this population. We analyzed the real-world outcomes of older women who were treated with T-DM1 therapy. METHODS: We performed a multicenter, observational, retrospective analysis of patients aged ⩾65 years treated with T-DM1. A total of 93 patients from 10 cancer centers were involved in the study. Our goal was to determine the survival, response rates, and toxicity profile in T-DM1-treated patients, as well as the factors that influence survival. RESULTS: Median follow-up was 12.2 months. Objective response rate was 29%. Median progression-free survival (PFS) and overall survival (OS) were 8.47 and 15.0 months, respectively. In multivariate analysis, Eastern Cooperative Oncology Group Performance Score 2 was found to be an independent prognostic factor for worse PFS (hazard ratio [HR] 1.81, p = 0.032) and OS (HR 2.33, p = 0.006). Any adverse event (AE) was seen in 92.5% of patients; grade 3 or 4 AEs were seen in 30.1%. Dose reduction or treatment discontinuation rates were 11.8% and 6.5%, respectively. CONCLUSION: The efficacy of T-DM1 was acceptable and it was generally well-tolerated among older patients with advanced HER2-positive breast cancer.

Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study.

PURPOSE: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1). METHODS: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing. RESULTS: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80). CONCLUSION: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.

Trastuzumab emtansine for patients with non-small cell lung cancer positive for human epidermal growth factor receptor 2 exon-20 insertion mutations.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) mutations are present in ∼3% of patients with non-small cell lung cancer (NSCLC), with exon-20 insertions accounting for ∼90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody-cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations. PATIENTS AND METHODS: Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR). RESULTS: Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0-55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low. CONCLUSION: T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations. CLINICAL TRIAL NUMBER: JapicCTI-194620.

Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer.

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.

Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring. Clinical Trial Registration: NCT04457596 (ClinicalTrials.gov).