Neoadjuvant T-DM1 for HER2-positive breast cancer used as a bridging strategy during COVID-19 pandemic: lessons learned-a case series.

Background: Coronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH). Case Description: Five patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up. Conclusions: Our findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Use of Antibody-Drug Conjugates in the Early Setting of Breast Cancer.

Antibody-drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody-drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody-drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody-drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials.

Impact of Pertuzumab and Ado-Trastuzumab Emtansine on Cumulative Avoidance of Recurrence Among Women Treated for Locally Advanced, Inflammatory, or Early-Stage Nonmetastatic HER2-Positive Breast Cancer in the United States.

INTRODUCTION: We assessed the impact of HER2-positive early breast cancer (EBC) treatment landscape changes following the introduction of pertuzumab and ado-trastuzumab emtansine (T-DM1) on cumulative population-level recurrences avoided since 2013 (first pertuzumab approval for EBC in the United States; US). METHODS: We constructed a multi-year epidemiologic population treatment-impact model to estimate annual recurrences between 2013 and 2031. Parameters were: BC incidence; stage I-III proportion; HER2-positive disease proportion; treatment proportions for neoadjuvant-only, adjuvant-only, and neoadjuvant-adjuvant continuation; and therapeutic agent proportions within each of those settings (chemotherapy only, trastuzumab ± chemotherapy, pertuzumab with trastuzumab ± chemotherapy, or T-DM1). The primary endpoint was cumulative recurrences, estimated by incorporating extrapolated clinical trial data for each regimen of interest into the model under four scenarios. RESULTS: Approximately 889,057 women were predicted to be diagnosed with stage I-III HER2-positive BC from 2006 to 2031 in the US and potentially indicated for HER2-targeted treatment. In steady-state equilibrium, the model estimated that real-world utilization of pertuzumab and T-DM1 will reduce the population-level number of recurrences by approximately 32%, with 7226 recurrences predicted in 2031 based on current utilization rates. In different modeled scenarios, use of neoadjuvant pertuzumab, continuation of pertuzumab in the adjuvant setting, and T-DM1 in the adjuvant setting in women with residual disease after neoadjuvant treatment were all predicted to reduce the number of recurrences. CONCLUSION: Given the improvement of HER2-targeted treatments, alongside increases in BC disease burden, we expect that the population-level impact of HER2-targeted treatments will accelerate over the next decade. Our results suggest that utilization of HER2-targeted treatments in the US has the potential to change the epidemiology of HER2-positive EBC by preventing a substantial number of women from experiencing disease recurrence. These improvements may help to inform our understanding of the future disease and economic burden of HER2-positive BC in the US.

We predicted whether two treatments for a type of breast cancer called "HER2-positive," that had not yet spread from the breast, could be used to avoid the cancer coming back in women in the United States (US), using computer modeling. The model estimated that approximately 889,057 women were predicted to be diagnosed with this type of breast cancer from 2006 to 2031, and that use of the treatments pertuzumab and ado-trastuzumab emtansine (T-DM1) would reduce the number of breast cancers that came back by around 32%. Treating with pertuzumab before surgery, continuing pertuzumab treatment after surgery, and giving T-DM1 after surgery (in the event that some of the breast cancer remained after being treated before surgery) were all predicted to reduce the number of breast cancers that come back. Overall, we expect use of pertuzumab and T-DM1 to keep lowering the number of breast cancers that come back over the next decade in the US.

Development, efficacy and side effects of antibody­drug conjugates for cancer therapy (Review).

Antibody-drug conjugates (ADCs) are anticancer drugs that combine cytotoxic small-molecule drugs (payloads) with monoclonal antibodies through a chemical linker and that transfer toxic payloads to tumor cells expressing target antigens. All ADCs are based on human IgG. In 2009, the Food and Drug Administration (FDA) approved gemtuzumab ozogamicin as the initial first-generation ADC. Since then, at least 100 ADC-related projects have been initiated, and 14 ADCs are currently being tested in clinical trials. The limited success of gemtuzumab ozogamicin has led to the development of optimization strategies for the next generation of drugs. Subsequently, experts have improved the first-generation ADCs and have developed second-generation ADCs such as ado-trastuzumab emtansine. Second-generation ADCs have higher specific antigen levels, more stable linkers and longer half-lives and show great potential to transform cancer treatment models. Since the first two generations of ADCs have served as a good foundation, the development of ADCs is accelerating, and third-generation ADCs, represented by trastuzumab deruxtecan, are ready for wide application. Third-generation ADCs are characterized by strong pharmacokinetics and high pharmaceutical activity, and their drug-to-antibody ratio mainly ranges from 2 to 4. In the past decade, the research prospects of ADCs have broadened, and an increasing number of specific antigen targets and mechanisms of cytotoxic drug release have been discovered and studied. To date, seven ADCs have been approved by the FDA for lymphoma, and three have been approved to treat breast cancer. The present review explores the function and development of ADCs and their clinical use in cancer treatment.

Implementation of Systematic Bioanalysis of Antibody-Drug Conjugates for Preclinical Pharmacokinetic Study of Ado-Trastuzumab Emtansine (T-DM1) in Rats.

Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an ADC that received US FDA approval for the treatment of HER2-positive breast cancer. The purpose of this study was to optimize methods for the quantification of T-DM1 in rats. We optimized four analytical methods: (1) an enzyme-linked immunosorbent assay (ELISA) to quantify the total trastuzumab levels in all drug-to-antibody ratios (DARs), including DAR 0; (2) an ELISA to quantify the conjugated trastuzumab levels in all DARs except DAR 0; (3) an LC-MS/MS analysis to quantify the levels of released DM1; and (4) a bridging ELISA to quantify the level of anti-drug antibodies (ADAs) of T-DM1. We analyzed serum and plasma samples from rats injected intravenously with T-DM1 (20 mg/kg, single dose) using these optimized methods. Based on these applied analytical methods, we evaluated the quantification, pharmacokinetics, and immunogenicity of T-DM1. This study establishes the systematic bioanalysis of ADCs with validated assays, including drug stability in matrix and ADA assay, for future investigation on the efficacy and safety of ADC development.

Cost-efficiency analysis of conversion to biosimilar filgrastim for supportive cancer care and resultant expanded access analysis to supportive care and early-stage HER2+ breast cancer treatment in Saudi Arabia: simulation study.

AIMS: This study estimated, for Saudi Arabia, the cost-efficiency of converting patients from reference Neupogen and Neulastim to one of two filgrastim biosimilars (Nivestim, Zarzio); the budget-neutral expanded access to supportive care with biosimilar filgrastim and therapeutic care to ado-trastuzumab emtansine thus afforded; and the number-needed-to-convert (NNC) to provide supportive or therapeutic treatment to one patient. MATERIALS AND METHODS: Replicating prior studies, we modeled the cost-efficiencies gained from converting varying proportions of a hypothetical panel of 4,000 patients undergoing six cycles of cancer treatment from Neupogen or Neulastim to one of the two biosimilar G-CSF formulations, using national cost inputs. Cost-savings in USD were used to estimate the additional doses of biosimilar G-CSF and expanded access to ado-trastuzumab emtansine on a budget-neutral basis, and NNC to purchase one additional dose of supportive or therapeutic treatment. RESULTS: Savings from conversion from reference to a biosimilar filgrastim were $3,086,400 (Nivestim) and $3,460,800 (Zarzio). With reference pegfilgrastim, savings from conversion were $11,712,240 (Nivestim) and $12,086,640 (Zarzio). Biosimilar conversion from reference to biosimilar filgrastim enabled expanded access to ado-trastuzumab emtansine ranging from 61 patients (5 days, Nivestim) to 191 patients (14 days, Zarzio). For supportive care, biosimilar conversion enabled expanded access ranging from 8,244 patients (5 days, Nivestim) to 25,882 patients (14 days, Zarzio). For biosimilar conversion from daily filgrastim, the NNC for treatment with ado-trastuzumab emtansine decreased as days of injections increased [5 days: 395 (Nivestim), 352 (Zarzio); 14 days: 141(Nivestim), 126 (Zarzio)]. Alternately, for biosimilar conversion from single-injection pegfilgrastim to daily biosimilar filgrastim, the NNC for treatment with ado-trastuzumab emtansine rose as days of injections increased, being highest under the 14-day scenario (146, Nivestim; 130, Zarzio). CONCLUSION: This simulation study demonstrated significant potential cost-savings from biosimilar conversion. These savings provide budget-neutral increased access to supportive and therapeutic cancer care.

Addition of trastuzumab emtansine (T-DM1) in a human epidermal growth factor receptor 2-overexpressed metastatic carcinoma of the gallbladder patient to enhance survival: A case study.

Biliary tract cancers are clinically and genetically heterogeneous cancer type with a worst prognosis among gallbladder adenocarcinoma patients. Systemic therapeutic options for metastatic biliary tract cancers are fewer, and there are limited treatment choices for the patients who progress on first line apart from symptomatic treatment. Thus, a biomarker-guided personalized treatment approach needs to be explored among biliary tract cancer subtypes. We encountered a case of 53-year-old male patient with human epidermal growth factor receptor 2 (HER2, ERBB2) positive metastatic gallbladder cancer, treated with first-line gemcitabine and cisplatin combination-based chemotherapy along with trastuzumab followed by second-line treatment with mFOLFIRINOX. On progression in third line, treated with single agent ado-trastuzumab emtansine targeting human epidermal growth factor receptor 2 and got survival benefit of nearly 6 months. This is the first reported case from India that explored the possibility and impact of ado-trastuzumab emtansine in advanced gallbladder cancer after exhausting standard treatment options. It highlights the possibility of exploring ado-trastuzumab emtansine for treatment resilient, human epidermal growth factor receptor 2-positive and advanced gallbladder adenocarcinoma.

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).

Antibody-drug Conjugates for Breast Cancer Treatment.

The use of antibody-drug conjugates is expected to transform the management of human malignancy. Antibody-drug conjugates for cancer treatment are designed to deliver anticancer drugs to tumor cells. The main components of such conjugates are a monoclonal antibody that binds to a tumor antigen, an anticancer drug to inhibit tumor cell growth and a linker that serves to conjugate the antibody and drug. The antibody-drug conjugates developed and approved for breast cancer treatment are ado-trastuzumab emtansine, (fam)-trastuzumab deruxtecan-nxki and sacituzumab govitecan. The mechanisms of action, clinical uses and toxic effects of these antibody-drug conjugates are discussed.

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer.

BACKGROUND: The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited. MATERIALS AND METHODS: We retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd. RESULTS: Twenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0-not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6-NR] vs. 8.3 months [95%CI, 7.1-NR]; hazard ratio, 1.86 [95%CI, 0.53-6.57], p = 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (≥6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1+ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1. CONCLUSIONS: T-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression.

How we treat patients with metastatic HER2-positive breast cancer.

HER2-positive breast cancer represents 15%-20% of breast malignancies and is characterized by an aggressive behavior and high recurrence rates. Anti-HER2-directed agents represent the mainstay of treatment of patients with HER2-positive metastatic breast cancer (MBC). In this review we propose a treatment algorithm for patients with HER2-positive MBC based on the currently available literature on the topic. The combination of trastuzumab, pertuzumab and a taxane (THP) remains the preferred first-line therapy in most scenarios. Results of trials recently presented at the European Society for Medical Oncology (ESMO) Congress 2021 might have direct clinical impact in the second- and later-line settings. The randomized DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane. T-DXd significantly improved progression-free survival and showed a trend towards improved overall survival, establishing this agent as preferred second-line therapy. Treatment with T-DM1, or the combination of tucatinib, trastuzumab and capecitabine, are considered reasonable options after second-line therapy. For subsequent lines, trastuzumab duocarmazine, neratinib plus capecitabine or the continuation of trastuzumab with different chemotherapy partners are valid options. For patients experiencing disease relapse up to 6 months after completion of adjuvant therapy, as well as for those relapsing within 12 months from the completion of pertuzumab-based adjuvant treatment, we recommend T-DXd as preferred first-line option. For those relapsing between 6 and 12 months after non-pertuzumab-based adjuvant treatment, we recommend first-line THP. Finally, for patients with active brain metastasis, tucatinib-based combination represents a suitable second-line option.

Case series of docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and ado-trastuzumab emtansine (T-DM1) as second line for recurrent or metastatic HER2-positive salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) overexpresses Human Epidermal growth factor Receptor 2 (HER2) in 29-46% of cases, favoring anti-HER2 therapy. Here, we present the results of patients with recurrent or metastatic HER2-positive SDC treated with docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and subsequently ado-trastuzumab emtansine (T-DM1) in second line. Furthermore, we searched for potential biomarkers. METHODS: Retrospective case series from a tertiary hospital. First line anti-HER2 treatment consisted of DTP, after progression T-DM1 was considered for patients with an adequate performance status. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed and related to mRNA-based PI3K and MAPK signaling pathway activity scores. RESULTS: Thirteen SDC HER2 + patients received DTP. In twelve evaluable patients, one complete response (CR) and six partial responses (PR) were observed (ORR 58%), with a median PFS of 6.9 months (95%-CI 5.3-8.5). Seven patients received subsequent T-DM1 in second line, resulting in four PR (ORR 57%), with a median PFS of 4.4 months (95%-CI 0-18.8). Median OS after start of DTP was 42.0 months (95%-CI 13.8-70.1). Grade ≥ 3 toxicity on DTP was seen in 39% of patients, and 14% on T-DM1. Highest combined PI3K and MAPK signaling was seen in the patient with CR and lowest in the patient with progressive disease on DTP. CONCLUSION: In R/M HER2-positive SDC patients DTP followed by T-DM1 upon progression are promising treatments, leading to responses in the majority (58%) of the patients at an acceptable toxicity profile.

Ado-trastuzumab emtansine associated spider telangiectasia.

INTRODUCTION: Breast cancer is the most common cancer in women. Human epidermal growth factor receptor 2 (HER2) positivity rate is 20% and generally has a poor prognosis. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of HER2 target monoclonal antibody trastuzumab and microtubule inhibitor emtansine. The most common side effects are fatigue, diarrhea, anemia, and it is generally a safe and tolerable agent. CASE REPORT: In our case, we reported our patient who developed mucosal and cutaneous telangiectasia after T-DM1 treatment and who had a complete response in metastases after skin lesions. MANAGEMENT AND OUTCOME: While no side effects were observed during the use of T-DM1 for HER2 positive disease, nose bleeding and spider telangiectasia on the skin developed in the 9th month of the treatment. In these lesions, which did not require any treatment, no regression was observed during T-DM1 treatment. DISCUSSION: We think that T-DM1, which was detected with a low incidence of skin toxicity in studies, may form telangiectatic lesions due to vascular dilatation through emtansine, and therefore care should be taken in the treatment of T-DM1.

Comparison of the Efficacy, Safety, Pharmacokinetic and Immunogenicity of UJVIRA (ZRC-3256, Trastuzumab Emtansine) With the Kadcyla (Trastuzumab Emtansine) in the Treatment of HER2-Positive Metastatic Breast Cancer: A Randomized, Open-Label, Multicenter Study in India.

BACKGROUND: UJVIRA is the first DCGI approved biosimilar of trastuzumab emtansine (Kadcyla) which may offer an alternative cost-effective treatment option for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients in India. This article summarizes the available clinical evidence supporting the biosimilarity of UJVIRA and Kadcyla with respect to efficacy, pharmacokinetic, safety, and immunogenicity. MATERIALS AND METHODS: A phase 3, randomized, open-label, active-controlled study was conducted at 31 sites across India. A total of 168 patients were enrolled and randomized to receive either UJVIRA or Kadcyla. Of which, only first 50 patients were included in pharmacokinetic assessment. UJVIRA or Kadcyla were administered at a dose of 3.6 mg/kg by intravenous infusion every 3 weeks (21 days) for 8 cycles or until disease progression or unmanageable toxicity, whichever was earlier. The study assessed efficacy (ORR), safety, pharmacokinetics, and immunogenicity. RESULTS: The ORR at the end of Week 24 was 37.76% in the UJVIRA and 33.33% in the Kadcyla group. The risk difference was 4.42% [-12.01, 20.85]. It met noninferiority margin of -15%. The pharmacokinetic parameters were comparable between groups. No antidrug antibody was detected in any of the treatment groups. The overall safety profile in terms of TEAEs and laboratory abnormalities was also comparable between the treatment groups. CONCLUSION: Results demonstrated biosimilarity between UJVIRA and Kadcyla in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Therefore, UJVIRA could prove to be a cost-effective treatment alternative for HER2-positive metastatic breast cancer patients in India.

Pneumonitis associated with Trastuzumab emtansine in a patient with metastatic breast cancer.

INTRODUCTION: Trastuzumab emtansine (TDM-1) is an antibody-drug conjugate effective in human epidermal growth factor receptor-2 - expressing advanced breast cancer. Pulmonary complications of TDM-1 are rarely reported. TDM-1-associated interstitial lung disease is referred to as pneumonitis. CASE REPORT: A 47-year-old female patient who underwent modified radical mastectomy and axillary lymph node dissection operations due to a palpable mass in the right breast and axillary region. The patient who had received multiple chemotherapy was last receiving TDM-1 treatment. Fatigue, dyspnea, and tachypnea were detected for the first time on 20 days after the 6th treatment. MENAGEMENT AND OUTCOME: In our case, we first considered metastasis, pneumonia and fungal infection based on radiological findings, but the lack of response to the treatments and the results of the investigations suggested drug-induced pneumonia and steroid treatment was started. Our case had a complete radiological recovery and complete response to sterod therapy. In such cases, it is important to first exclude infections and metastasis. In cases of drug-induced pneumonia, the first treatment option is systemic corticosteroids and generally responded well. DISCUSSION: Unlike other cases of interstitial pneumonia, lung imaging of our case was resembling a metastasis, pneumonia and fungal infection. With increasing use of TDM-1, we will have more experience in both efficacy and complications of TDM-1. Although TDM-1 is a well-tolerated drug, clinicians should be aware of rare pulmonary complications and prepared to respond appropriately.

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.

Cost-effectiveness analysis of Ado-trastuzumab emtansine for the treatment of residual invasive HER2-positive breast cancer

ABSTRACT Objective Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. Methods The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. Results The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. Conclusion Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.

Case Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab linked to the maytansinoid DM1 with potential antineoplastic activity and is approved for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. An analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System identified 124/1,243 (10%) renal adverse events for trastuzumab. However, there are no published case reports describing kidney biopsy findings related to nephrotoxicity of either trastuzumab or T-DM1. We report kidney biopsy findings in a case of nephrotic range proteinuria due to collapsing focal segmental glomerulosclerosis (FSGS) and tubular injury after initiation of T-DM1 therapy. After systematic exclusion of other causes, it is likely that the observed collapsing FSGS was associated with the prior initiation of T-DM1 therapy. This is further supported by the clinical course with improvement of proteinuria and kidney function 3 weeks after discontinuation of T-DM1 therapy without further specific treatment. In summary, we provide the first report of kidney biopsy findings in a case of nephrotic range proteinuria after initiation of T-DM1 therapy due to collapsing FSGS. This issue is especially relevant since T-DM1 is widely used, and nephrologists have to be aware of this potentially rare but severe complication.

Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer.

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.