Abstract
Objective:
HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment.
Methods:
We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed.
Results:
This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated.
Conclusions:
We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy.
ClinicalTrials.gov identifier:
Keywords: endometrial cancer, zanidatamab, antibody, HER2, clinical trial
INTRODUCTION
Endometrial cancer is the most common gynecologic malignancy in the United States. In 2023, an estimated 66,200 patients will be diagnosed with endometrial cancer, and 13,030 will die from this disease.1 Endometrial cancers harbor specific molecular alterations, making these tumors ideally suited for targeted therapies. HER2 overexpression, as measured by protein overexpression and ERBB2 amplification, is an important prognostic and predictive biomarker associated with significantly shorter overall survival (OS) compared to tumors with normal HER2 expression.2,3 HER2 overexpression is identified in up to 31% of grade 3 endometrial carcinomas, 43% of endometrial serous carcinomas, and 11% of endometrial carcinosarcomas.4,5 Trastuzumab, a monoclonal antibody against HER2, when combined with carboplatin and paclitaxel, has demonstrated improved efficacy for patients with stage III/IV HER2+ endometrial carcinoma in the first-line setting compared to carboplatin and paclitaxel alone (median progression-free survival [PFS], 17.9 vs 9.3 months; HR, 0.40; 90% CI, 0.20–0.80).6 However, response rates to standard single-agent chemotherapy for patients with disease progression following first-line carboplatin and paclitaxel are <15%,7 and treatment strategies that harness HER2 as a biomarker in endometrial cancer after progression on trastuzumab are limited.8
The combination of trastuzumab and pertuzumab, a monoclonal antibody that binds to the extracellular domain of HER2, was evaluated in a basket study including 28 patients with heavily pretreated endometrial carcinoma with ERBB2/3 amplification. In the study, 37% of patients with endometrial carcinoma achieved disease control, although the objective response rate (ORR) was low.9 Zanidatamab (ZW25) is a novel, humanized, bispecific antibody that simultaneously binds 2 distinct extracellular domains of the HER2 receptor (ECD4 and ECD2, the epitopes bound by trastuzumab and pertuzumab, respectively) in a trans configuration.10 This binding induces HER2 downregulation, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis, similar to the response induced by trastuzumab; however, zanidatamab may have greater antitumor activity than the combination of trastuzumab and pertuzumab due to its distinct and enhanced mechanism of complement-dependent cytotoxicity.10–12 The first-in-human, multicenter, phase 1, dose-escalation and expansion study of zanidatamab in a mixed cohort of HER2+ solid tumors demonstrated safety and antitumor activity (ORR, 37%; 95% CI, 27.0%−48.7%).13
Here, we report the results of a single-arm, phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with metastatic endometrial carcinoma or carcinosarcoma with HER2 overexpression.
METHODS
Trial Design and Treatments
This single-arm, phase 2, open-label study was designed to evaluate the efficacy and safety of zanidatamab in patients with advanced or recurrent endometrial carcinoma or carcinosarcoma with HER2 overexpression. The primary objective was to determine the ORR. Secondary objectives included determination of the clinical benefit rate (CBR) by 24 weeks, PFS, OS, and duration of response (DOR). Adverse events were assessed by the current version of Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) to evaluate the safety profile and tolerability of zanidatamab therapy in this cohort.
Zanidatamab was supplied by Zymeworks Inc. (Vancouver, BC, CAN) and administered intravenously at a dose of 20 mg/kg every 2 weeks over 28-day treatment cycles. Patients continued to receive study treatment until progressive disease (PD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1),14 unacceptable toxicity, or withdrawal of consent. Radiological tumor assessment was performed at screening by computed tomography or magnetic resonance imaging every 8 weeks for the first 24 weeks, and subsequently every 12 weeks, until PD, death, or initiation of subsequent anticancer therapy. All patients who discontinued study treatment were followed every 3 months until death, loss to follow-up, or withdrawal of consent, for survival up to 2 years.
The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and ethical principles from the Declaration of Helsinki. All patients provided written informed consent. The Memorial Sloan Kettering Cancer Center (MSK) institutional review board approved the trial protocol. The Data and Safety Monitoring Plan was aligned with MSK’s Data Safety and Monitoring Plan. The trial was registered at ClinicalTrials.gov (NCT04513665).
Patients
Eligible patients were 18 years of age or older with confirmed advanced, recurrent, or metastatic endometrial carcinoma or carcinosarcoma with HER2 overexpression. HER2 overexpression was defined as 3+ by immunohistochemistry (IHC), 2+ by IHC with gene amplification by fluorescence in situ hybridization (FISH; HER2/CEP17 ratio ≥2), or ERBB2 amplification (fold change ≥2) by next-generation sequencing with MSK-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT.15 Eligible patients had progression after 1 or 2 prior lines of systemic therapy, including chemotherapy as a radiation sensitizer, but not including prior hormonal therapy. Patients were required to have measurable disease by RECIST v1.1 at the time of enrollment. A baseline echocardiogram demonstrating a left ventricular ejection fraction ≥50% was required for all patients.
Clinical Data Collection
Clinical data was prospectively collected and entered into a secure database (Medidata Rave®). Race and ethnicity were reported in the medical record based on self-report and identified for the study database by the clinical research coordinator.
Molecular Analysis
Surgical pathology was reviewed clinically at the time of diagnosis. HER2 testing on the primary specimen was used to determine study eligibility. The study gynecologic pathologist (MHC) conducted a comprehensive exploratory analysis of the archived pathology specimens obtained prior to initiation of zanidatamab therapy for all patients. The primary surgical pathology specimens and subsequent archived metastatic biopsies obtained closer to zanidatamab treatment initiation were assessed for HER2 status. On all available pretreatment archival tissue specimens, HER2 immunohistochemistry (4B5, Ventana, Tucson, AZ, USA) was scored using College of American Pathologists (CAP)-endorsed criteria for endometrial cancer16 based on methodology used in the clinical trial by Fader et al, as follows: 0, complete absence of staining; 1+, weak complete membranous expression in <10% of tumor cells or incomplete faint membrane staining in any proportion; 2+, intense complete or basolateral/lateral membrane staining in ≤30% of tumor cells or weak to moderate staining in ≥10% of tumor cells; 3+, intense complete or lateral/basolateral membranous expression in ≥30% of tumor cells.6,16,17 HER2 FISH was performed using an FDA-approved ERBB2 dual-probe FISH assay, HER2 IQFISH pharmDx (Agilent Dako, Santa Clara, CA, USA). HER2 amplification was defined as an HER2/CEP17 ratio of ≥2.0 or an HER2 average copy number per cell of ≥6.0. Intratumor HER2 genetic heterogeneity was assessed by FISH and defined as >5% and <50% of cells amplified by FISH.18,19 Next-generation sequencing using MSK-IMPACT was performed for all patients.15
Statistical Analysis
The trial was designed with a binary endpoint of response measured within 24 weeks of treatment initiation, defined as best overall response of either complete response (CR) or partial response (PR) versus no response. Based on historical data demonstrating an ORR <10% and a PFS rate <20% at 6 months in similar patient populations receiving standard chemotherapy,7 we estimated a sample size of 25 patients would provide 90% power to test the hypothesis that the response rate is promising (30% or higher) against a non-promising rate of 10% or lower. A Simon 2-stage minimax design with Type I error of 10% was used, with a plan to enroll 16 patients in the first stage. If ≥2 of the 16 patients responded, the study would continue to stage 2 and enroll 9 additional patients, for a total of 25 patients. If 1 or fewer patients responded, the study would end for lack of activity (Supplemental Figure S1).
The CBR of zanidatamab therapy (defined as the percentage of patients with CR, PR, or stable disease (SD) ≤24 weeks from the start of treatment) was calculated and the 90% confidence interval was estimated using exact binomial proportions. PFS was defined as the duration of time from the start of treatment to time of recurrence, progression, or death due to any cause, whichever occurred first. OS was defined as the duration of time from the start of treatment to time of death due to any cause. Median survival time was estimated using the Kaplan Meier method. The DOR to zanidatamab therapy was defined as the time from which measurement criteria were met for CR or PR (whichever status was recorded first) until the first date of documented disease progression.
RESULTS
Patient Characteristics
Patients were enrolled between October 1, 2020, and December 14, 2022, and the data cutoff date was June 21, 2023, for PFS and OS analyses (Supplemental Figure S2). Median follow-up time for survivors was 8.6 months (range, 5.9–32.5 months). At the data cutoff date, all patients had completed study treatment.
The baseline characteristics of the 16 patients enrolled on trial are included in Table 1; additional information is listed in Supplemental Table S1. Median age at treatment start was 72 years (range, 64–86 years). One patient (6.3%) was Asian (from the Indian subcontinent), 5 (31.3%) were Black or African American, and 10 (62.5%) were White.
Table 1:
Patient characteristics at baseline.
| Overall (N=16) | |
|---|---|
|
| |
| Age at treatment start | |
| Median [Min-Max] | 72 [64–86] |
| Ethnicity | |
| Not Hispanic or Latino | 16 (100%) |
| Race | |
| Asian / Far East / Indian Subcontinent | 1 (6.3%) |
| Black or African American | 5 (31.3%) |
| White | 10 (62.5%) |
| Diagnosis | |
| Endometrial carcinoma | 16 (100%) |
| Histology | |
| Carcinosarcoma | 1 (6.3%) |
| Clear cell carcinoma | 1 (6.3%) |
| High-grade endometrial carcinoma | 1 (6.3%) |
| Mixed carcinoma, serous and clear cell | 2 (12.5%) |
| Mixed carcinoma, serous and endometrioid | 2 (12.5%) |
| Serous carcinoma | 9 (56.3%) |
| MMR | |
| MSS/pMMR | 16 (100%) |
| P53 | |
| Aberrant | 7 (43.8%) |
| Heterogeneous | 2 (12.5%) |
| Unknown | 7 (43.8%) |
| HER2 IHC | |
| 2+ | 5 (31.3%) |
| 3+ | 9 (56.3%) |
| Not performed | 2 (12.5%) |
| HER2 FISH | |
| Amplified | 7 (43.8%) |
| Not performed | 9 (56.3%) |
| ERBB2 amplification | |
| Amplified | 10 (62.5%) |
| Not amplified | 6 (37.5%) |
| Lines of prior treatment | |
| Mean (SD) | 1.44 (0.629) |
| Median [Min, Max] | 1.00 [1.00, 3.00] |
| Stage at diagnosis | |
| I | 7 (43.8%) |
| III | 4 (25.0%) |
| IV | 5 (31.3%) |
|
Time on treatment (by EOT)
Median [Min, Max] |
56.0 [49.0, 425] |
|
Time on treatment (by date last treatment)
Median [Min, Max] |
48.0 [42.0, 406] |
MMR: mismatch repair; MSS: microsatellite stable; pMMR: proficient mismatch repair; IHC: immunohistochemistry; FISH: fluorescence in situ hybridization; EOT: end of treatment
With regard to disease histology, 9 patients (56.3%) had serous carcinoma, 4 (25%) had mixed carcinoma, 1 (6.3%) had high-grade endometrial carcinoma, 1 (6.3%) had clear cell carcinoma, and 1 (6.3%) had carcinosarcoma. HER2 overexpression was confirmed by IHC 3+ in 9 patients (56.3%), and by HER2 amplification via FISH in the remaining 7 patients (43.8%) (Table 1). Next-generation sequencing using MSK-IMPACT demonstrated ERBB2 amplification in 10 patients (62.5%) (Table 1, Supplemental Figure S3). TP53 was mutated in all samples and CCNE1 amplification was observed in 5 samples, only 3 of which had concurrent ERBB2 amplification (Supplemental Figure S3). All patients had microsatellite stable/mismatch repair-proficient disease.
Ten patients (62.5%) received prior radiation; 8 patients (50%) had prior intravaginal radiation (IVRT) and 2 (12.5%) had prior chemoradiation. Median number of lines of prior systemic therapy was 1 (range, 1–3). Ten patients (62.5%) received prior trastuzumab, with a median time from last trastuzumab to start of zanidatamab of 50 days (range, 33–300 days). Median time on trastuzumab was 6.3 months (range, 0.7–37.3 months). None of the patients received prior trastuzumab deruxtecan or other HER2-directed therapies. Four patients (25%) received prior checkpoint inhibition with second-line pembrolizumab in combination with lenvatinib.
Efficacy
The CBR of zanidatamab therapy at ≤24 weeks from the start of treatment was 37.5% (95% CI, 17.8%−60.9%); 10 patients had PD, 5 had SD, and 1 had PR. However, only 1 patient had a clinical response to treatment (PR), and the study did not proceed to the second stage due to futility (Figure 1A, Figure 1B). The DOR on zanidatamab therapy for the 1 patient who achieved a PR was 7.17 months; this patient was on treatment for 140 days (Figure 1B). This patient notably did not receive prior trastuzumab.
Figure 1. A. Change in tumor burden with zanidatamab treatment and pretreatment HER2 expression across samples.
Waterfall plot demonstrating maximum clinical response after treatment. Initial pretreatment tumor samples are available for all patients and HER2 IHC and FISH results are shown. Subsequent pretreatment samples were available for 4 patients and HER2 IHC and FISH results are also reported. The asterix (*) indicates the result reported by the study pathologist differed from that reported clinically. A single patient had HER2 IHC reported as 3+ clinically, and on review of the same specimen, the study pathologist reported this as HER2 IHC 2+ and non-amplified by FISH. A single patient had HER2 FISH reported clinically as amplified, and on repeat FISH analysis performed by the study pathologist, the patient was found to have no amplification. B. Change in tumor burden with zanidatamab treatment over time. Spider plot demonstrating change in tumor burden relative to baseline. Most patients had an increase in tumor burden consistent with progressive disease. Five patients had stable disease with a slight decrease or minimal increase in tumor burden over time. A single patient had a partial response to zanidatamab therapy.
IHC: immunohistochemistry; FISH: fluorescence in situ hybridization; PD: progressive disease; PR: partial response; SD: stable disease; NA: not available
Survival
Median PFS was 1.7 months (90% CI, 1.6–4.1 months), with a median follow-up for non-progressed survivors of 7.2 months (Figure 2A). Median OS was 14.5 months (90% CI, 11.2-not estimable), with a median follow-up of 8.6 months for survivors (Figure 2B).
Figure 2. A. Progression-free survival. B. Overall survival.
POD: progression of disease; NR: not reported
Safety
Fourteen patients (87.5%) experienced grade 1 or 2 adverse events during the study period (Table 2). No grade 3 or 4 adverse events were observed. The most common adverse events were diarrhea (12 of 16, 75%), followed by nausea (4 of 16, 25%), anorexia (3 of 16, 18.8%), muscle cramps/myalgias (3 of 16, 18.8%), fatigue (3 of 16, 18.8%), rash (3 of 16, 18.8%), and infusion-related reaction (3 of 16, 18.8%; included definite, probable, possible; excluded unlikely or unrelated). All other adverse events observed occurred in 2 or fewer patients (≤12.5% of the cohort) (Table 2).
Table 2.
Grade 1 and 2 adverse events experienced by patients enrolled on trial.
| N (%) | |
|---|---|
|
| |
| Gastrointestinal | |
| Abdominal pain | 1 (6.3%) |
| Anorexia | 3 (18.8%) |
| Diarrhea | 12 (75%) |
| Dysgeusia | 2 (12.5%) |
| Dyspepsia | 2 (12.5%) |
| Gastroesophageal reflux | 1 (6.3%) |
| Mucositis, oral | 1 (6.3%) |
| Nausea | 4 (25%) |
| Vomiting | 2 (12.5%) |
| Weight loss | 1 (6.3%) |
| Skin/Dermatologic | |
| Alopecia | 1 (6.3%) |
| Pruritis | 1 (6.3%) |
| Rash | 3 (18.8%) |
| Neurological/Musculoskeletal | |
| Headache | 1 (6.3%) |
| Muscle cramps/myalgias | 3 (18.8%) |
| Paresthesia | 1 (6.3%) |
| Cardiac | |
| Palpitations | 2 (12.5%) |
| Sinus tachycardia | 1 (6.3%) |
| Constitutional | |
| Fatigue | 3 (18.8%) |
| Malaise | 1 (6.3%) |
| Other | |
| Cough | 1 (6.3%) |
| Infusion-related reaction | 3 (18.8%) |
| Nasal congestion/mucositis | 2 (12.5%) |
| Anemia | 1 (6.3%) |
Exploratory Molecular Analysis: HER2 Heterogeneity
Central review of HER2 IHC was performed by the study pathologist for all 16 patients. Median time from tissue sampling to study treatment initiation was 15 months (range, 2–71 months). Findings were concordant with those reported clinically for 13 (93%) of 14 patients with clinical testing available. One patient was identified as HER2+ (3+) by IHC on clinical testing but was found to have HER2 intermediate staining (2+) on pathology rereview. Subsequent HER2 FISH demonstrated lack of amplification. This patient had PD (best RECIST +56.6%). The 2 patients who did not have clinical IHC performed were reportedly HER2 amplified by FISH; however, on reevaluation by the study pathologist, HER2 IHC was 2+ and FISH was non-amplified. One of these 2 patients had PD and the other had SD.
Overall, 7 (58%) of 12 evaluable cases were identified as having intratumor HER2 genetic heterogeneity on the initial biopsy, and 4 cases were identified as HER2 non-amplified by FISH. Considering heterogeneity and absence of amplification together, 8 (67%) of 12 evaluable cases had heterogeneity and/or HER2 non-amplification.
Five patients had subsequent pretreatment biopsies obtained closer to zanidatamab initiation (median, 12 days prior; range, 4–180 days prior). All of these patients had non-metastatic disease at diagnosis and therefore did not have concurrent primary tumor and metastatic site HER2 testing. Three of 5 patients had a decrease in HER2 expression by IHC; 2 patients decreased from 3+ to 2+ and 1 patient from 2+ to 1+, while 2 patients maintained HER2 expression at 3+ with HER2 amplification by FISH (SD, best RECIST −26.4%; PD, best RECIST +21.3%). HER2 FISH results were unchanged for the other 3 patients (2 with IHC 2+ and 1 with IHC 1+) on subsequent samples (amplified [n=2], non-amplified [n=1]). The patient who had HER2 IHC 2+ and lack of amplification by FISH had PD (+53.7%), while the patient who had HER2 IHC 2+ and amplification by FISH achieved SD (best RECIST −7.4%).
Of the 21 total samples from the 16 patients, only 7 were from metastatic sites (1 at initial diagnosis and 6 at metastatic recurrence), and 5 (71%) of these 7 were HER2+. Examining the 14 primary tumor samples, 2 were negative by FISH and IHC (patients 2 and 11), 7 were positive by IHC, and 5 were amplified by FISH. Overall, 12 (86%) of 14 primary tumor samples were positive.
Exploratory Molecular Analysis: Response to Treatment
For the single patient who had a PR, the tumor was HER2+ by IHC (3+) and amplified by FISH (best RECIST −69.3%) (Figure 1). The patient did have intratumor HER2 genetic heterogeneity, with distinct HER2-amplified and non-amplified areas (cluster-type heterogeneity), corresponding to regions with HER2 IHC 3+ and 0, respectively.
Among the remaining 4 patients who had negative changes in tumor volume but met criteria for SD, all tumors were confirmed HER2+ by IHC (n=2) or FISH (n=2); 2 of these patients had subsequent pretreatment biopsies prior to initiation of zanidatamab treatment, and these samples were HER2+ (IHC 3+ [n=1], IHC 2+ [n=1] with amplification by FISH). The tumor from the single patient who had SD but an increase in tumor volume (+3.7%) had HER2 IHC 2+ and lack of amplification by FISH, with intratumor HER2 genetic heterogeneity identified and no subsequent tissue available.
Of the 10 patients with PD, 5 (50%) had HER2 IHC 3+ and 5 (50%) had HER2 IHC 2+, with 2 non-amplified by FISH (20% negative at study start) and 3 (30%) amplified by FISH. Two of these patients had HER2 testing on subsequent pretreatment samples, which showed IHC 2+ (HER2 non-amplified by FISH) and IHC 1+ (HER2 amplified by FISH). Overall, 3 (30%) of 10 cases with PD had negative HER2 testing prior to enrollment.
DISCUSSION
This phase 2, open-label study evaluating the efficacy and safety of zanidatamab in 16 patients with metastatic endometrial carcinoma or carcinosarcoma with HER2 overexpression after at least 1 line of prior therapy did not meet its primary endpoint for efficacy. Although we did observe a CBR of 37.5%, only 1 patient achieved regression of their disease by RECIST v1.1 criteria, and these findings did not warrant further investigation with the proposed second stage of the study.
While our results fail to offer an additional treatment strategy for patients with HER2+ recurrent endometrial carcinoma, they do shed light on potential underlying mechanisms of resistance and provide directions for future study. Studies have shown that HER2 expression can change over time due to the selective pressure of systemic therapy20,21 and that loss of HER2 expression can be observed at metastatic sites.22 While all patients included in this study had HER2+ disease at the time of diagnosis, we do not have repeat HER2 testing results for all patients prior to enrollment. Although a higher percentage of HER2+ samples was observed at primary compared with metastatic sites (86% vs 71%), the sample size is insufficient to confirm whether there was a significant decrease in HER2 expression over time. It is possible that lower HER2 expression is responsible for the low response rates observed in this study, highlighting the need to repeat tumor biopsies prior to treatment change for patients with HER2+ disease. While zanidatamab has been proposed to have greater efficacy compared to trastuzumab in patients with HER2-low cancers, both are antibodies without a cytotoxic component.23 The only therapy that has demonstrated efficacy in treating HER2-low tumors is trastuzumab deruxtecan, an anti-HER2 antibody linked to a cytotoxic agent.24 In contrast to zanidatamab, which relies upon tumor dependency on HER2 overexpression to achieve cytotoxicity, antibody-drug conjugates such as trastuzumab deruxtecan consist of a cleavable linker and a membrane permeable payload, which can penetrate tumor cells that have low or absent HER2 expression.24
Limitations of this study include the small sample size, heterogeneous tumor histologies, and participation of a single institution.
Our findings suggest that HER2 expression can evolve over time and may indicate the need for repeat tumor testing among patients with HER2+ disease prior to treatment change. Potential strategies to address downregulation of HER2 expression or selection of HER2 negative clones include alternative sequencing of available therapies and novel combination strategies. Although zanidatamab did not demonstrate efficacy in this cohort of patients with recurrent disease after 1 to 3 lines of prior therapy, its efficacy may be distinct in patients with newly diagnosed, untreated disease. Lastly, given that zanidatamab is not linked to a cytotoxic agent, and most data supporting the use of trastuzumab for HER2+ solid tumors include combination chemotherapy with antibody blockade, there may be a role for the combination of zanidatamab with standard chemotherapy, such as carboplatin and paclitaxel, in advanced endometrial cancer. An ongoing phase 2, open-label, first-line study (ZWI-ZW25–201) is investigating the safety, tolerability, and antitumor activity of zanidatamab plus physician’s choice combination chemotherapy in patients with unresectable, locally advanced recurrent or metastatic HER2-expressing gastroesophageal adenocarcinoma, which may shed light on this treatment strategy. Similarly, there are data to support the combination of trastuzumab and pembrolizumab, and a future area of investigation may include the efficacy of zanidatamab in combination with these and other checkpoint inhibitors.
Supplementary Material
Highlights.
HER2 overexpression associated with decreased survival in advanced endometrial cancer (EC)
Zanidatamab in HER2+ metastatic EC/carcinosarcoma did not meet its primary endpoint
Intratumor heterogeneity/lack of HER2 amplification could have attributed to poor efficacy
FUNDING
This study was funded by a research grant from Zymeworks Inc. and was supported in part by funding from the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30CA008748).
CONFLICTS OF INTEREST
V Makker reports meeting/travel support by Eisai and Merck; participation on Data Safety Monitoring or Advisory Board of Duality, Merck, Karyopharm, Exelexis, Eisai, Karyopharm, BMS, Clovis, Faeth Immunocore, Morphosys, AstraZeneca, Novartis, GSK, Bayer (all unpaid); and study support to the institution by Merck, Eisai, AztraZeneca, Faeth, Karyopharm, Zymeworks, Duality, Clovis, Bayer and Takeda. CF Friedman reports institutional research support from Seagen, Merck, BMS, AstraZeneca, Mersana, and Hotspot Therapeutics; consulting fees from BMS, Seagen, and Aadi Biosciences; honoraria for lectures from Onclive; meeting/travel support by PUMA; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). A Iasonos reports consulting fees from Mylan. MM Rubinstein reports research funding from Merk, Zentalis, and AstraZeneca. C Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. RN Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. C Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). The other authors do not have potential conflicts of interest to declare.
Footnotes
CONSENT STATEMENT
This study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, and all patients provided written consent.
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DATA AVAILABILITY STATEMENT
The data underlying this article are available in the article and in its online supplementary material.
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