zanidatamab (ZW25)

P1/2, N=52, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=93 --> 52 | Trial primary completion date: Jul 2024 --> Oct 2024

P2, N=168, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting

P2; Active, not recruiting --> Completed | Trial completion date: Feb 2025 --> Mar 2024 | Trial primary completion date: Feb 2025 --> Mar 2024

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=362 --> 74

P2; Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P3, N=286, Recruiting, Jazz Pharmaceuticals

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.

P1/2, N=71, Active, not recruiting, BeiGene | Phase classification: P1b/2 --> P1/2

P3, N=800, Not yet recruiting, UNICANCER

P2, N=168, Not yet recruiting, Canadian Cancer Trials Group | Initiation date: Oct 2023 --> Jan 2024

HERIZON-BTC-01 (NCT04466891), an ongoing, open-label, Phase 2b study, is assessing zani (20 mg/kg IV Q2W) in patients with HER2+ (gene amplification and immunohistochemistry 2+ or 3+ [Cohort 1] and 0 or 1+ [Cohort 2]), locally advanced, unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who received prior gemcitabine-containing treatment (tx). Patients with HER2+ BTC who responded to zani reported less pain and pain interference compared with BL, further supporting the development of zani as a tx option for these patients, with the goal of improving patient outcomes. Clinical trial information: NCT04466891. >Change from BL for each patient is post-BL value minus BL value; negative values for change from BL indicate better outcomes and positive indicate worse.

P2, N=51, Active, not recruiting, Jazz Pharmaceuticals | Phase classification: P2a --> P2

P2, N=87, Active, not recruiting, Jazz Pharmaceuticals | Phase classification: P2b --> P2

P1/2, N=93, Recruiting, Jazz Pharmaceuticals | Phase classification: P1b/2 --> P1/2 | Trial completion date: Oct 2024 --> Jan 2025 | Trial primary completion date: Apr 2024 --> Jul 2024

Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients...Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.

More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

Eligible pts had HER2+ (by local HER2 testing) and HR+, unresectable, locally advanced or mBC; ECOG PS ≤1; prior treatment with at least trastuzumab, pertuzumab, and T-DM1; and no prior CDK4/6 inhibitor...In the metastatic setting, pts received a median (range) of 4 (1-12) prior systemic regimens, 3 (1-10) prior different HER2-targeted therapies, and 1 (0-5) prior endocrine therapy; 12 (24%) pts had prior T-DXd and 11 (22%) had prior fulv... Zani + palbo + fulv showed a promising PFS6 and mPFS with durable responses. The safety profile was manageable. These results support further development of a novel chemotherapy-free treatment regimen for heavily pretreated pts with HER2+/HR+ mBC.

Background: The addition of trastuzumab+/-pertuzumab to chemotherapy has changed the natural history of earlyHER2+ breast cancer...Six received tamoxifen and 8 letrozole... Neoadjuvant zanidatamab demonstrates significant preliminary efficacy, (pCR/RCB-1 64%) with a good safety profile in patients with stage I node negative HER2+ BC. An update of efficacy and safety of all patients will be presented at the time of meeting

P2, N=20, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Pts had received ≥1 prior systemic Tx for advanced disease, including gemcitabine. Lancet Oncol. 2023).

P2, N=168, Not yet recruiting, Canadian Cancer Trials Group

No abstract available

P2b, N=87, Active, not recruiting, Jazz Pharmaceuticals | Trial primary completion date: Oct 2022 --> Jul 2023

P2b, N=87, Active, not recruiting, Jazz Pharmaceuticals | Trial completion date: Jun 2024 --> Oct 2024

P2, N=362, Recruiting, Jazz Pharmaceuticals | Trial completion date: Apr 2024 --> Oct 2026 | Trial primary completion date: Mar 2023 --> Nov 2025

P1, N=279, Active, not recruiting, Jazz Pharmaceuticals | Trial completion date: Aug 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P2a, N=51, Active, not recruiting, Jazz Pharmaceuticals | N=86 --> 51 | Trial completion date: Jun 2023 --> Oct 2025 | Trial primary completion date: Dec 2022 --> Apr 2023

Both cohorts also received standard capecitabine-oxaliplatin (CAPOX). Safety was consistent with previous findings. A phase III trial (NCT05152147) evaluating this regimen is ongoing.

Methods HERIZON-BTC-01 (NCT04466891), an ongoing open-label, global phase 2b study, evaluated zani (20 mg/kg IV every 2 wks) in pts with HER2+ (gene amplification with immunohistochemistry of 2+ or 3+), locally advanced, unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who received prior gemcitabine-containing treatment (tx). Table: 101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conclusions In HERIZON-BTC-01, pts with HER2+ BTC who responded to zani reported improved QoL compared with BL, while those with PD reported worsening QoL compared with BL. These results support the continuing development of zani as a HER2+ BTC tx option.

Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Eisai Inc, Exelixis Inc, Incyte Corporation, Jazz Pharmaceuticals Inc, Merck, Seagen Inc, and Servier Pharmaceuticals LLC. Spectrum and frequency of molecular alterations in cholangiocarcinoma and other BTCs; optimal timing and type of genomic analysis to identify actionable abnormalities Principal efficacy and safety findings with pemigatinib and futibatinib for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements Published outcomes from the Phase III ClarIDHy study of ivosidenib for previously treated advanced cholangiocarcinoma with an IDH1 mutation; optimal incorporation into clinical practice Ongoing research evaluating targeted therapies, such as FGFR inhibitors or ivosidenib, for newly diagnosed cholangiocarcinoma Emerging results from the pivotal Phase IIb HERIZON-BTC-01 trial investigating the novel HER2-targeted bispecific antibody zanidatamab for previously treated HER2-amplified and HER2-expressing BTCs Published (eg, the Phase II HERB study) and emerging (eg, the Phase II DESTINY-PanTumor02 study) efficacy and safety outcomes with trastuzumab deruxtecan for HER2-expressing BTCs Emerging efficacy and safety findings among patients with previously treated HER2-positive BTCs from the Phase II SGNTUC-019 basket study of tucatinib and trastuzumab Other promising biomarker-based strategies for advanced BTCs

Zani combined with docetaxel demonstrated promising antitumor activity as 1L therapy for advanced HER2+ BC, with a manageable safety profile. Clinical trial information: NCT04276493. >*Four pts without any postbaseline tumor assessments were excluded from the EE analysis set.Data cut off: November 22, 2022.†Censored.

P2; Recruiting --> Active, not recruiting | N=25 --> 17

Background Outcome of patients (pts) w/ stage I node neg HER2+ treated w/ wkly paclitaxel x 12 doses and trastuzumab x 1yr is excellent (10yr RFS 96%)...Three received tamoxifen and 3 letrozole...Conclusions Neoadjuvant zanidatamab for 3 months showed significant efficacy, (pCR/RCB-1 64%) w/ acceptable safety profile in pts w/ stage I node neg HER2+ BC. The trial is ongoing and has been modified to increase treatment duration to 5mths (10 cycles).

These results indicate that ERBB2 amplification detected by the Guardant360 assay could be used as a surrogate for FISH analysis in lieu of invasive surgical procedures.

Anti-tumor activity was observed in 5/7 (71%) PDX models of gastric cancer after a single i.v. dose of 6 mg/kg, including in models with moderate and weak HER2 expression. The strong anti-tumor activity of ZW-49 in vivo, together with its ability to induce ICD and potential adaptive immune responses, support ZW49 as a promising ADC for the treatment of HER2-expressing cancers warranting further investigation, including potential combination with checkpoint inhibitors.

P2; Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.

Pts were enrolled between Aug 29, 2019 and Feb 18, 2022 with a data cutoff of July 28, 2022 (N=46 pts; zani + mFOLFOX6 [24], zani + CAPOX [20], or zani + FP [2])... In pts with HER2+ mGEA, zani + chemo is a highly active treatment regimen with a manageable safety profile. This maturing data set demonstrates durable disease control with encouraging cORR, DOR, PFS and OS results. A global Ph 3 study (HERIZON-GEA-01; NCT05152147) evaluating zani in combination with physician’s choice of standard chemo with or without the PD-1 inhibitor, tislelizumab, for first-line treatment of advanced HER2+ mGEA is currently enrolling.

P2a, N=86, Active, not recruiting, Zymeworks Inc. | Recruiting --> Active, not recruiting