Zanidatamab zovodotin (ZW49) was found to produce encouraging responses and to have a manageable toxicity profile when used as a monotherapy in heavily pretreated patients with HER2-positive solid cancers, according to data from a first-in-human phase 1 trial (NCT03821233) presented during the 2022 ESMO Congress.

Among 29 patients, the HER2-targeting antibody-drug conjugate (ADC) elicited a confirmed objective response rate (cORR) of 31% (95% CI, 15.3%-50.8%), which included a partial response (PR) rate of 31% and a stable disease (SD) rate of 41%. Twenty-four percent of patients experienced disease progression (PD). The disease control rate (DCR) achieved with the ADC was 72% (95% CI, 52.8%-87.3%) and the clinical benefit rate (CBR) was 38% (95% CI, 20.7%-57.7%).

“The maximum tolerated dose [MTD] has not been reached. Two dose-limiting toxicities [in the form of] grade 2 keratitis were observed in 1 patient each at the 1.75 mg/kg weekly and 2.5 mg/kg every-3-week cohorts,” Komal Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, said in a presentation on the data. “No interstitial lung disease or pneumonitis were reported, [and] there were no treatment-related deaths.”

Zanidatamab zovodotin has an immunoglobulin 1–like antibody backbone that is directed against extracellular domain 4 and 2 of HER2, with an antibody sequence that is identical to that of zanidatamab (ZW25). The proprietary auristatin payload is covalently linked with a protease cleavable valine-citruline linker. The agent has an average drug-to-antibody ratio of 2.

Investigators launched the first-in-human, dose-escalation and -expansion trial to further evaluate zanidatamab zovodotin’s safety and efficacy in patients with HER2-expressing or -amplified solid cancers.

To be eligible for enrollment, patients were required to have refractory disease and must have received trastuzumab (Herceptin), pertuzumab (Perjeta), and fam-trastuzumab emtansine (T-DM1; Kadcyla). They also needed to have an ECOG performance status of 0 or 1. Furthermore, those with HER2-positive gastroesophageal adenocarcinoma (GEA) were required to have received trastuzumab.

The trial had a 3+3 design, and patients received zanidatamab zovodotin weekly, as part of a 28-day treatment cycle, on a 3-weeks-on/3-weeks-off schedule; every 2 weeks, as part of a 28-day cycle; or every 3 weeks, as part of a 21-day cycle. The dose-expansion cohorts included those with HER2-positive breast cancer, HER2-positive GEA, and other HER2-positive solid cancers.

The primary objectives of the research were to identify the MTD and the recommended phase 2 dose (RP2D) of zanidatamab zovodotin, as well as to characterize the safety and tolerability of the agent. Examining the antitumor activity of the ADC in those with HER2-expressing cancers served as a key secondary objective.

As of June 9, 2022, a total of 77 patients received treatment with the ADC across the dose-escalation portion of the trial, as well as in the dose-expansion portion. Those in the expansion portion of the research were given zanidatamab zovodotin at 2.5 mg/kg every 3 weeks. Of these patients, 12% (n = 9) continue to receive the ADC.

In the total population, the median age was 59 years (range, 24-83), 58% were female, 57% were White, and 66% had an ECOG performance status of 1. Regarding primary diagnosis, 27% had GEA, 22% had breast cancer, and 51% had other solid cancers. Other tumors included ovarian cancer, endometrial cancer, bladder cancer, biliary tract cancer, anal cancer, colorectal cancer, pancreatic cancer, and non–small cell lung cancer.

Regarding HER2 status, 58% of patients were IHC3+ and 16% were IHC2+/FISH+. Sixty-nine percent of patients previously received HER2-targeted therapies, and the median number of previous systemic regimens received in the metastatic setting was 3 (range, 1-16).

Additional data showed that among the 8 patients with breast cancer, zanidatamab zovodotin induced a cORR of 13% (95% CI, 0.3%-52.7%), which included a PR rate of 13% and a SD rate of 38%; 38% of patients experienced PD. The DCR in these patients was 50% (95% CI, 15.7%-84.3%), and the CBR was 25% (95% CI, 3.2%-65.1%).

In the 11 patients with GEA, the cORR achieved with the ADC was 37% (95% CI, 10.9%-69.2%), which comprised a PR rate of 36% and a SD rate of 36%; 27% experienced PD. In this group, the DCR and CBR were 73% (95% CI, 39.0%-94.0%) and 36% (95% CI, 10.9%-69.2%), respectively.

In the remaining 10 patients with other solid cancers, zanidatamab zovodotin elicited a cORR of 40% (95% CI, 12.2%-73.8%), which included a PR rate of 40% and a SD rate of 50%; 10% of patients had PD. Here, the DCR was 90% (95% CI, 55.5%-99.7%) and the CBR was 50% (95% CI, 18.7%-81.3%).

In those who received zanidatamab zovodotin at 2.5 mg/kg every 3 weeks in both portions of the trial (n = 30), 90% of patients experienced any-grade treatment-related adverse effects (TRAEs). The most common TRAEs experienced with the ADC were keratitis (43%), alopecia (17%), and diarrhea (30%). All keratitis effects decreased to grade 1 in severity or resolved; there was mandatory ocular prophylaxis.

Grade 3 or higher TRAEs were experienced by 17% of patients, with 3% experiencing grade 3 or higher keratitis. Treatment-related serious AEs were experienced by 7% of patients, with 3% experiencing infusion-related reactions, and 3% experiencing electrocardiogram QT prolongation.

“Dose reduction was required in 21% of patients due to TRAEs, [which included] 19% of those in the dose-escalation [portion of the research] and 24% of patients in the dose-escalation [portion],” the study authors concluded. “These patients continued receiving zanidatamab zovodotin at a reduced dose level.”

Jahveri K, Han HS, Dotan E, et al. Preliminary results from a phase 1 study using the bispecific, Human Epidermal Growth Factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers. 2022;33(suppl 7):S749-S750. doi:10.1016/j.annonc.2022.07.589

Articles

Zanidatamab zovodotin was found to produce encouraging responses and to have a manageable toxicity profile when used as a monotherapy in heavily pretreated patients with HER2-positive solid cancers.

Zanidatamab Zovodotin Showcases Promising Safety, Activity in HER2+ Solid Cancers

The FDA has granted an orphan drug designation to the novel PD-L1/4-1BB bispecific antibody ATG-101 for the treatment of patients with pancreatic cancer.

If approved, the agent could represent the first PD-L1/4-1BB bispecific antibody indicated for the treatment of patients with pancreatic cancer worldwide.

“We are very encouraged by this orphan drug designation from the US FDA and are hopeful that ATG-101 will offer a novel therapeutic to patients with pancreatic cancer. As Antengene’s first in-house developed asset with global rights, ATG-101 has already entered clinical development in Australia, China, and the US. We will strive to accelerate the global clinical development of ATG-101 in efforts to provide a new treatment option to patients around the world,” Bo Shan, PhD, chief scientific officer of Antengene, stated in a press release.

ATG-101 is a novel PD-L1/4-1BB bispecific antibody that was designed to inhibit the binding of immunosuppressive PD-1/PD-L1 and conditionally induce 4-1BB stimulation to activate antitumor immune effectors, while delivering enhanced antitumor activity with an improved safety profile.

In preclinical studies, ATG-101 showed substantial antitumor activity in animal models of resistant tumors in addition to those that had progressed on anti–PD-(L)1 treatment. ATG-101 has also shown a favorable safety profile in Good Laboratory Practice toxicology studies.

ATG-101 is the first PD-L1/4-1BB bispecific antibody entering clinical development in Australia and is currently being evaluated in clinical studies in Australia, China, and the US.

In November 2021, the FDA approved the investigational new drug application for ATG-101, allowing Antengene to initiate the phase 1 PROBE trial (NCT04986865) to evaluate the safety and tolerability of ATG-101 in patients with metastatic and advanced solid tumors and mature B-cell non-Hodgkin lymphoma.

On August 2, 2022, the company announced that the first patient had been dosed in China in the phase 1 PROBE-CN trial.

“Since many patients with advanced cancer are resistant to existing chemotherapy, targeted drugs, and monoclonal antibodies or relapse in a short time after receiving treatment, there is an urgent need for innovative therapies that can improve treatment options. Increasing evidence suggests that bispecific antibodies will become a critical component of cancer therapy. We are excited to have the opportunity to collaborate with a number of prominent investigators in China to conduct the first clinical study of ATG-101, a novel PD-L1/4-1BB bispecific antibody,” Ye Guo, MD, deputy director of medical oncology at Shanghai East Hospital of Tongji University, and principal investigator of the study, said in a press release. “ATG-101 has a high affinity for PD-L1 and can achieve conditional activation of 4-1BB agonist, which is expected to bring a lower risk of systemic toxicity, particularly the hepatotoxicity that has been seen with previous agonists of 4-1BB. We hope that ATG-101 will demonstrate efficacy and safety, and bring a new treatment option to patients with resistant or relapsed cancers,” Guo concluded.

Antengene announces ATG-101 granted orphan drug designation by the U.S. FDA. News release. Antengene. September 18, 2022. Accessed September 19, 2022. 

Antengene receives FDA approval of IND for phase 1 trial of ATG-101 (PD-L1/4-1BB bispecific antibody) in solid tumors and non-Hodgkin lymphoma. News release. Antengene. November 1, 2021. Accessed September 19, 2022. 

A study evaluating the safety and efficacy of ATG-101 in patients with metastatic/advanced solid tumors and mature B-cell non-Hodgkin lymphomas (PROBE). ClinicalTrials.gov. Updated April 13, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04986865

Antengene announces first patient dosed in the PROBE-CN study of ATG-101 (PD-L1/4-1BB bispecific antibody) for the treatment of solid tumors and non-Hodgkin lymphoma. News release. Antengene. August 2, 2022. Accessed September 19, 2022. 

FDA Grants Orphan Drug Designation to ATG-101 for Pancreatic Cancer 

The FDA has granted an orphan drug designation to WP1122 as a potential therapeutic option for patients with glioblastoma multiforme, according to an announcement from Moleculin Biotech, Inc.

The investigative agent was developed as a 2-DG prodrug to offer a more favorable pharmacological profile. In preclinical models where tumor cells required greater glycolytic activity than normal cells, WP1122 was observed to have stronger potency than 2-DG alone.

The preclinical data reported with WP1122 illustrated the potential of the agent in this disease and supported the regulatory agency’s decision to grant it investigational new drug (IND) status.

The drug developer, Moleculin Biotech, Inc., is currently examining collaboration opportunities for the clinical development of WP1122.

“The receipt of orphan drug designation represents an important milestone for our promising WP1122 development program,” Walter Klemp, chairman and chief executive officer of Moleculin Biotech, Inc., stated in a press release. “Given the progress of our phase 1 clinical trial [NCT05195723] in healthy volunteers, the strong preclinical data supporting glioblastoma multiforme as 1 of many potential indications and the recent clearance by the FDA of IND status for WP1122 in [this disease], we believe this designation further supports the potential of WP1122 and is another step forward in further validating our deep pipeline.”

In the phase 1 study, investigators set out to explore the effects of a single dose and several days of dosing of WP1122 administered as an oral solution in healthy human volunteers.

 To be eligible for enrollment, participants needed to be between the ages of 18 years and 55 years, fully vaccinated against COVID-19 and willing to undergo testing for the virus, have a minimum body weight of at least 50 kg for men and at least 45 kg for women.

Participants needed to be healthy per physician assessment and based on a medical evaluation, which included medical history, physical examination, laboratory tests, and echocardiogram.

Those who were pregnant, breastfeeding, or intending to become pregnant were excluded, as were those with evidence of SARS-CoV-2 infection, those with respiratory disease, hypersensitivity or severe allergic reactions to vaccines or drugs, diabetes mellitus, clinically relevant hypertension, history of bleeding diathesis or coagulopathy, or cardiovascular diseases.

Each study group is comprised of 10 volunteers who are randomly assigned 4:1 to receive WP1122 or placebo. Dose escalation will take place in sequential single-dose cohorts.

In the first portion of the study, the single ascending dose portion, 8 volunteers will receive the oral investigational drug and 2 will receive placebo. Up to 40 volunteers will be enrolled to this portion of the research.

The second portion of the study, or the multiple ascending dose portion, will start after the third group in the single dosing portion of the trial has completed dosing and WP1122 is found to be safe and well tolerated. In up to 4 groups, 8 volunteers will be administered oral WP1122 and 2 will be given placebo twice daily, 12 hours apart for the duration of 7 days. Up to 40 volunteers will be enrolled to this portion of the study.

The primary outcome measures for the trial are to evaluate the safety and tolerability of escalating doses of WP1122 given as a single oral dose in sequential cohorts of healthy volunteers and to determine the maximum tolerated dose of the agent. Investigators also want to analyze the safety and tolerability of 7 days of escalating doses of the agent given every 12 hours in sequential cohorts of healthy volunteers and to identify the recommended phase 2 dose for a trial being done in patients with COVID-19.

Secondary outcome measures include examining the activity of WP1122 in the body after a single dose and multiple ascending doses; to do this, investigators will examine participants’ maximum plasma concentration.

Glioblastoma multiforme represents the most aggressive malignant primary brain tumor; this disease continues to be incurable and those diagnosed with it have a median survival of only 15 months. Glioblastoma multiforme accounts for 54% of all glioma cases and 16% of all primary brain tumors.

With orphan drug status, the clinical-stage pharmaceutical company is provided with select benefits, such as financial incentives to support clinical development. Moleculin Biotech, Inc. also has the potential for up to 7 years of market exclusivity for WP1122 in the United States if the agent is eventually approved in its designated indication.

Moleculin receives FDA orphan drug designation of WP1122 for the treatment of glioblastoma multiforme. News release. Moleculin Biotech, Inc. September 6, 2022. Accessed September 7, 2022. 

Study to assess the safety and pharmacokinetics of WP1122 in healthy volunteers. ClinicalTrials.gov. Updated May 13, 2022. Accessed September 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05195723

The FDA has granted an orphan drug designation to WP1122 as a potential therapeutic option for patients with glioblastoma multiforme.

Pipeline Report: September 2022

Articles

Zanidatamab Zovodotin Showcases Promising Safety, Activity in HER2+ Solid Cancers

FDA Grants Orphan Drug Designation to ATG-101 for Pancreatic Cancer