ESMO 2021: Gastrointestinal cancer Highlights

Today marks the beginning of ESMO 2021, major key players in gastric cancer (GC) and gastroesophageal junction (GEJ) cancer such as Merck, Innovent Biologics, Leap therapeutics, Zymeworks, Macrogenics and others are excitingly presenting their lead candidates. Out of them Macrogenics and Zymeworks have their candidates in First-Line HER2+ Gastric Cancer and with recently approved Keytruda in first line GEJ the landscape is changing rapidly.

Poster#1379P: Margetuximab with Retifanlimab in HER2+, PD-L1+ First-Line Unresectable/Metastatic Gastroesophageal Adenocarcinoma (GEA): MAHOGANY Cohort A

Macrogenics presented the results from the Part 1 of Cohort A of the MAHOGANY (NCT04082364) Phase II/III study with the safety and efficacy cutoff dates of July 19, 2021 and August 3, 2021, respectively. The trial has two cohorts designed to evaluate margetuximab in combination with a checkpoint inhibitor, with or without chemotherapy, as a potential first-line treatment for patients with advanced or metastatic HER2+ GEJ/GC. In Cohort A, the efficacy of the margetuximab/retifanlimab combination is evaluated in approximately 100 patients that are HER2 IHC3+, PD-L1+, and non–MSI-H with ORR as a primary endpoint.

MAHOGANY Cohort A: Interim Analysis

As of the cutoff date 43 patients were treated with: 25 (58%) with GC and 18 (42%) with GEJ, out of them most (84%) with metastatic disease. In the 7.6 months follow-up 23 patients discontinued the study treatment; reasons were progressive disease (n=18), adverse events (n=3), and physician decision (n=2).

In terms of efficacy the tumor shrinkage was seen in 78% of patients and an objective response of 52.5% which includes a complete response in 10% and partial response in 42.5% of patients. The 6-month, 9-month, and 12-month PFS are 71%, 50%, and 50% respectively. While the OS at 12-month and 18-month is 85%.

On the safety front the combination (margetuximab + retifanlimab) was well tolerated, with durable antitumor activity in 43 patients. Nine Grade 3 TRAEs were reported in eight patients and no Grade 4 TRAEs while eight serious TRAEs were reported in 7 patients.

 “This study is designed to support potential registration of margetuximab in combination with other agents for patients with gastric or gastroesophageal junction cancer as part of our strategy to advance margetuximab in HER2+ cancer. The findings suggest the combination of margetuximab and retifanlimab may potentially provide a chemotherapy-free option as a first-line treatment for patients whose tumors are positive for both HER2 and PD-L1. We are pleased these data support the protocol’s prespecified advancement into Part 2 of MAHOGANY Cohort A. We plan to discuss these results and future development of the combination in an upcoming scheduled meeting with the FDA.”

—    President and CEO of MacroGenics

Margetuximab: Margenza (margetuximab), approved in HER2+ breast cancer with two black box warnings, is an Fc-engineered, monoclonal antibody that targets the HER2 oncoprotein, provides HER2 blockade, and has similar HER2 binding and antiproliferative effects as trastuzumab. It has Orphan drug designation from FDA for Gastric cancers.

Retifanlimab: Retifanlimab is an investigational, humanized, proprietary anti-PD-1 monoclonal antibody being developed for use as monotherapy as well as in combination with other potential cancer therapeutics.

Poster#1380P: Phase II Study of Zanidatamab + Chemotherapy in First Line (1L) HER2-expressing Gastroesophageal Adenocarcinoma (GEA)

In this phase II study ZWI-ZW25-201 (NCT03929666) antitumor activity of zanidatamab + standard first-line combination chemotherapy regimens in subjects with locally advanced, unresectable, or metastatic HER2-expressing gastrointestinal cancers including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer.

The data was extracted on July 28, 2021: 36 subjects with GEA, 19 (53%) continue on study treatment and 12 (33%) subjects discontinued treatment due to disease progression, 4 (11%) due to treatment-related AE, and 1 (3%) due to physician decision.

Out of 36, 28 patients with metastatic HER2-positive GEA were evaluated in three experimental arms zanidatamab plus CAPOX (capecitabine plus oxaliplatin; n=12), zanidatamab plus FP (5-FU and cisplatin; n=2), and zanidatamab plus mFOLFOX6 (5-FU plus oxaliplatin and leucovorin; n=14). A complete ORR (cORR) of 75% and disease control rate (DCR) of 89% overall was observed. The cORR in zanidatamab plus CAPOX, zanidatamab plus FP, and zanidatamab plus mFOLFOX6 was 92%, 100% and 57% while DCR was 100%, 100% and 79%. Based on this zanidatamab plus CAPOX/FP with a combined cORR of 93% and DCR of 100% are proposed for Phase III regimen. The median PFS is 12 months and mDOR is 16.4 months. The tumor shrinkage was observed in all patients.

Based on these promising data, a phase III study (HERIZON-GEA-01) is planned to begin enrollment in Q4 2021 and will evaluate zanidatamab + chemotherapy (CAPOX or FP) ± the PD-1 inhibitor tislelizumab for first-line treatment of locally advanced, unresectable, or metastatic HER2-positive GEA.

 “Our long-standing vision for zanidatamab has been for it to become a best-in-class HER2‑targeted therapeutic that could address the needs of a broad spectrum of patients with HER2‑expressing cancers. Over the years we have shared data that have showcased the promising anti-tumor activity and safety profile of zanidatamab; that said, the data shared today stand out as they represent the first clinical validation of zanidatamab in a front-line setting. As we embark on our second pivotal trial and prepare for commercialization, these data represent a landmark moment for zanidatamab and for Zymeworks.”

—    President and CEO of Zymeworks

“Herceptin and chemotherapy have been the standard of care in first-line HER2-positive GEA for over 10 years. The data presented today give us the confidence that we have developed a next-generation HER2-targeted agent that has the potential to provide patients with an improved option in this setting”

-         Expert Opinion

Zanidatamab: Zanidatamab is a bispecific antibody, based on Zymeworks Azymetric platform that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. The FDA has granted Fast Track designations to zanidatamab in combination with standard of care chemotherapy for first-line gastroesophageal adenocarcinoma (GEA). Zanidatamab has also received Orphan Drug designations for the treatment gastric cancer from the EMA and FDA.

INSIGHTS: HER2 is overexpressed in nearly 20% of the patients. Herceptin (trastuzumab) and chemotherapy have been the standard of care in first-line HER2-positive GEA for almost a decade while the other therapeutics options are available if only disease progresses. The recent accelerated approval of Keytruda (pembrolizumab) does not changes the current SOC as it is approved as a combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy or the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

But the margetuximab and zanidatamab are looking forward to compete with Herceptin in the first-line setting. Moreover, the approval of Keytruda was based on the interim analysis of the first 264 patients of the ongoing KEYNOTE-811 trial with an ORR of 74% in the pembrolizumab arm and 52% in the placebo arm. Although the initial results of both margetuximab and zanidatamab look promising with zanidatamab even getting better in terms of ORR but the results are from a smaller cohort as compared to Keytruda. So, more data in larger trial will decide their fate but it would not be easy to replace the Keytruda.