November 12 2024
Written by Geoffrey Y. Ku, MD; Gastrointestinal Oncology Service, Dept of Medicine, Memorial Sloan Kettering Cancer Center
Introduction
HER2 has emerged as a crucial biomarker and therapeutic target in various solid tumors, including esophagogastric (EG) adenocarcinoma. In 2010, the ToGA study established the efficacy of trastuzumab, an anti-HER2 antibody, alongside chemotherapy as a first-line treatment for advanced gastroesophageal junction (GEJ)/gastric cancer
1. Recently, the KEYNOTE-811 study also confirmed benefit for adding an immune checkpoint inhibitor to first-line trastuzumab/chemotherapy
2,3.
Zanidatamab, a biparatopic antibody against HER2, is currently being tested in a phase III study in the first-line setting4. The NRG is also incorporating zanidatamab into a proposed phase II/III study in the peri-operative setting for HER2-positive EG adenocarcinoma.
First-line Therapy for Advanced HER2+ EG cancer: the ToGA study
The landmark ToGA trial established the benefit of a targeted therapy in GEJ/gastric cancer.1 In this phase III study, 584 patients with HER2-positive tumors (defined as HER2 IHC 3+ or FISH positive) were randomized to receive standard chemotherapy with or without trastuzumab, an anti-HER2 antibody. The results showed a substantial improvement in median overall survival (OS) in the trastuzumab group (13.8 vs. 11.1 months), as well as in median progression-free survival (PFS; 6.7 vs. 5 5months) and objective response rate (ORR; 47% vs. 35%). Further subgroup analyses, using the pre-planned alternative criteria for HER2+ positivity (IHC 3+ or IHC 2+/FISH positive), confirmed this benefit, with a median OS of 16 months in the trastuzumab group vs. 11.8 months in the chemotherapy-only group, establishing the contemporary definition of HER2 positivity.
On the basis of this study, trastuzumab/chemotherapy was approved by the US FDA in 2010 for HER2 positive GEJ/gastric cancer.
The Current Standard-of-Care: the KEYNOTE-811 study
Further improvement in the standard-of-care established by the ToGA study had to await the KEYNOTE-811 trial, which randomized HER2-positive GEJ/gastric cancer patients to trastuzumab/chemotherapy with or without pembrolizumab, an anti-programmed death-1 (PD-1) antibody.3 A pre-planned interim analysis revealed a statistically and clinically significant improvement in the ORR to 74.4% in the pembrolizumab arm vs. 51.9% in the placebo arm, leading to the FDA approval in May 2021 for all patients irrespective of PD-L1 status. This was the first FDA approval of an anti-cancer therapy based on an improvement in ORR alone without mature survival data.
More recently, the third interim analysis from March 2023 confirmed an improvement in the co-primary endpoint of median PFS (10.0 vs. 8.1 months, p=0.0002), as well as a numerically improved OS (20.0 vs. 16.8 months) that is not statistically significant.2
This updated analysis also showed that the greatest benefit was restricted to tumors with PD-L1 combined positive score (CPS) ³1 (85% of patients). In fact, in patients whose tumor PD-L1 CPS was <1, the HRs for PFS and OS were 1.03 and 1.41, respectively. The point estimate for the HR for OS suggests harm for the addition of pembrolizumab to standard therapy, and is concerning but could be related to undetermined imbalance in the small number of patients with PD-L1 CPS <1 tumors.
These data led to the FDA approval of this combination becoming restricted only to HER-2 positive tumors whose PD-L1 CPS is ³1 in November 2023.
Novel anti-HER therapy: zanidatamab
Zanidatamab is a subclass of bispecific antibodies known as a biparatopic antibody. This means that it binds to two different epitopes (the juxtamembrane and dimerization domains) of the HER2 protein. It exerts therapeutic actions by inducing receptor clustering, internalization, downregulation, and activating ADCC and complement-dependent cytotoxicity.5
In a first-in-human phase I dose-escalation study, zanidatamab demonstrated safety and tolerability in patients with HER2-over-expressing or HER2-amplified advanced solid tumors, including GEJ/gastric cancer.5
This led to a phase II trial in first-line treatment for advanced HER2-positive GEJ/gastric cancers, which combined zanidatamab with various fluoropyrimidine/platinum doublets (mFOLFOX6, capecitabine/cisplatin and 5-FU/cisplatin) in 46 patients.6 In 37 response-evaluable patients, the study revealed aconfirmed ORR rate of 84% (including a complete response rate of 11%). The median duration of response is 18.7 months, while the median PFS is 15.2 months and the estimated 24-month OS rate is 65%. Notable grade 3/4 toxicities include diarrhea in 35% of patients; this incidence was reduced in patients who received loperamide prophylaxis vs. those who did not receive prophylaxis (14% vs. 52%).
These encouraging results paved the way for the ongoing phase III HERIZON-GEA-01 trial (NCT05152147), a global phase III study evaluating zanidatamab in combination with chemotherapy with or without tislelizumab, an anti-PD-1 antibody, as first-line treatment for advanced HER2-positive GEJ/gastric cancers.4 The trial's co-primary endpoints, PFS and OS, aim to establish zanidatamab as a superior option compared to trastuzumab.
Anti-HER2 therapy in the locally advanced setting
Even though it has been nearly 15 years since the FDA approval of trastuzumab as part of 1st-line therapy for metastatic GEJ/gastric cancer, no randomized study has shown a benefit for adding anti-HER2 therapy to standard therapy for locally advanced EG cancer.
The NRG previously enrolled patients to the RTOG 1010 study, which randomized 203 patients with HER2-positive esophageal/GEJ adenocarcinoma to pre-operative carboplatin/paclitaxel and radiation with or without trastuzumab.7 Very disappointingly, this study did not reveal any benefit for adding trastuzumab to chemoradiation in terms of pathologic complete response (pCR) and survival outcomes.
In Germany, investigators initiated the randomized phase II/III PERTRACA study, which evaluated peri-operative chemotherapy with the FLOT regimen (bolus and infusional 5-FU/leucovorin/oxaliplatin/docetaxel) with or without trastuzumab and pertuzumab, an antibody that binds to a different HER2 domain than trastuzumab.8 This study did not proceed to phase III based on the negative results of the phase III JACOB study, which evaluated pertuzumab in the first-line setting for metastatic disease.9 As such, 81 patients were randomized to the phase II component of PERTRACA prior to study closure.
The primary endpoint of pCR was improved with the addition of trastuzumab/pertuzumab to FLOT (35% vs. 12%, p=0.02). However, the trasutuzumab/pertuzumab arm was associated with significantly more toxicity, including grade a 3/4 diarrhea rate of 41% vs. 5%, grade 3/4 leukopenia rate of 23% vs.13% and grade 1/2 weight loss of 38% vs. 10%. These toxicities led to an increased rate of dose modification (70% vs. 44%) and dose delay (78% vs. 68%) in the trasutuzumab/pertuzumab arm.
NRG-proposed study of zanidatamab for locally advanced HER2-positive EG cancer
Based on the promising activity of zanidatamab in the metastatic setting as well as the potential benefit of anti-HER2 therapy with chemotherapy in the locally advanced setting observed in the PERTRACA study, we are currently developing a randomized phase II/III study of peri-operative FLOT chemotherapy with or without zanidatamab for HER2-positive esophageal/GEJ/gastric cancer.
The inclusion of patients with esophageal/GEJ cancer in a peri-operative chemotherapy study is now supported by the phase III ESOPEC study.10 The results were recently presented in abstract form and demonstrated improved survival outcomes for patients with esophageal/GEJ cancer who were treated with peri-operative FLOT vs. pre-operative carboplatin/paclitaxel and radiation.
Two notable considerations in our proposed study design are:
- We plan to include a safety run-in with zanidatamab/FLOT chemotherapy to determine if it is safe/feasible; if not, zanidatamab/FOLFOX will be the experimental regimen
- We are also awaiting the results of the completed phase III MATTERHORN study, which added durvalumab to peri-operative FLOT for locally advanced GEJ/gastric cancer. If this study reveals an improvement in the primary endpoint of event-free survival, durvalumab/FLOT would become the new standard-of-care and the experimental arm would also include durvalumab
REFERENCES
1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687-97, 2010
2. Janjigian YY, Kawazoe A, Bai Y, et al: Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 402:2197-2208, 2023
3. Janjigian YY, Kawazoe A, Yanez P, et al: The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600:727-730, 2021
4. Tabernero J, Shen L, Elimova E, et al: HERIZON-GEA-01: Zanidatamab + chemo +/- tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol 18:3255-3266, 2022
5. Meric-Bernstam F, Beeram M, Hamilton E, et al: Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol 23:1558-1570, 2022
6. Elimova E, Ajani J, Burris H, et al: Zanidatamab + chemotherapy for first-line (1L) treatment of HER2+ advanced or metastatic gastro-oesophageal adenocarcinoma (mGEA): New and updated data from a phase II trial. Ann Oncol 35:S878-912, 2024 [abstr]
7. Safran HP, Winter K, Ilson DH, et al: Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial. Lancet Oncol 23:259-269, 2022
8. Hofheinz RD, Merx K, Haag GM, et al: FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group. J Clin Oncol 40:3750-3761, 2022
9. Tabernero J, Hoff PM, Shen L, et al: Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 19:1372-1384, 2018
10. Hoeppner J, Brunner T, Lordick F, et al: Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol 42:LBA1, 2024 [abstr]