ENHERTU® Receives Time-Limited Reimbursement in Canada for Gastric Cancer
AstraZeneca and Daiichi Sankyo announced that Canada's Drug Agency (CDA) has issued a Time-Limited Reimbursement (TLR) recommendation for ENHERTU® (tr...
Breakthrough Clinical Results
AstraZeneca and Daiichi Sankyo announced that Canada's Drug Agency (CDA) has issued a Time-Limited Reimbursement (TLR) recommendation for ENHERTU® (trastuzumab deruxtecan) to treat adult patients with unresectable, locally advanced, or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received prior trastuzumab-based therapy. This accelerated access is facilitated by the TLR and pTAP processes, aiming to make ENHERTU available approximately two years sooner than traditional pathways. The conditional approval is based on Phase II trial data, with a confirmatory Phase III trial (DESTINY-Gastric04) ongoing.
Key Highlights
- Canada's Drug Agency recommends time-limited reimbursement for ENHERTU® in HER2-positive gastric cancer.
- Accelerated access through TLR and pTAP processes, potentially providing treatment up to two years earlier.
- Conditional approval based on Phase II trial data; Phase III confirmatory trial underway.
- Collaboration between AstraZeneca and Daiichi Sankyo to improve access to innovative cancer treatments in Canada.
Incidence and Prevalence
Global Incidence and Prevalence of Gastric Cancer
Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide, making it a significant global health concern. Despite its high ranking, the incidence of gastric cancer has been declining worldwide over the past century. However, it remains a major killer across the globe.
Regional Variations
There is significant geographical variation in gastric cancer incidence:
- A higher incidence of gastric cancer is found in East Asia compared to other regions
- South Asia is a low risk region for gastric cancer, despite having a contradictory high prevalence for Helicobacter pylori
- In China, gastric cancer rates were 1.6-fold higher in northern China than in southern China
- According to a French study in Côte-d'Or, age-standardized incidence rates were 0.8/100,000 in men and 0.3/100,000 in women
Trends in Specific Regions
In Karachi, Pakistan, the age-standardized rate (ASR) for gastric cancer per 100,000 was: - 3.9 for males and 3.0 for females in 1995-7 - Increased to 6.0 for males and 3.6 for females in 1998-2002 - An 18% increase in gastric cancer was observed in males and 14% in females during a seven-year study period
In France, the proportion of early gastric cancers among all gastric cancers increased from 3.4% (1976-1980) to 7.9% (1991-1995).
Screening and Detection
Gastric cancer screening is mainly carried out in eastern Asia, with gastroscopy and biopsy as the main screening techniques starting at age 40 or above.
Relationship with Helicobacter pylori
There is a significant connection between gastric cancer and H. pylori infection:
- The World Health Organization International Agency for Research on Cancer classified H. pylori as a type I, or definite carcinogen in 1994
- Over 50% of the world's population is colonized with Helicobacter pylori in the gastric mucosa
- All individuals infected with Helicobacter pylori exhibit chronic gastric inflammation
- Approximately 1% of patients infected with H. pylori develop gastric cancers
- There is an inverse relationship between gastric cancer rates and duodenal ulcer rates in China
Despite the global decline in incidence, gastric cancer continues to be a significant health challenge, particularly in East Asia, with varying trends across different regions.
Key Unmet Needs and Target Populations in Gastric Cancer Research
Global Burden
Gastric cancer represents a significant global health challenge, ranking as the fifth most common cancer in incidence and the third leading cause of cancer mortality worldwide. With nearly one million cases globally and approximately 800,000 annual deaths, the disease burden is substantial.
Unmet Needs
Geographic Disparities
- Mali, West Africa has the 15th highest incidence of gastric cancer worldwide (20.3/100,000), yet there is scarce published data for evaluating etiology, prevention, or management
- The highest incidence of stomach cancer is found in China, South America, and Eastern Europe, with a 20-fold variation worldwide
Clinical Challenges
- Late diagnosis remains a critical issue, with most patients presenting with unresectable or metastatic disease at the time of diagnosis
- There is an urgent demand for rapid and precise diagnosis of metastases in regional lymph nodes, particularly as treatment modalities diversify
Research and Data Needs
- Sparse data collection and under-reporting in Africa impact accurate assessment of incidence and mortality rates
- The potential for immunotherapy advances represents a promising frontier in gastric cancer management
Biomarker Development
- Research into microbial markers shows potential, as studies reveal significant differences in gastric microbiota between patients with gastric cancer and non-cancerous patients
- FAP-α is being investigated as a potential novel biomarker for personalized medicine in gastric cancer
Target Populations
African Patients
- Patients in Africa present with unique characteristics, including younger age (3rd-4th decade) and later stage disease at presentation
High-Risk Geographic Regions
- Populations in China, South America, and Eastern Europe represent high-priority target groups due to elevated incidence rates
Technology Integration
- Research is exploring how computer technology, including machine learning, deep learning, and ensemble learning can assist physicians in gastric cancer diagnosis through pathological image analysis
HER2-Positive Patients
- Patients with HER2-positive gastric cancer represent an important target population for specialized treatment approaches
Molecular Subtypes
- Patients with specific molecular characteristics such as FGFR2 amplifications and PD-L1 positive status (CPS > 5) are being targeted in research
Early Stage Patients
- Stage IB node-negative patients at risk of recurrence represent a key target population for intervention
Study Design Parameters
Key Trials for Gastric Cancer: Study Design Parameters and Endpoints
Study Design Parameters
Several key clinical trials have investigated treatments for gastric cancer with varied designs and approaches:
The Jinlongshe Granule Trial used a randomized, double-blind, placebo-controlled design with 50 stage IV gastric cancer patients. Participants received either routine Chinese herbal decoctions plus JLSG or placebo for at least 3 months with 6 months follow-up.
A retrospective analysis of HER2/VEGF Expression examined 678 consecutive patients who underwent curative surgery between October 2010-December 2012, measuring HER2 and VEGF expression in resected tissue.
The Claudin-4 Expression Study retrospectively analyzed 66 patients with gastric adenocarcinoma who underwent gastrectomy between 2003-2011, measuring Claudin-4 expression by immunohistochemistry.
A propensity-score matched analysis studied clinical trial effects in 229 patients with metastatic/recurrent gastric cancer, comparing 83 trial participants against 146 non-participants, all receiving fluoropyrimidine and platinum as first-line palliative chemotherapy.
A systematic review of neoadjuvant chemotherapy analyzed 4 randomized controlled trials with 250 patients in the NAC group and 332 in control groups.
The ACTS-GC Trial conducted a retrospective exploratory biomarker analysis of 829 patients with stage II/III gastric cancer, analyzing 63 genes by quantitative real-time RT-PCR.
The Camrelizumab Trial used a prospective, open-label, single-arm design with 70 patients with Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer, treating with Camrelizumab + docetaxel + S-1, followed by camrelizumab + S-1.
CRITICS-II trial was a multicenter phase II non-comparative study randomizing patients with clinical stage IB-IIIC resectable gastric adenocarcinoma between three preoperative treatment arms.
A multicenter randomized controlled superiority trial compared laparoscopic vs. open gastrectomy with 210 patients with resectable gastric cancer.
Another multicenter trial compared D2 vs. D2+para-aortic lymph node dissection (D4) with 270 patients randomized for potentially curable gastric adenocarcinoma.
Key Endpoints
The trials employed various primary endpoints:
- Quality of life measured via EORTC QLQ-C30 questionnaire (Jinlongshe Granule Trial)
- Overall survival (HER2/VEGF Expression Study, Clinical Trial Effect Study)
- Correlation of Claudin-4 expression with tumor characteristics and survival
- Survival benefits of neoadjuvant chemotherapy
- 5-year survival correlated with biomarkers (ACTS-GC Trial)
- 3-year disease-free survival rate (Camrelizumab Trial)
- Event-free survival at 1 year after randomization (CRITICS-II)
- Postoperative hospital stay in days (laparoscopic vs. open gastrectomy trial)
- Objective response rate, disease control rate, progression-free survival, and overall survival (camrelizumab study)
Secondary endpoints included:
- Adverse effects and laboratory abnormalities
- Toxicity, surgical outcomes, percentage of radical (R0) resections
- Pathological tumor response
- Disease recurrence
- Health-related quality of life
- Postoperative morbidity and mortality
- Oncologic outcomes
- Readmissions
- Cost-effectiveness
Some trials also included exploratory endpoints focused on translational studies of predictive and prognostic biomarkers.
Drug used in other indications
ENHERTU® Clinical Trials Beyond Gastric Cancer
ENHERTU® (trastuzumab deruxtecan) is being evaluated in several indications beyond gastric cancer:
- HER2-expressing biliary tract cancer (BTC) in the phase II HERB trial
- The drug's efficacy has already been proven in HER2-positive breast cancer
HER2 positivity, which is targeted by ENHERTU®, is found in: - 5-20% of biliary tract cancer patients - 5-6% of colorectal cancer patients - 7% of pancreatic cancer patients - 16% of extrahepatic biliary cancers
For the HERB trial specifically, the primary endpoint is centrally assessed objective response rate in HER2-positive patients.
Research has identified high d16HER2 mRNA scores in HER2-positive colorectal cancer (CRC), suggesting potential for trastuzumab-based therapy in this cancer type. The d16HER2 marker may be investigated for trastuzumab susceptibility in several HER2-driven cancers, including colorectal cancer.
