Study highlights high costs, treatment challenges for older adults with HER2-positive advanced gastric cancer

In the ever-changing landscape of cancer care, a recent study in the Journal of Managed Care & Specialty Pharmacy shed light on the real-world experiences of older adults battling advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Researchers examined treatment patterns, healthcare resource use, costs and clinical outcomes among patients who started first-line therapy with trastuzumab-based regimens before immunotherapy became standard. Trastuzumab is older under the brand name Herceptin but several biosimilars are available.The findings reveal substantial economic burdens and underscore opportunities for payers to improve care management in this vulnerable population.

Liya Wang, Ph.D., from Merck, and team drew on data from the Surveillance, Epidemiology and End Results-Medicare linked database for their study. They focused on 315 patients diagnosed between 2011 and 2019. All were at least 65 years old, with a mean age of about 74, and had stage 3 or 4 disease. Most (77%) were male and white (84%), and more than 8 in 10 had stage 4cancer at diagnosis. Researchers used trastuzumab initiation as a proxy for HER2-positive status, given the drug's targeted action against that biomarker.

Trastuzumab, combined with chemotherapy, has been a cornerstone of treatment since its approval in 2010, based on the ToGA trial that showed improved survival. But the landscape shifted in 2021 with approvals for immunotherapy combinations, such as Keytruda (pembrolizumab) plus trastuzumab and chemotherapy. This retrospective analysis provides a pre-immunotherapy benchmark, highlighting how older patients fared under the earlier standard of care.

In practice, treatment didn't always mirror clinical trial protocols. About 58% of patients received trastuzumab with a chemotherapy doublet, such as FOLFOX or CAPOX, aligning with guidelines. But 16% got trastuzumab with monotherapy, often in older or frailer individuals, while 15% received it with a taxane-based doublet and 11% with other combinations.

Fewer than half (50%) advanced to second-line therapy, and of those, about 47% went on to a third line. Second-line options varied widely, including ramucirumab-based regimens (13%), irinotecan-based (7%) and platinum-based (7%). This heterogeneity points to a lack of clear standards beyond first line, which could complicate payer decisions on coverage and prior authorizations.

The time from diagnosis to first-line therapy averaged two months, but it stretched to more than four months for the monotherapy group. That delay, researchers noted, might reflect patient frailty or access issues, potentially worsening outcomes.

Survival metrics showed a mixed picture. The median real-world overall survival was 15 months from the start of first-line therapy, comparable to the 16 months seen in the high-HER2 subgroup of the ToGA trial. But it dropped to 12 months for those on trastuzumab plus monotherapy, versus 16 months for the doublet group and 17 months for the taxane-based subset.

These outcomes highlight the durability, or lack thereof, of pre-immunotherapy regimens in older adults. With Medicare covering most of these patients, the data suggest a need for strategies that extend survival while managing the high churn to subsequent lines.

Biomarker testing has become critical to tailoring treatments for gastric and gastroesophageal junction cancers, especially with the rise of immunotherapy. HER2 itself is a key biomarker, and testing for its overexpression or amplification has long guided the use of targeted therapies like trastuzumab. In this study, researchers relied on trastuzumab prescriptions to identify HER2-positive cases, reflecting how biomarker results directly influenced treatment choices even back then.

But the field has advanced rapidly. Today, additional biomarkers help decide when to add immunotherapies. Programmed death-ligand 1 (PD-L1) expression is a prime example: higher PD-L1 levels, often measured by a combined positive score (CPS), predict better responses to drugs like pembrolizumab. In HER2-positive cases, if PD-L1 CPS is greater than 1, or even 10 in some guidelines, clinicians might combine pembrolizumab with trastuzumab and chemotherapy.

Other biomarkers play a role too. Microsatellite instability-high (MSI-H) or mismatch repair deficiency status indicates tumors prone to mutations, making them more responsive to immune checkpoint inhibitors. Tumor mutational burden (TMB), which counts mutations in the cancer's DNA, is another guide, high TMB often signals potential benefit from immunotherapy.

This biomarker-driven approach wasn't standard during the study's timeframe, which ended in 2019. Back then, HER2 testing was the main focus for targeted therapy, without the routine PD-L1 or MSI checks that now help layer on immunotherapy. The research captures a snapshot of outcomes and costs before these tools became widespread, offering a baseline to measure progress. For instance, while the study's median survival hovered around 15 months, modern regimens guided by multiple biomarkers have pushed that to 20 months or more in trials. Yet, in older adults like those studied here, factors like comorbidities might limit immunotherapy's real-world gains, making biomarker testing even more crucial to avoid overtreatment.

Healthcare resource utilization was intensive across the board. More than half of patients (56%) had inpatient admissions before disease progression, rising to 66% afterward and 53% in the final month of life. Cancer-related stays accounted for most of these, with average lengths of stay at about one day per person-month pre- and post-progression but jumping to four days in terminal care.

Outpatient visits were nearly universal, averaging six events per person-month before progression and five after. Emergency department visits affected 45% of patients in both phases, though they tapered off at end of life.

These patterns translated to steep costs, adjusted to 2022 dollars. Mean monthly all-cause expenses hit $12,356 before progression, $13,545 after and $19,085 in the last month. Cancer-related costs made up 80% of the total, driven largely by treatment (57% pre- and post-progression) and inpatient care (27%).

In terminal care, inpatient costs dominated at more than $10,000 per month, followed by treatment at about $2,000 and hospice at $1,277. Overall, the economic toll underscores the strain on Medicare budgets, especially as gastric cancer ranks among the costlier malignancies.

"High costs and limited treatment durability highlight unmet needs," Wang and team concluded, calling for better first- and second-line options to curb end-of-life expenses.

The study has drawbacks, notably its dependence on claims data, which may overlook subtleties such as precise HER2 levels or the rationale behind treatment selections. Nonetheless, it addresses a deficiency in the comprehension of elderly patients, who are little represented in clinical studies.