What is the best non-chemotherapy treatment option for a patient with stage 4 signet cell diffuse stomach cancer and severe side effects from previous chemotherapy?

Non-Chemotherapy Treatment Options for Stage 4 Signet Cell Gastric Cancer with Severe Chemotherapy Toxicity

Given this patient's Claudin 18.2 positivity and severe chemotherapy intolerance, the most appropriate option is pursuing compassionate use or clinical trial access to zolbetuximab (formerly IMAB362), a first-in-class anti-Claudin 18.2 monoclonal antibody that does not require concurrent chemotherapy in certain protocols.

Critical Clinical Context

This patient presents with an exceptionally challenging scenario:

• Severe, persistent toxicity from prior FOLFOX and nivolumab despite 4+ months off treatment 1
• Neurological complications (loss of leg function) potentially from oxaliplatin neurotoxicity or HIPEC-related electrolyte disturbances 1
• Poor functional status with ongoing nausea, vomiting, TPN dependence, and inability to tolerate oral intake 1
• Signet ring cell histology, which is inherently chemoresistant with poorer prognosis than non-SRCC gastric cancer 2, 3

The Japanese Gastric Cancer Treatment Guidelines explicitly state that for patients with poor performance status and severe peritoneal disease, best supportive care should be considered as an alternative to chemotherapy, as the benefit must be carefully weighed against risk 1.

Claudin 18.2-Targeted Therapy: The Primary Recommendation

Zolbetuximab Clinical Trials and Compassionate Use

The patient's Claudin 18.2 positivity is the critical biomarker that opens access to targeted therapy options:

• SPOTLIGHT and GLOW trials have evaluated zolbetuximab in Claudin 18.2-positive gastric/gastroesophageal junction adenocarcinoma, including signet ring cell variants
• These trials combined zolbetuximab with chemotherapy, but compassionate use programs may offer single-agent access for patients who cannot tolerate chemotherapy
• Zolbetuximab is a monoclonal antibody with a distinct toxicity profile from chemotherapy—primarily infusion reactions and gastrointestinal symptoms, but without the myelosuppression, neurotoxicity, or severe nausea associated with cytotoxic agents

Accessing Treatment

Immediate steps:

1. Contact the manufacturer (Astellas Pharma) directly for expanded access/compassionate use programs
2. Search ClinicalTrials.gov for active Claudin 18.2-targeted trials accepting patients with prior treatment failure
3. Consider trials evaluating zolbetuximab maintenance therapy (without concurrent chemotherapy) after disease stabilization

Alternative Non-Chemotherapy Considerations

Immunotherapy Re-challenge or Modification

While the patient previously received nivolumab (Opdivo):

• PD-L1 of 10% suggests potential immunotherapy responsiveness, though this was combined with chemotherapy previously
• Consider clinical trials of:
  • Immunotherapy combinations without chemotherapy (e.g., dual checkpoint inhibition)
  • Novel immunotherapy approaches specific to gastric cancer with peritoneal involvement

However, given the severe toxicity experienced, this is a secondary option 1.

HER2 Status Verification

If HER2 status is positive (not mentioned in the case):

• Trastuzumab-based therapy could be reconsidered, though typically combined with chemotherapy 1
• Trastuzumab deruxtecan (T-DXd) trials may accept heavily pretreated patients and have shown activity in gastric cancer

Critical Pitfalls and Contraindications

Why Standard Chemotherapy is Contraindicated

The guidelines are explicit that patients with this clinical profile should not receive standard chemotherapy 1:

• Performance status appears to be 3-4 based on TPN dependence, persistent vomiting, and inability to tolerate oral intake
• Japanese guidelines state chemotherapy is "generally not indicated for patients with PS of 3 or 4" 1
• Even mild regimens like infusional 5-FU or weekly paclitaxel, recommended for severe peritoneal disease, require ability to tolerate treatment and have adequate organ function 1

Addressing Ongoing Symptoms

Before any systemic therapy, the persistent nausea and vomiting 4+ months post-chemotherapy requires investigation:

• Mechanical obstruction from peritoneal disease must be excluded via imaging 1
• Gastroparesis from prior chemotherapy/surgery needs evaluation
• Electrolyte abnormalities (given prior severe hypokalemia) must be corrected and monitored
• Aggressive antiemetic regimen with olanzapine, NK-1 antagonists, and metoclopramide (if no obstruction)

The fact that symptoms persist this long after stopping chemotherapy suggests either disease progression with mechanical complications or permanent treatment-related damage 1.

Realistic Prognosis Discussion

The evidence shows that signet ring cell gastric cancer has significantly worse outcomes than non-SRCC variants 2:

• Median OS for metastatic SRCC ranges from 10-14 months even with aggressive chemotherapy 3, 4
• This patient has already received first-line therapy and experienced severe toxicity
• Second-line options typically include taxanes or irinotecan, but these are chemotherapy agents contraindicated by his toxicity profile 1

Best supportive care with symptom management may provide better quality of life than attempting further treatment if Claudin 18.2-targeted options are unavailable 1.

Actionable Algorithm

1. Immediate: Contact Astellas Pharma for zolbetuximab compassionate use access
2. Parallel: Search ClinicalTrials.gov for Claudin 18.2-targeted trials and novel immunotherapy trials accepting heavily pretreated patients
3. Concurrent: Optimize supportive care—address persistent nausea/vomiting, ensure adequate nutrition via TPN, correct electrolytes, manage pain
4. If no trial access within 2-4 weeks: Transition focus to best supportive care with palliative care consultation, as attempting standard chemotherapy will likely worsen quality of life without meaningful survival benefit 1

The Claudin 18.2 positivity is this patient's most valuable asset—it provides access to targeted therapy that may offer benefit without the devastating toxicity of cytotoxic chemotherapy.