Trials like the dostarlimab study in rectal cancer and NICHE in colon cancer show neoadjuvant immunotherapy can induce profound responses in MSI-high tumors. This is creating a new paradigm where major surgery might be avoided entirely for some patients, marking a significant shift in treatment strategy.

Following positive Phase III data for adjuvant atezolizumab plus chemotherapy in Stage III MSI-high colon cancer, clinicians are extrapolating this approach to high-risk Stage II patients. For some, they favor using immunotherapy alone, omitting chemotherapy due to its perceived limited additional benefit in the Stage II setting.

Experts favor a Nivolumab plus Ipilimumab (NIVO+EP) combination for newly diagnosed, MSI-high, stage IV gastroesophageal cancer patients who can tolerate it. This approach avoids chemotherapy and yields high, sustained response rates, including potential for complete pathologic responses in metastatic settings.

For fit patients with technically stage IV gastroesophageal cancer but limited disease (e.g., only non-regional lymph nodes), a curative-intent approach is viable. This involves initial systemic biomarker-driven therapy, followed by multidisciplinary reassessment and potential consolidation with radiation or surgery on any residual disease sites.

New targeted therapies are often approved only for first-line use. This forces clinicians into a difficult choice: using one effective drug like a checkpoint inhibitor means forfeiting the chance to use another, like zolbetuximab, in a subsequent line of treatment, thereby losing a valuable therapeutic option.

For patients with very high-burden or symptomatic mesothelioma, clinicians may deviate from standard guidelines. They may choose chemo-immunotherapy to maximize the chance of a rapid response, viewing it as their single best opportunity to control the disease, especially if the patient's condition is precarious.

For patients on immunotherapy who develop an isolated site of progression while other lesions remain controlled, a practical strategy is to continue the checkpoint inhibitor and treat the single progressive site with localized therapy, such as radiation.

The COMET study found combining chemotherapy with atezolizumab did not improve overall survival versus atezolizumab alone. However, it nearly eliminated early progressive disease (2.8% vs. 32.4%), suggesting a critical role for patients with high tumor burden who cannot risk initial progression on monotherapy.

Frontline treatment selection hinges on histology. Non-epithelioid mesothelioma responds poorly to chemotherapy, making dual immunotherapy (Nivo/Ipi) the clear choice. For epithelioid cases, chemo-immunotherapy is a strong option, especially for symptomatic patients, due to its higher and faster response rate.