The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

As neoadjuvant therapies become more potent, they create complex post-treatment tissue changes. This makes it incredibly difficult for pathologists—the ultimate arbiters of treatment success—to assess residual disease and surgical margins, leading to significant interpretation variability that directly impacts subsequent patient care.

While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

While the ATOMIC trial established FOLFOX plus atezolizumab as a new standard for adjuvant therapy in MSI-high colon cancer, its design lacked an immunotherapy-only arm. This leaves a critical, unanswered question about the actual contribution and necessity of the chemotherapy component.

Standard cancer surgery often removes lymph nodes—the factories producing immune cells. Administering immunotherapy *before* this destructive process is critical. It arms the immune system while it is still intact and capable of mounting a powerful, targeted response against the tumor.

A significant criticism of the pivotal KEYNOTE-564 trial is that only half the patients in the control arm received standard-of-care immunotherapy upon relapse. This lack of subsequent optimal treatment complicates the interpretation of the overall survival benefit, raising questions about its true magnitude.

The failure of the NRG trial (atezolizumab) in limited-stage SCLC suggests a negative interaction between concurrent IO and radiation. The prevailing hypothesis is that radiating the chest destroys immune cells in lymph nodes, eliminating the very T-cells crucial for the immunotherapy's mechanism of action, unlike consolidation IO which has proven effective.

A significant real-world barrier to implementing superior neoadjuvant immunotherapy strategies is the referral pattern in community settings. Medical oncologists often don't see patients until after surgery is completed, by which point the opportunity to give neoadjuvant treatment and potentially avoid chemotherapy or major surgery has been lost.

While KEYNOTE-905 showed dramatic survival benefits with neoadjuvant plus adjuvant EV-pembrolizumab, its design makes it impossible to isolate the benefit of each phase. The high (57%) pathologic complete response after neoadjuvant therapy alone suggests many patients may be overtreated with adjuvant cycles, risking unnecessary long-term toxicity like neuropathy.