Historically, resectability was a static, pre-treatment judgment. With neoadjuvant immunotherapy causing significant tumor and nodal downstaging, surgeons must now dynamically re-evaluate resectability after systemic therapy, expanding surgical options for patients previously deemed inoperable.
Data from KEYNOTE-671 and other trials show that even patients achieving a pathological complete response (PCR) after neoadjuvant chemo-IO have better outcomes with the full perioperative regimen. This challenges the idea of de-escalating adjuvant therapy based on surgical pathology alone.
Multiple trials, including PACIFIC-2, have shown no survival benefit from adding immunotherapy concurrently with chemoradiation for unresectable Stage III NSCLC. This suggests that concurrent radiation may disrupt the immune-activating pathways necessary for immunotherapy to work, a critical lesson for future trial designs.
The ALCHEMIST trial took a decade to reveal that adjuvant nivolumab offered no disease-free survival benefit. This lengthy timeline highlights the strategic advantage of neoadjuvant trial designs, which use surrogate endpoints like pathological response (PCR) to assess drug activity much more rapidly.
Data from the KEYNOTE-671 trial demonstrates a meaningful survival benefit from perioperative pembrolizumab even in patients with PD-L1 negative (<1%) tumors. This finding supported broad regulatory approval without PD-L1 restrictions, suggesting the biomarker is not an absolute requirement for benefit in this setting.
The key rationale for neoadjuvant immunotherapy is that an in-situ tumor provides a rich source of antigens. Treatment primes the immune system against these targets, creating a powerful, systemic immunological memory that can effectively eliminate micrometastatic disease before and after surgery.