A patient's severe hypothyroidism from neoadjuvant nivolumab required a one-month surgical delay to stabilize thyroid levels before anesthesia. This highlights a seemingly manageable side effect as a critical barrier to timely, curative-intent surgery, underscoring the need for vigilant monitoring of endocrinopathies.
Contrary to expectations from metastatic disease trials like FLAURA2, the NeoAdura study showed that combining chemotherapy with neoadjuvant osimertinib did not yield a better major pathologic response (MPR) than osimertinib alone for resectable EGFR-mutant lung cancer, questioning the role of upfront chemo in this setting.
The most clinically relevant finding from the NeoAdura trial was not the pathologic response rate, but that giving osimertinib pre-operatively led to more patients successfully undergoing surgery with complete resection, as 8% of patients in the control arm progressed or became unresectable before their operation.
A practical application for ctDNA is for patients with tumors not meeting strict stage criteria for adjuvant osimertinib (e.g., a T1C tumor), but who have high-risk features. A positive ctDNA result provides a compelling rationale to offer therapy in this evidence gap to target minimal residual disease.
Unlike chemotherapy, neoadjuvant immunotherapy appears more effective than adjuvant therapy because it leverages the in-situ tumor and its associated lymph nodes as a 'training ground.' This allows the immune system to generate a robust, specific anti-tumor response before the primary tumor and nodal basin are surgically removed.
Keynote 671 data shows patients without a pathologic complete response after neoadjuvant chemoimmunotherapy have a 5-year event-free survival of only 43%. This outcome is comparable to standard chemoradiation (the PACIFIC regimen), questioning the benefit of pushing for surgery in poor responders.
The adoption of Major Pathologic Response (MPR), defined as ≤10% viable tumor cells, as a primary endpoint in lung cancer trials was a pragmatic decision. It was proposed because early therapies were not effective enough to consistently induce Pathologic Complete Response (pCR), which remains the ideal gold standard.
Despite growing interest in converting borderline resectable patients to surgical candidates, there is reason for caution. Citing data that poor responders have outcomes similar to non-surgical chemoradiation, this approach may not be beneficial, and chemoradiotherapy should remain the standard for many of these patients.
A critical design flaw in most perioperative chemo-immunotherapy trials is the lack of a 'contribution of component' analysis. This makes it impossible to determine if the benefit comes from the neoadjuvant phase, the adjuvant phase, or both, thus complicating interpretation and clinical application.