Adaptive Chemotherapy for Pd-l1 High REsEctablE NSCLC: A Chemo-PHREE Trial

Current standard of care for patients with EGFR/ALK wild-type, resectable non-small cell lung cancer (NSCLC) is a combination of platinum-doublet chemotherapy plus anti-PD (L)1 therapy given pre-operatively prior to definitive resection. This is based on repeated positive phase III trials showing improvement in pathologic response, event-free survival and overall survival compared to neoadjuvant chemotherapy alone. However, this one-size-fits all approach does not take into account the role of prognostic and predictive biomarkers to help further personalize and refine neoadjuvant systemic therapy approaches. In the metastatic setting biomarkers, including PD L1 expression of tumors, can help select patients who may receive anti-PD-(L)1 monotherapy. Specifically, for patients with PD-L1 ≥ 50%, evidence shows equivalent survival benefit compared to combination chemoimmunotherapy, effectively sparing this portion of patients the toxicity of chemotherapy. Whether a similar approach may be applied to the early-stage setting is an active question. To further explore this question our group has performed an extensive systematic review and meta-analysis from 29 prospective neoadjuvant trials utilizing either PD-(L)1 monotherapy or chemoimmunotherapy, assessing pathologic response and EFS rates based on available PD-L1 expression data. Our findings showed PD-L1 expression was associated with both pathologic complete response (pCR) and major pathologic response (MPR) rates after neoadjuvant chemoimmunotherapy and PD-(L)1 monotherapy. Through meta-regression analysis, both PD-L1 expression and type of systemic therapy were independently associated with pCR and MPR. Although chemoimmunotherapy had a numerically higher pCR and MPR rates, a notable proportion of patients with PD L1≥ 50% achieved a MPR when treated with PD-(L)1 monotherapy before surgical resection, suggesting a significant cohort of patients may receive meaningful pathologic regression with just PD-(L)1 therapy alone. Preliminary findings from our analysis utilizing individual patient data with reconstruction of available KM-curves has also indicated superior EFS/RFS with PD-(L)1 monotherapy compared to chemoimmunotherapy for patients with PD-L1 ≥1% disease, again highlighting the potential durable impact of ICB for biomarker-selected patients. Therefore, in order to prospectively validate the utility of neoadjuvant PD-1 monotherapy for the treatment of resectable NSCLC in patients with PD-L1 ≥50%, the investigators propose a phase 2 pilot study of 30 patients using a novel adaptive treatment strategy. This adaptive treatment strategy will incorporate upfront neoadjuvant single-agent cemiplimab for two cycles followed by radiographic and clinical reassessment. Pending this interval assessment patients will proceed with either one final cycle of cemiplimab monotherapy followed by resection or combination chemotherapy plus cemiplimab for two cycles followed by resection. This interval assessment will allow treating physicians to escalate neoadjuvant systemic therapy if there is any concern for clinical or radiographic progression with single-agent cemiplimab, all in an effort to appropriately tailor our neoadjuvant approach in this biomarker selected cohort.