Platinum-based chemotherapy, given either before (neoadjuvant) or after (adjuvant) surgery for stage II and III NSCLC is associated with a 5% improvement in long-term survival. Despite consensus guidelines recommending its use, uptake of chemotherapy for earlier-stage NSCLC remains low when compared with other common cancers, and, currently, most chemotherapy that is given is delivered postoperatively. There are, however, potential advantages to presurgical administration of systemic therapy, including early treatment of micrometastasis and assessment of pathologic response during resection, which allows adoption of adjuvant therapy. There is also a theoretical benefit of having a large volume of intact tumor neoantigen present to help elicit a strong immune response at the time of neoadjuvant therapy.
CheckMate-816 is an international phase III clinical trial evaluating the addition of nivolumab to neoadjuvant platinum-doublet chemotherapy for patients with newly diagnosed, resectable, stages IB (≥ 4 cm), II, and IIIA NSCLC (according to the 7th edition of the IASLC lung cancer staging system). Patients received three cycles of neoadjuvant therapy; curative surgery was planned within 6 weeks of the last dose. The primary endpoints of the study were pathologic complete response (pCR; defined as 0% residual viable tumor cells in both the resected tumor and lymph nodes) and event-free survival, both evaluated by blinded independent review. The study enrolled 358 patients who were randomly assigned 1:1 and stratified by stage, PD-L1 expression, and sex. Arms of the study were well-matched: approximately 50% of tumors were squamous, 63% of patients had clinical stage IIIA NSCLC, and 50% of tumors had PD-L1 expression of 1% or greater.
Surgical outcomes were similar between the two arms: 83% of patients in the neoadjuvant nivolumab–chemotherapy arm and 75% in the chemotherapy arm underwent curative resection. Patients who received nivolumab–chemotherapy had higher rates of lung-sparing surgery (77%, vs. 61% with chemotherapy alone), lower rates of requiring pneumonectomy, and lower rates of requiring conversion from minimally invasive to open surgery.
At the 2021 annual meeting of the American Association for Cancer Research, the final results for the pCR endpoint were reported, showing that the addition of nivolumab to neoadjuvant chemotherapy increased the pCR rate from 2.2% to 24% (OR = 13.94, 99% CI: 3.49, 55.75, p < 0.0001). The pCR rate increased across subgroups, including stage, histology, and PD-L1 expression levels. Rates of major pathologic response (defined as ≤ 10% residual viable tumor cells) and RECIST objective response rate, similarly, were significantly increased when neoadjuvant nivolumab was added to chemotherapy. Rates of treatment-emergent adverse events were similar across the two arms, as were delays to surgery, most of which were administrative in nature. Rates of immune-mediated adverse events were low in the nivolumab–chemotherapy arm; only two cases of low-grade pneumonitis were reported. Correlative analyses showed no significant association between tumor mutational burden and pCR; however, in a subset analysis, patients who received nivolumab–chemotherapy had greater clearance of circulating tumor DNA (ctDNA) during neoadjuvant treatment and higher pCR rates. Of note, using a tumor-informed ctDNA assay (ArcherDx), the rates of detection of ctDNA were high at baseline (approximately 97%) across stages, highlighting the potential for highly sensitive liquid biopsies to play a significant role in early-stage lung cancer.
In summary, the addition of neoadjuvant nivolumab to standard platinum-doublet chemotherapy for early-stage lung cancer delivered similar or improved surgical outcomes compared with neoadjuvant chemotherapy alone, with no indication of longer delays to surgery or increased toxicity. The pCR rate was increased 13-fold with the addition of nivolumab, and follow-up continues for event-free survival and OS. The results of CheckMate-816 will ultimately help inform the treatment paradigm for earlier-stage lung cancer, particularly for surgically resectable, clinical-stage IIIA disease, for which, currently, optimal treatment is not well-defined and relapse rates are high. Uptake of this approach, however, will likely depend on longer-term DFS and OS results.