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Adding the immune checkpoint inhibitor nivolumab (Opdivo) to neoadjuvant chemotherapy dramatically increased pathologic complete response (pCR) in patients with operable lung cancer, a randomized trial showed.

The pCR rate increased from 2.2% with chemotherapy alone to 24.0% with the addition of nivolumab. The between-group difference increased in an analysis limited to patients who had complete resection. Clearance of circulating tumor (ct) DNA during neoadjuvant therapy increased the likelihood of pCR, reported Patrick M. Forde, MD, of the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, at the American Association for Cancer Research (AACR) virtual meeting.

" showed a statistically significant improvement in pCR," said Forde. "This benefit was consistent across disease stages, histology, TMB (tumor mutational burden) and PD-L1 expression. The study continues to mature for the event-free survival (EFS) primary endpoint."

"The addition of neoadjuvant nivolumab to chemo maintained a tolerable safety profile and did not impede the feasibility of surgery," he added. "We saw in an exploratory subset analysis that circulating tumor DNA clearance was more frequent with nivolumab plus chemo compared to chemo, and this appeared to be associated with pathologic complete responses. CheckMate 816 is the first phase III trial to show a benefit of neoadjuvant immunotherapy plus chemo, and this has the potential to represent a new neoadjuvant option for patients with early-stage resectable non-small cell lung cancer (NSCLC)."

Pathologic CR has a close relationship with survival in NSCLC, said AACR program chair Charles Swanton, MBPhD, of University College London and Cancer Research UK. Prior studies of chemotherapy alone produced pCR rates of 0%-16% and , emphasizing the need for better neoadjuvant options. Nivolumab plus chemotherapy did not adversely affect patients' ability to undergo definitive surgery, and more patients in the nivolumab-chemo arm had lung-sparing surgery (77% vs 61%).

Clearance of ctDNA had only a modest association with pCR rate in the combination arm, Swanton estimated. Additionally, about a third of patients randomized to chemotherapy alone also had clearance of ctDNA.

"CheckMate 816 is the first phase III trial that showed the benefits of neoadjuvant immunotherapy plus chemotherapy for resectable non-small cell lung cancer," he concluded.

Forde noted that or chemotherapy is recommended for patients with high-risk resectable NSCLC. However, the addition of systemic therapy before or after surgery has been associated with a modest 5% improvement in OS.

Several recent phase II trials showed encouraging outcomes with neoadjuvant single-agent immunotherapy or immunotherapy-chemotherapy combinations. The results provided a rationale for continued investigation, including the CheckMate 816 randomized trial.

Investigators in the multicenter trial enrolled patients who had newly diagnosed, resectable stages Ib-IIIa NSCLC and no known EGFR or ALK alterations. The trial evaluated two combination strategies (fixed-dose nivolumab plus chemotherapy and weight-adjusted nivolumab plus ipilimumab [Yervoy]) versus chemotherapy alone. Forde reported data only for the nivolumab-chemotherapy combination. Following radiologic restaging, patients underwent surgery within 6 weeks, followed optionally by adjuvant chemotherapy with or without radiotherapy.

The primary endpoints were pCR and event-free survival, both assessed by blinded independent review. Investigators defined pCR as no residual visible tumor cells in the primary tumor and sampled lymph nodes (ypT0N0). Major pathologic response (MPR), a secondary endpoint, was defined as ≤10% residual viable tumor cells in the primary tumor and lymph nodes. Data analysis included 358 patients, and Forde limited his presentation to the pCR endpoint.

The trial design included biomarker assessments, which represented exploratory endpoints. The assessments consisted of TMB and clearance of ctDNA from cycle 1 to cycle 3 of neoadjuvant therapy.

Forde reported that 98% of patients in nivolumab-chemotherapy and chemotherapy arms received assigned therapy, including 94% and 85%, respectively, who received the three planned cycles of therapy. Additionally, 83% of the nivolumab group underwent definitive surgery as did 75% of patients treated with chemotherapy alone. Rates of delayed surgery were 21% with nivolumab and 18% with chemotherapy alone.

The 22.8% absolute difference in pCR translated into an odds ratio of 13.94 in favor of neoadjuvant nivolumab plus chemotherapy (99% CI 3.49-55.75, P<0.0001). An analysis limited to patients who underwent resection yielded ypT0N0 rates of 30.5% and 3.2% with nivolumab-chemotherapy versus chemotherapy. An analysis of patients who had no residual disease in the primary tumor only showed ypT0 rates of 25.7% versus 2.8% in favor of nivolumab. Forde said MPR and overall response rates also were improved with the addition of nivolumab.

In a subgroup of patients with ctDNA assessment, clearance occurred in 24 of 43 (56%) patients in the nivolumab group versus 15 of 44 (34%) in the chemotherapy arm. Forde reported that 11 of 24 in the nivolumab group and two of 15 in the chemotherapy arm achieved pCR. Among patients without ctDNA clearance, only one patient in the chemotherapy group achieved pCR status.

Treatment-related adverse events (TRAEs) were consistent with the known effects of the drugs evaluated. Rates of grade ≥3 TRAEs were 34% with nivolumab plus chemotherapy and 37% with chemotherapy alone.

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