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NEW ORLEANS -- The addition of the immune checkpoint inhibitor nivolumab (Opdivo) to neoadjuvant chemotherapy substantially improved event-free survival (EFS) in patients with operable non-small cell lung cancer (NSCLC), the phase III showed.

The combination reduced the risk of cancer recurrence or death by more than a third compared with chemotherapy alone, reported Nicolas Girard, MD, PhD, of Institut Curie in Paris, speaking here at the American Association for Cancer Research (AACR) annual meeting.

At a follow-up of 29.5 months, median EFS was 31.6 months for patients receiving the nivolumab/chemotherapy combination versus 20.8 months for those who received chemotherapy alone (HR 0.63, 97.38% CI 0.43-0.91, P=0.005), according to the results, which were published concurrently in the (NEJM).

"CheckMate 816 is the first phase III study with a neoadjuvant immunotherapy-based combination for resectable non-small cell lung cancer to show improved event-free survival and [pathological complete response], along with promising overall survival [OS] results," Girard said during a plenary session at the meeting. "These results support neoadjuvant nivolumab in combination with chemotherapy as a new standard of care."

AACR-designated discussant, David Carbone, MD, PhD, of the Ohio State University Comprehensive Cancer Center in Columbus, called the results "another quantum leap in lung cancer therapy."

"Combining immunotherapy with surgery, I think, is the new standard of care and will almost certainly improve overall survival in early-stage disease, for the first time in decades," said Carbone. He added that neoadjuvant immunotherapy has multiple theoretical advantages over adjuvant immunotherapy and that "CheckMate 816 suggests practice will prove this theory correct."

The trial randomized 358 patients with stage IB-IIIA NSCLC to receive three cycles of neoadjuvant nivolumab with platinum-doublet chemotherapy, or chemotherapy alone, before definitive resection.

As reported at last year's AACR meeting, pathological complete response (pCR) rates were significantly higher in the nivolumab group versus the chemotherapy-alone group (24.0% vs 2.2%, respectively, P<0.001).

EFS and pCR rates favored nivolumab plus chemotherapy over chemotherapy alone across most subgroups, Girard said, adding that EFS was improved in patients with a pCR, "suggesting pCR as an early indicator of therapeutic benefit" with the combination.

At the first prespecified interim analysis for OS, the hazard ratio was 0.57 (99.67% CI 0.30-1.07) in favor of the nivolumab group, but did not meet the criteria for significance. Landmark analyses at 24 months showed OS rates of 82.7% for the nivolumab arm and 70.6% for the chemotherapy-alone arm.

Of the patients who underwent randomization, 83.2% of those in the nivolumab group and 75.4% of those in the chemotherapy-alone group underwent surgery.

Grade 3/4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab group and 36.9% of those in the chemotherapy-alone group. The combination "showed a safety profile consistent with previous reports and did not impact the feasibility of surgery versus chemotherapy alone," Girard said.

Carbone pointed to several unanswered questions, however.

For example, "how are we going to pick adjuvant versus neoadjuvant therapies? We are going to be forced to do cross-comparisons only -- there is really no data yet from adjuvant chemotherapy-immunotherapy. We've got six or seven studies that are in the works, and we're going to be forced to look at hazard ratios and landmark survivals across trials, which is very unsatisfying scientifically."

In a NEJM that accompanied the study, Christine Lovly, MD, PhD, of Vanderbilt University Medical Center in Nashville, said the results from the trial are expected to be "practice changing," particularly with last month's FDA approval of the neoadjuvant combination.

However, she added, there are challenges that need to be addressed. Patients with tumors harboring EGFR or ALK mutations were excluded from the study, she noted.

"Implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine," she wrote. "To meet this requirement, protocols must be put in place to ensure successful tissue stewardship, avoiding the potential for delays in obtaining biomarker results needed to plan preoperative therapy."

Neoadjuvant therapy requires a disease-management team involving oncology, surgery, pathology, and other specialties, Lovly explained. Implementing it will thus require a multidisciplinary approach, which could be challenging, she said. "How can these cutting-edge treatments be implemented broadly regardless of location, to prevent widening the survival gaps that already exist for lung cancer so that all patients may have access to potentially life-saving therapies?"