Surgical outcomes after neoadjuvant nivolumab or nivolumab with ipilimumab in patients with non-small cell lung cancer

Abstract

Background: Surgical outcomes for non-small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non-small cell lung cancer.

Methods: Forty-four patients with stage I to IIIA non-small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; n = 21). Curative-intent operations were planned between 3 and 6 weeks after the last dose of neoadjuvant N. Patients who completed resection upfront or after chemotherapy from the same time period were used as comparison.

Results: In the N arm, 21 (91%) were resected on-trial, 1 underwent surgery off-trial, and one was not resected (toxicity-related). In the NI arm, 16 (76%) resections were performed on-trial, one off-trial, and 4 were not resected (none toxicity-related). Median time to operation was 31 days, and consisted of 2 (5%) pneumonectomies, 33 (89%) lobectomies, and 1 (3%) each of segmentectomy and wedge resection. The approach was 27 (73%) thoracotomy, 7 (19%) thoracoscopy, and 3 (8%) robotic-assisted. Conversion occurred in 17% (n = 2/12) of minimally invasive cases. All 37 achieved R0 resection. Pulmonary, cardiac, enteric, neurologic, and wound complications occurred in 9 (24%), 4 (11%), 2 (5%), 1 (3%), and 1 (3%) patient, respectively. The 30- and 90-day mortality rate was 0% and 2.7% (n = 1), respectively. Postoperative complication rates were comparable with lung resection upfront or after chemotherapy.

Conclusions: Operating after neoadjuvant N or NI is overall safe and effective and yields perioperative outcomes similar to those achieved after chemotherapy or upfront resection.

Keywords: immunotherapy; ipilimumab; lobectomy; lung resection; lung surgery; neoadjuvant; nivolumab.

FIGURE 1.

Consolidated Standards of Reporting Trials diagram for patients in Nivolumab With or Without Ipilimumab in Treating Patients With Previously Untreated Stage I-IIIA Non–Small Cell Lung Cancer (NEOSTAR). TRAE, Treatment-related adverse events.

FIGURE 2.

Surgical approach and resection type. A, Proportion of surgical approach: open (n = 27; 73%), VATS (n = 7; 19%), and RATS (n = 3; 8%). B, Proportion of resection type: pneumonectomy (n = 2; 5%), lobectomy (n = 30; 81%), bilobectomy (n = 1; 3%), sleeve lobectomy (n = 2; 5%), segmentectomy (n = 1; 3%), and wedge resection (n = 1; 3%). VATS, Video-assisted thorascopic surgery; RATS, robot-assisted thoracoscopic surgery.

FIGURE 3.

Distribution of 30-day Clavien–Dindo postoperative morbidity scores for Nivolumab With or Without Ipilimumab in Treating Patients With Previously Untreated Stage I-IIIA Non–Small Cell Lung Cancer (NEOSTAR) and The Immunogenomic Profiling of Non–Small Cell Lung Cancer (ICON) patients. Clavien–Dindo classification 1 = deviation from normal postoperative course without the need for intervention; 2 = complication requiring pharmacological intervention including blood transfusion; 3 = complication requiring invasive intervention; 4 = complication requiring intensive care unit care; and 5 = death. NEOSTAR-N, NEOSTAR-neoadjuvant nivolumab; NEOSTAR-NI, NEOSTAR-neoadjuvant nivolumab with ipilimumab; ICON-Chemo, ICON-neoadjuvant chemotherapy; ICON-Upfront, ICON-upfront surgical resection.

FIGURE 4.

Surgical complexity rating. A, Distribution of surgical complexity after neoadjuvant treatment with nivolumab versus nivolumab with ipilimumab. B, Operative time (minutes) for each surgical complexity score after neoadjuvant treatment with nivolumab versus nivolumab with ipilimumab. C, Estimated blood loss (mL) for each surgical complexity score after neoadjuvant treatment with nivolumab versus nivolumab with ipilimumab. D, Percent viable tumor for surgical complexity score after neoadjuvant treatment with nivolumab versus nivolumab with ipilimumab. The green dashed line indicates 10% viable tumor threshold for major pathologic response. The box is drawn from the first quartile to the third quartile with inside line indicating the median value. The whiskers extend from the ends of the box to the minimum and maximum nonoutliers. Outliers are 1.5 times outside the interquartile range above the upper quartile and below the lower quartile. Surgical complexity scale: 1 = easier than normal tissue dissection; 2 = normal tissue dissection; 3 = difficult tissue dissection because of inflammation; and 4 = very complex tissue dissection.

FIGURE 5.

Summarization of the main purpose and outcome of the study. Clavien–Dindo classification 1 = deviation from normal postoperative course without the need for intervention; 2 = complication requiring pharmacological intervention including blood transfusion; 3 = complication requiring invasive intervention; 4 = complication requiring intensive care unit care; and 5-death. NEOSTAR, Nivolumab With or Without Ipilimumab in Treating Patients With Previously Untreated Stage I-IIIA Non–Small Cell Lung Cancer; ICON, The Immunogenomic Profiling of NSCLC.