Neoadjuvant Nivolumab Demonstrates Promising Pathologic Response Rate in Resectable NSCLC

Drew Pardoll, MD, PhD

According to results of a pilot study presented at the 2018 AACR Annual Meeting and simultaneously published in theNew England Journal of Medicine,neoadjuvant treatment with the PD-1 inhibitor nivolumab (Opdivo) demonstrated a 45% major pathologic response rate in patients with resectable stage I to III non—small cell lung cancer (NSCLC) irrespective of PD-L1 expression.^1,2

Nivolumab was also associated with a tolerable safety profile and was not associated with any delays in surgery, said senior study author Drew Pardoll, MD, PhD, director of Bloomberg-Kimmel Institute for Cancer Immunotherapy and director of Cancer Immunology at Johns Hopkins School of Medicine.

“Preoperative nivolumab did not delay surgery in any of these patients, and 45% of resected tumors demonstrated major pathologic response with robust infiltration of T cells,” said Pardoll in a press conference during the meeting. “The pathologic complete response did correlate with mutational burden.”

Perioperative chemotherapy is recommended for patients with resectable stage IB through IIIB lung cancer; however, this is linked with relatively little benefit, Pardoll explained. Neoadjuvant chemotherapy is typically administered to reduce tumor size, therefore allowing surgery to be technically easier for resection. The notion to administer neoadjuvant anti—PD-1 therapy, he said, is to expand and activate tumor-specific T cells; investigators also sought to study the in vivo effect of PD-1 blockade on the tumor microenvironment and peripheral blood.

The single-arm safety and feasibility study enrolled 22 patients—21 of whom were eligible for inclusion—with stage I, II, or IIIA NSCLC between August 2015 and October 2016, all of whom received at least 1 3 mg/kg dose of intravenous nivolumab. The median time from second dose was 18 days.

Twenty patients underwent complete tumor resection, as 1 patient with stage IIIA disease was determined to have tracheal invasion during surgery. All patients were aged 18 years or older, had an ECOG performance status of 0 or 1, and had normal organ function and adequate pulmonary function. Sixty-two percent had adenocarcinoma, 81% had stage II or IIIA disease, and 86% of patients were current or former smokers. All patients were offered adjuvant conventional chemotherapy or radiation therapy, if indicated.

The primary endpoints of the study were safety and feasibility, with additional endpoints being tumor pathological response, PD-L1 expression, mutational burden, and mutation-associated, neoantigen-specific T-cell responses.

At a median follow-up of 12 months, 16 of 20 patients who underwent surgical resection were alive and recurrence-free. Additionally, the 18-month recurrence-free survival (RFS) rate was 73% and the median RFS had not yet been reached.

Nine of 20 patients achieved a major pathologic response (45%; 95% CI, 23%-68%), and 3 patients had a pathologic complete response. Of the 21 patients with evaluable radiographic results, 2 (10%) had a partial response, 18 (86%) had stable disease, and 1 (5%) had disease progression. Pathological down-staging occurred in 8 of 20 patients (40%) who underwent resection.

“[The complete response] means there was no evidence of viable cancer in the tumor just 4 weeks after they were given 1 of 2 doses of nivolumab,” said Pardoll. “[These results are] early and preliminary, but certainly very encouraging.”

Treatment-related adverse events (AEs) of any grade were reported in 23% of patients (n = 5), with 1 AE grade 3 or higher. Two deaths occurred; 1 was from recurrent disease and 1 from a patient who experienced a head injury and was unrelated to nivolumab therapy. Two additional patients had disease progression.

Though major pathologic responses were observed in patients’ tumors regardless of PD-L1 expression, tumor mutational burden was a closer factor in predicting response, Pardoll said.

Moreover, researchers analyzed T-cell responses in plasma on the day of nivolumab treatment as well as 44 days following resection. Using deep sequencing of T-cell receptor-β chain CDR3 regions, known as TCRseq, the number of T-cell clones identified in the tumor and peripheral blood increased following treatment with nivolumab in 8 of 9 evaluable patients.

T-cell clones from a primary tumor that were mutation-associated and neoantigen-specific, and had a complete response on pathological assessment, rapidly expanded in the peripheral blood 2 to 4 weeks following treatment. Additionally, some clones were not identified prior to PD-1 inhibitor therapy.

While PD-1 inhibitors have improved survival in patients with advanced NSCLC, there have been less investigations in resectable disease. Five-year survival rates range from 50% for stage IA tumors to 20% for patients with stage IIIA NSCLC.

“Every day, thousands of patients around the world will get operated on for so-called ‘operable’ or ‘resectable’ cancer, and will be told by their surgeons, ‘We got it all.’ Unfortunately, that frequently is not the case,” Pardoll said. “When one looks at resectable lung cancer and looks at 5-year survival as a function of stage, this is the group that would get operated on. Somewhat less than 50% will have survived 5 years. There is indeed a great need for additional therapies to be applied in the context of this surgically resectable setting.”

Clinical follow-up is encouraging, Pardoll said, but explained that larger studies are needed to determine the effective duration of neoadjuvant therapy and optimal biomarkers to predict response and to correlate pathological response from neoadjuvant treatment.

“This is a very exciting and interesting study that shows, for the first time, that in lung cancer the benefit of immunotherapy may extend beyond advanced or metastatic disease to early-stage disease,” said press conference moderator Alice T. Shaw, MD, PhD, director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center. “This was a small pilot of about 20 patients, but the findings are very compelling, particularly the major pathologic response rate of 45%.”

References:

1. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT079.
2. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer [published online ahead of print April 16, 2018].N Eng J Med. doi: 10.1056/NEJMa1716078.