Neoadjuvant Nivolumab Induces Pathological Response In Early-Stage NSCLC

Preliminary findings for neoadjuvant nivolumab suggest that patients with resectable early-stage non-small-cell lung cancer might derive benefit from the strategy

medwireNews: A pilot study of neoadjuvant nivolumab for patients with resectable early-stage non-small-cell lung cancer (NSCLC) led to a major pathological response in almost half of patients without delaying surgery and with few adverse events.

In all, 21 patients with treatment-naive stage I, II or IIIA NSCLC were given two doses of nivolumab 3 mg/kg at 2-week intervals within approximately a month before surgery, explain Drew Pardoll, from the Sidney Kimmel Comprehensive Cancer Centre in Baltimore, Maryland, USA, and co-investigators.

The majority of patients had stage II or IIIA disease (81%), adenocarcinoma histology (62%) and were current or former smokers (86%).

The neoadjuvant treatment had an “acceptable side-effect profile,” the researchers say, with 23% of patients experiencing a treatment-related adverse event of any grade. One patient experienced a more severe event, namely grade 3 pneumonia, and went forward for surgery without a second dose of nivolumab.

Surgery was successfully performed in 20 of the patients a median of 18 days after their last dose of nivolumab, with the remaining patient found to have tracheal invasion preventing complete resection.

Just two (10%) of the 21 patients achieved a partial radiographical response to nivolumab, while 86% had stable disease and one patient experienced disease progression, the investigators report.

Nevertheless, eight (40%) of the patients had pathological down-staging of their clinical stage between their preoperative and postoperative assessments, while a major pathological response was reported for nine (45%) of the group, including three complete pathological responses.

“In primary tumors with a major pathological response, we observed large numbers of infiltrating lymphocytes and macrophages, a finding that was compatible with an immunologic mechanism of response, along with necrotic tumor associated with fibrotic tissue repair,” the team says.

Furthermore, whole-exome sequencing of specimens from 11 tumours indicated that patients who achieved a major pathological response had a significantly higher average mutational burden than those who did not. However, response was not linked to whether tumours were positive or negative for PD-L1 expression, as defined using a 1% threshold of expression.

The researchers note that tumours with a major pathological response to nivolumab therapy had a greater number of T-cell clones shared between the intratumoral and peripheral compartments than those without, as well as a higher proportion of their total T cells formed from a group of distinct clones.

“This finding is in concordance with analyses in patients with advanced melanoma, who had increased clonality of tumor-infiltrating lymphocytes in response to PD-1 blockade,” they observe.

And after treatment, eight of nine assessed patients showed peripheral expansion of multiple T-cell clones that were present in the tumour, but not necessarily peripheral blood samples, at the time of surgery.

At 1 year, 80% of the 20 patients who underwent resection were alive and free from disease recurrence, as were 73% at 18 months, with the median duration yet unreached, the investigators report.

A patient with 75% residual primary tumour at resection experienced a solitary brain metastasis but has experienced no further recurrence over 16 months’ follow-up, while a second patient with 5% residual tumour at resection underwent chemoradiotherapy for lymph node recurrence but has been free from further events for more than 12 months. A third patient experienced distant metastasis 1 year after resection and died 4 months later; a fourth patient died from trauma.

“These findings represent pathological evidence supporting the possibility that some patients may derive clinical benefit from immunotherapy without initial radiographic tumor shrinkage and that this process occurs because of immune-cell infiltration into the tumor, rather than true tumor growth”, Drew Pardoll et al propose.

They add: “Larger studies are needed to determine the most effective duration of neoadjuvant therapy and the best predictive biomarkers of response and to correlate the pathological response resulting from neoadjuvant immunotherapy with overall survival.”

The research was presented at the American Association of Cancer Research annual meeting 2018, in Chicago, Illinois, USA, and simultaneously published in The New England Journal of Medicine.



Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer . N Engl J Med; Advance online publication 16 April 2018.
DOI: 10.1056/NEJMoa1716078  

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