1. Simoneaux, Richard

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CHICAGO-Several clinical trials have shown that antibodies that disrupt the immunosuppressive PD-1/PD-L1 interaction are effective immunotherapies for patients with advanced non-small cell lung cancer (NSCLC). However, to date, there have been no reports from trials evaluating these important antibodies in patients with resectable NSCLC, which have a greater than 50 percent relapse rate and for whom there have been few therapeutic advances in the last decade.

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To evaluate the use of checkpoint immunotherapy in this patient population, a small pilot study was initiated by Johns Hopkins University School of Medicine's Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, and Memorial Sloan Kettering Cancer Center, New York City. This study assessed the use of the anti-PD-1 antibody nivolumab in patients with early stage (i.e., stage I, II, or IIIA) resectable NSCLC.


Recently, results from this study were presented at the AACR Annual Meeting 2018 by Drew Pardoll, MD, PhD, Director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Simultaneous to that presentation was a publication of those results in the New England Journal of Medicine (2018; doi:10.1056/NEJMoa1716078).


Regarding their initial results, Pardoll noted, "The most stunning finding was that nine of the 20 patients who had surgery after neoadjuvant anti-PD1 had a major pathologic response. Three patients had no evidence of viable cells in the resected specimen. This is particularly striking given that surgery was done, in most cases, just 4 weeks after the first dose of anti-PD1 treatment."



Although the use of checkpoint immunotherapy has been shown to be an effective means to attain tumor regression and prolonged survival in certain sub-populations of advanced inoperable NSCLC patients, the use of this therapy has not been previously applied in the neoadjuvant setting for patients with resectable NSCLC.


There is an unmet need of effective therapies for early-stage NSCLC patients, as 5-year survival rates vary from 50 percent for patients with stage IA disease to 20 percent for those with stage IIIA disease. Unfortunately, most of these patients will experience postsurgical tumor relapse. The additional use of perioperative platinum-based chemotherapy increases the associated survival rate by only 5.4 percentage points compared to surgery alone. Also, for these platinum-treated patients, 60 percent or more experience treatment-related toxicities of grade 3 or higher.


For many patients with early-stage NSCLC, neoadjuvant therapy prior to surgical resection of the tumor is a common option. "Conventional neoadjuvant therapy, chiefly comprising chemotherapy or chemoradiotherapy, is given to lung cancer patients to shrink a large, non-metastasized tumor located near an important organ or a blood vessel. The tumor is temporarily shrunk prior to surgery to improve surgical outcomes," Pardoll explained.


As a result of the greater host immunity fitness and lower tumor clonal heterogeneity noted in early-stage lung cancer, it is thought that PD-1 pathway blockade may result in enhanced antitumor responses in this patient subpopulation. The use of neoadjuvant immunotherapy may be advantageous, as the primary tumor may serve as an antigen source for tumor-specific T-cell expansion and activation.


"The rationale for neoadjuvant anti-PD1 treatment of resectable NSCLC was essentially to use the primary tumor as a 'vaccine' to induce T cells against the tumor antigens that would then circulate through the body systemically and seek out any distant sites of micrometastases," Pardoll noted. "These micrometastases serve as the primary source of relapse after surgery."



Inclusion in this study was limited to participants who were 18 years or older who had pre-enrollment-confirmed, surgically resectable stage I, II, or IIIA NSCLC. Additionally, inclusion was limited to patients having an ECOG performance status of 0 or 1, as well as normal organ and adequate pulmonary functioning. Among the exclusion criteria were active autoimmune or infectious disease, immunodeficiency, ongoing systemic immunosuppressive therapy, and clinically significant concurrent cancer.


Patients received two doses of 3 mg/kg nivolumab intravenous Q2W, with their surgical tumor resection scheduled for approximately 4 weeks after the first dose. The primary endpoints included safety and feasibility; key secondary and exploratory endpoints were pathological and radiologic treatment responses and the genomic, immunologic, and pathological response correlates in both blood (i.e., systemic) and tumor.


For the purposes of this study, feasibility was defined as any delay in the planned tumor resection of no more than 37 days. Primary tumors were assessed for the percentage of residual viable tumor cells using routine hematoxylin and eosin staining; tumors with 10 percent or fewer viable tumor cells were defined as having had a major pathological response.


When asked about immunological testing, Pardoll replied, "T-cell receptor DNA sequencing was utilized to define T-cell clonal distribution and functional specificity for mutant tumor antigens."


Whole-exome sequencing was performed on pretreatment tumor samples and matched normal tissue samples. Tumor and normal sequence data were compared to identify somatic and germline alterations, with a focus on copy-number changes, single-base substitutions, and small insertions and deletions.



Between August 2015 and October 2016, 22 patients were enrolled in this study; all enrollees received at least one dose of nivolumab, while 21 were eligible for inclusion in the study. Among the participants, 86 percent were current or former smokers, 81 percent had stage II or IIIA disease, and 62 percent had adenocarcinoma histology. One patient was found to have small-cell lung carcinoma, and as a result, study treatment was discontinued.


Neoadjuvant nivolumab did not have association with any previously unreported toxicities. Treatment-related adverse events of any grade were noted in five of 22 patients (23%; 95%CI: 7.8-45.4%), with only one event of grade 3 or higher. Two planned doses of nivolumab were given to 20 of the 22 patients; one patient who had grade 3 pneumonia underwent an uncomplicated surgical resection after one dose of nivolumab, while the other patient was ineligible as per the study protocol.


Regarding the feasibility primary endpoint, Pardoll noted, "There were no treatment-related surgical delays, as defined in the protocol, and the median interval between the administration of the second dose of nivolumab and surgery was 18 days (range 11-29 days), with 95 percent of the 21 eligible patients undergoing complete tumor resection. One patient with stage IIIA NSCLC, once operated on, was found to have tracheal invasion, so complete tumor resection could not be performed."


Major pathological responses were noted in 45 percent of the participants (nine of 20) who had samples that could be evaluated (95% CI: 23-68%). "Three patients had a complete pathological response (i.e., no viable tumor cells) in the primary tumor; however, one of these patients had residual tumor in hilar lymph nodes," he noted.


Some apparent tumor enlargement was detected on preoperative CT scans for one patient who displayed a major pathological response and another who showed complete pathological response. These were thought to possibly result from immune-cell infiltration into the tumor. A major pathologic response is defined as cancer cells representing less than 10 percent of the total viable cells remaining in the tumor resection bed. Large numbers of infiltrating lymphocytes and macrophages were observed in primary tumors that showed major pathological response, which was compatible with an immunologic response mechanism. Expression levels of PD-L1 could be evaluated in 15 patients' pretreatment biopsy samples. Major pathological responses were observed in patients having both PD-L1-positive and PD-L1-negative tumors.


One patient displaying major pathological response had three pretreatment biopsy samples that had PD-L1-negative tumor cells and PD-L1-positive infiltrating immune cells. One pretreatment sample contained PD-L1-positive, CD68+ macrophages that were adjacent to PD-1-positive, CD8+ T cells.


"The surgical specimen contained an influx of CD8+ T cells and had a higher expression of PD-L1 on immune cells than was found in the pretreatment biopsy sample, a finding that was consistent with an adaptive PD-L1 upregulation mechanism," Pardoll explained.


Although 12 patients provided samples for sequencing, only 11 had undergone complete tumor resection and could be evaluated for tumor response. "Among these 11 patients," Pardoll noted "a significantly higher mean (+/-SE) mutational burden was observed in tumors with a major pathological response (311+/-55) than in tumors without a major response (74+/-60), with p=0.01 by exact Wilcoxon test." The number of sequence alterations had an inverse association with the percentage of residual tumor. "No significant correlation was noted between the mutational burden and tumor PD-L1 expression," Pardoll said.



Summing up the findings for the study, Pardoll stated, "Our result of a 45 percent major pathologic response rate is very encouraging, considering prior studies showing that a major pathologic response after neoadjuvant chemotherapy in lung cancer is associated with long-term survival. The anti-PD1 treatment was tolerated well and there were no surgical delays related to neoadjuvant treatment."


To test the hypothesis that checkpoint blockade could induce tumor-specific T-cell expansion in the circulation, T-cell responses in the blood were analyzed on the day of nivolumab treatment and 44 days after surgery.


"There was a big burst of tumor-specific T cells in the blood, in most cases, within 4 weeks after initiation of anti-PD1 treatment, suggesting that neoadjuvant treatment may have enhanced antitumor immunity systemically," Pardoll noted.


"I would like to emphasize that this was a study with a small number of patients with a relatively short follow-up period; it is still too early to draw any meaningful conclusions about long-term improvement in clinical outcome from our data, but these results are encouraging.


"While it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation by multiple larger studies that have recently been launched, we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection," he added.


Richard Simoneaux is a contributing writer.


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