Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have emerged as a new standard of care for patients with advanced-stage non-small-cell lung cancer (NSCLC).1,2 Profoundly changing the way cancer is now treated, the approach is currently being investigated in the earlier setting. The first piece of evidence came from a pilot study of nivolumab in patients with resectable stage I-IIIA NSCLC, which was reported at the American Association for Cancer Research (AACR) 2018 Annual Meeting and simultaneously published in the New England Journal of Medicine.1-3
“The rationale for neoadjuvant anti-PD-1 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,” said senior author Dr. Drew Pardoll, director of Bloomberg-Kimmel Institute for Cancer Immunotherapy and director of Cancer Immunology at Johns Hopkins School of Medicine, US.4
The final analysis of this small investigator-led study included 21 patients with stage I, II, or IIIA NSCLC that was deemed to be surgically resectable.3 These patients received two doses of intravenous nivolumab (at a dose of mg/kg) every 2 weeks.3 The primary endpoints were safety and feasibility (whether there is a surgical delay of >30 days and 7 days for scheduling), but the radiologic and pathological responses to treatment as well as immunologic, genomic, and pathological correlates of response in blood and tumor were also explored.3
One patient had grade 3 pneumonia, but he/she had an uncomplicated surgical resection without receiving the second dose of nivolumab.3 Few immediate adverse events (AEs) were reported in the study (4 patients with grade 1-2 AEs; 1 patient with grade 3 AEs), but most importantly, there were no treatment-related surgical delays and 20 (95%) of 21 patients underwent complete tumor resection.3
Major pathologic response (MPR; defined as ≤10% viable residual tumor cells) occurred in 9 (45%) of 20 patients with complete resection.3 “Two 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-PD-1 treatment,” Dr. Pardoll added.2
At a median of 12 months of postoperative follow-up (range: 0.8–19.7 months), 16 (80%) of 20 patients who had undergone resection were alive and recurrence-free.3,5 As reported in the published study, the median duration of recurrence-free survival had not been reached.3
However, only 2 (10%) of 21 patients had a radiologic partial response, which is in stark contrast to the high rate of MPR.3 “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,” the researchers wrote.3
The researchers also assessed tumor mutational burden (TMB) as a biomarker of pathological response to PD-1 blockade, and the findings revealed a significantly higher mean TMB in those with MPR than those without MPR (311±55 vs. 74±60, p=0.01 by exact Wilcoxon test).3 The percentage of viable residual tumor was inversely correlated with pretreatment TMB (Spearman’s Rho: −0.75; p=0.008) and predicted neoantigen load (Spearman’s Rho: −0.78, p=0.005).1,3 However, no significant correlation was found between TMB and PD-L1 expression.3
“Is it time to finally stop saving our best for last?” commented Dr. John V. Heymach, Chair of Department of Thoracic/Head and Neck Medical Oncology at the MD Anderson Cancer Center, Houston, Texas, US.3 Indeed, Dr. Pardoll and his team are very optimistic that this approach (i.e. anti-PD-1 in the neoadjuvant setting) will eventually be practice-changing and may even replace chemotherapy prior to surgical resection.4
1. Killock D. Neoadjuvant PD-1 blockade in NSCLC. Nat Rev Clin Oncol. 2018 [Epub ahead of print].
2. Neoadjuvant Nivolumab Shows Benefit in NSCLC. Medscape. 2018 (Accessed May 5, 2018, at https://www.medscape.com/viewarticle/895274#vp_1).
3. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018 [Epub ahead of print].
4. AACR 2018: Pilot Study of Neoadjuvant Nivolumab in Resectable NSCLC. The ASCO Post. 2018 (Accessed May 4, 2018, at http://www.ascopost.com/News/58749).
5. Neoadjuvant Nivolumab Demonstrates Promising Pathologic Response Rate in Resectable NSCLC. TargetedOnc. 2018 (Accessed May 4, 2018, at http://www.targetedonc.com/conference/aacr-2018/neoadjuvant-nivolumab-demonstrates-promising-pathologic-response-rate-in-resectable-nsclc).