Neoadjuvant pembrolizumab (Pembro) for early stage non-small cell lung cancer (NSCLC): Updated report of a phase I study, MK3475-223.

Abstract

8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. Immunotherapy might be more effective in low-burden disease. We hypothesized that neo-adjuvant immunotherapy is a feasible, safe and effective treatment (Tx) for early stage NSCLC. Methods: MK3475-223 is an ongoing phase I study of neoadjuvant pembrolizumab in stage I-II NSCLC. All Pembro Txs are 200mg q 3 weeks (wks). Objectives: determine safety; recommended phase 2 dose/schedule; pathological & radiological response. Doses-schedule limiting toxicities (DLT) were defined as significant surgical complications (bleeding, delayed wound healing, ARDS, prolonged air-leak) or a significant delay of surgery. The doses-schedule escalation cohorts were (i) single pembro dose 3 wk prior to surgery; (ii) 2 pembro doses, 2 wks later surgery; (iii) 2 pembro doses, 1 wk later surgery. Expansion cohort received the doses-schedule of cohort (iii). Percentages of remaining viable tumor in the post-Tx were assessed, 10% or less was considered amajor pathological response (MPR). IHC for pre-Tx PDL1 was done. Efficacy was evaluated for the patients who had received 2 doses of pembrolizumab. Results: No DLT occurred in the dose-schedule escalation cohorts. 10 patients received 2 cycles of neo-adjuvant pembrolizumab. 4 patients achieved a MPR (4/10 who received 2 cycles of pembro; 40%; 95% C.I. 16.7-68.8%). No correlation is seen between the levels of PDL1 pre-Tx and the pathologic response. Size of the tumor and N status was also not in any apparent correlation with MPR (data not shown). Interestingly, all of the MPR cases had a relatively long interval from 1st Tx till surgery. Clinical trial information: NCT02938624. Conclusions: Neo-adjuvant pembro is safe and feasible. A promising sign of efficacy is seen. Achieving MPR might require a longer 1st-Tx-surgery interval. Predictive biomarkers for response might be different from those in advanced disease. Recruitment and correlative studies are ongoing.[Table: see text]

Emerging Therapies in Thoracic Malignancies—Immunotherapy, Targeted Therapy, and T-Cell Therapy in Non–Small Cell Lung Cancer

“…These results overall are similar to the MPR after 3 cycles of nivolumab in the phase 2 randomized NEOSTAR ( NCT03158129 ) trial, 20 which demonstrated MPR of 17% in 23 treated patients. In another neoadjuvant study evaluating PD-1 inhibitor sintilimab in resectable NSCLC, 2 doses of neoadjuvant ICB induced 40.5% MPR rate, 21 which is similar to the results of phase I study MK3475-223 ( NCT02938624 ) 22 with pembrolizumab (MPR 40%). Although there is a clear intertrial variability in terms of MPR rates after ICB monotherapy, which may be driven by several variables, including the type of immunotherapy, tumor histology, oncogenic drivers, and perhaps number of doses prior to surgery, it appears that neoadjuvant anti–PD-1/PD-L1 therapy is overall safe and feasible and its efficacy appears to be very similar or slightly better than platinum doublet chemotherapy.…”

Neoadjuvant pembrolizumab with chemotherapy for the treatment of stage IIB–IIIB resectable lung squamous cell carcinoma

“…The NeoStar study indicated PD-L1 and pathological reaction to be correlated; compared with non-responders, responders had an increased median PD-L1 level prior to therapy (80% vs. 1%) (24). However, other researchers reported no such correlation (25)(26)(27). For instance, in the NADIM clinical trial, 58% of patients whose PD-L1 tumor proportion score was below 25% had a MPR or pCR.…”

Sintilimab: A Promising Anti-Tumor PD-1 Antibody

“…In NCT02259621, two preoperative doses of nivolumab (3 mg/kg) were administered every 2 weeks among 21 patients with stage I, II, or IIIA NSCLC; neoadjuvant nivolumab resulted in an ORR of 9.5% (2/21) and a DCR of 95.2% (20/21) among enrolled patients, with 42.9% (9/ 21) achieving MPR (39). In a phase I study MK3475-223, two doses of pembrolizumab (200 mg) was administered in stage I and II NSCLC patients, achieving an MPR of 40% (4/10) (40,41). Sintilimab seems to have a similar efficacy to nivolumab and pembrolizumab in resectable NSCLC patients when used preoperatively.…”

“…In NCT02259621, the incidences and rate were 22.7% (5/22), 4.5% (1/22), and 0 (39). In MK3475-223, the data were not available (40,41). Although the safety profile of sintilimab in NSCLC seems worse than nivolumab when used preoperatively, the conclusion needs more evidence since the sample size of the latter is small.…”