Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study

Abstract

Background: In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC.

Methods: This single-arm, phase-II trial enrolled operable T3-4N0-2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy.

Results: In a total of 30 patients in the intention-to-treat (ITT) population, grades 3-4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8⁺ T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8⁺CD39⁺ T cells and lower HLA-DR⁺ Tregs.

Conclusions: Neoadjuvant IPI-NIVO-CRT in T3-4N0-2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs.

Trial registration number: NCT04245514.

Keywords: Chemotherapy; Ipilimumab; Nivolumab; Radiotherapy.

Figure 1. The patient disposition in the INCREASE trial. (*) This patient achieved a metabolic complete response after induction chemo-immuno-radiotherapy and the MDT recommended to omit surgery that would have involved a most likely futile resection of three vertebrae. MDT, multidisciplinary tumor board; NSCLC, non-small cell lung cancer.

Figure 2. (A) The waterfall plot for pathological response (top row), shows that 15 (60%) out of 25 operated patients with NSCLC (excluding the patient with melanoma) achieved a pCR (dark blue bars), another 4/25 (16%) achieved an MPR (light blue bars), the remaining 6 (24%) patients had more than 10% residual viable tumor cells left (orange bars). In operated non-squamous cell lung cancers, genomic alterations associated with resistance to immunotherapy (EGFR, ERBB2, STK11 and NRAS) were seen in eight patients, all of which had no pCR. An STK11 mutation was seen in the only patient who developed PD on induction therapy (ie, patient 15). TP53 was seen in 81% (13/16) of operated patients where genomic analysis was performed, while only one tested patient had a KRAS mutation. Only 28% (7/25) of operated patients with NSCLC had squamous cell histology (dark green). All, except for one patient, were current or former smokers. The only never-smoker (patient 03) had an EGFR exon 21 (L858R) mutation, which was found post-surgery. High tumor PD-L1 expression rates were observed in 56% (14/25) of patients with resected NSCLC (bottom row). (B) Radiological tumor responses to the induction therapy, that is, change in the sum of longest diameters according to RECIST V.1.1, are shown in the patients with NSCLC. Partial response was seen in 11 patients and stable disease in 16 patients. In patient 32, pseudo-progression with new lung nodules were seen, while the primary tumor shrunk. In patient 15, PD was seen due to the appearance of new pleural lesions on induction therapy, while the treated baseline tumor lesions shrunk. Patient 19 did not complete induction therapy and could therefore not be evaluated. Patients with pCR (dark blue), MPR (light blue) and no MPR (orange) can be seen among the patients with radiological partial response and stable disease. KGA, key genomic alterations; MPR, major pathological response; NSCLC, non-small cell lung cancer; pCR, pathological complete response; PD, progressive disease; PD-L1, programmed death ligand-1; VTC, viable tumor cell.

Figure 3. The FDG PET/CT images of an adult patient (23), before (top row) and after (bottom row) induction chemo-immuno-radiotherapy are shown, using fused PET/CT images (A,E) and CT-attenuation corrected PET images of axial (B,F), sagittal (C,G) and coronal view (D,H) reconstructions. This patient had a tumor in the left upper lobe with, at baseline, ingrowth in the thoracic wall and adjacent structures such as the musculature and left ribs (red arrows). The tumor had a necrotic center (N), and there was no apparent mediastinal lymph node involvement. CTAC, CT-attenuation correction; FDG, fluorodeoxyglucose; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 4. Peripheral blood T-cell subset analysis and its correlation with pathological response. The tests used and the exact p values are shown in the (online supplemental data chapter 6 figures 2–5), here, asterisks indicate significant differences (p<0.05). (A) Immune checkpoint expression in CD8+T cells (red, first two panels) and regulatory T cells (blue, last two panels) from 13 patients at baseline. Data is shown as a “percentage of the T cell population”, which indicates the proportion of cells expressing a marker within the total CD8+T cell or Treg population, as well as the “mean fluorescence intensity” for each T-cell subset. Solid symbols denote patients with pCR (N=7) and hollow symbols denote those without pCR (N=6). Medians and ranges are displayed for each immune checkpoint. (B) Longitudinal expression of LAG3, TIGIT, and CTLA-4 in CD8+T cells (red) and Tregs (blue) for 11 patients at baseline, surgery, and 12 weeks post-surgery as a percentage of the total population of T-cell subsets (either CD8 or Treg). Solid symbols represent patients with pCR (N=6) and hollow symbols represent those without pCR (N=5). (C–D) Markers for proliferation (Ki67), activation (HLA-DR), and tumor association (CD39) in CD8+T cells (figure 4C) and Tregs (figure 4D) are shown for 11 patients at baseline, surgery, and 12 weeks post-surgery as a percentage of the total population of T-cell subsets (either CD8 or Treg). Solid symbols denote patients with pCR (N=6) and hollow symbols represent those without pCR (N=5). CTLA-4, cytotoxic T-lymphocyte associated protein 4; LAG3, Lymphocyte Activation Gene 3; pCR, pathological complete response; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; Treg, regulatory T cells.