Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

Abstract

Background: We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.

Methods: Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.

Results: While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.

Conclusions: Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Keywords: clinical trials as topic; immunotherapy; lung neoplasms; tumor biomarkers; tumor microenvironment.

Figure 1

Clinical follow-up with radiographic and pathologic response characteristics plus molecular correlates. (A) Swimmer-style clinical follow-up plot detailing clinical course of all enrolled patients. Residual viable tumor at resection is noted in the column to the right of patient number and to the left of outlined clinical course for that patient. NR indicates a tumor that was “not resected” due to primary disease progression precluding definitive surgery. Clinical course outlines time following surgery or biopsy-confirmed primary disease progression. (B) Genomic data for study patients including pathologic and radiographic response data, in addition to pre-treatment tumor PD-L1 expression. (C) Correlation between pre-treatment tumor PD-L1 expression and post-resection residual tumor. The solid dark line indicates the linear regression line, and the dashed lines indicate the upper and lower boundaries of the 95% CI. ^#All radiographic RECIST assessments were unconfirmed, as only one post-neoadjuvant treatment imaging assessment was made prior to surgical resection. Patient 2 demonstrated clear progressive disease on PET imaging despite stable disease on RECIST response assessment of chest CT and was thus categorized as having “PD”. NR, not resected; pCR, pathologic complete response; PD, progressive disease; PR, partial response; Prim. Progression, primary progression; RECIST, response evaluation criteria in solid tumors; Res. Tumor, residual tumor; SD, stable disease; TMB, tumor mutation burden.

Figure 2

Radiographic and pathologic response to neoadjuvant nivolumab plus ipilimumab for (A) patient with pathologic complete response (pCR) and (B) no pathologic response to treatment. (A) Radiographic and pathologic response for patient 5 with pCR to neoadjuvant nivolumab plus ipilimumab. Pre-treatment contrast-enhanced CT imaging demonstrates a 4.4×4.2 cm left lower infrahilar mass (red arrow) encasing adjacent bronchi with posterior post-obstruction atelectasis. Pre-treatment biopsy demonstrates abundant infiltrating malignant signet ring cells distinguished by atypical eccentric nuclei surrounding a large mucinous vacuole (black arrows). The pre-treatment tumor shows abundant PD-L1 positive tumor and stromal cells (PD-L1 in green, cytokeratin expression in orange highlights tumor cells (white arrows)). Post-treatment pre-resection imaging demonstrates decreased size of mass now measuring 2.2×2.7 cm (red arrow) with re-expansion of previously collapsed lung. Post-treatment resection tissue shows abundant inflammatory cells, cellular fibrosis and neovascularization; features typical of immune-mediated tumor regression. Multiplex immunofluorescence (mIF) highlights abundant cytotoxic T cells (CD8, yellow) and macrophages (CD163, magenta), as well as scattered regulatory T cells (Foxp3, red). No residual tumor cells are identified (note the absence of orange tumor cells on mIF), consistent with pCR. (B) Radiographic and histologic findings for patient 4 with primary tumor progression preventing definitive surgery. Pre-treatment contrast-enhanced CT imaging demonstrates a 6.8×6.5 cm posterior right upper lobe mass (red arrow) encasing the right upper lobe bronchus. Post-treatment imaging demonstrates enlargement of mass to 8.3×6.9 cm (red arrow) with worsening encasement and enlarging paratracheal adenopathy. On assessment of pre-treatment and post-treatment biopsies, atypical glandular structures (black arrows), including confluent (cribriform) glands, are present with no histologic evidence of tumor regression in post-treatment specimen. PD-L1 expression (green) is seen on tumor cells (orange, white arrows) both pre-treatment and post-treatment. Scant pre-treatment and post-treatment inflammatory infiltrates are composed largely of macrophages (CD163, magenta), which are predominantly localized to the intra-tumoral stroma. H&E photomicrographs taken at ×200 original magnification. mIF images taken at ×400 original magnification. mIF, multiplex immunofluorescence.