Neoadjuvant nivolumab plus chemotherapy confirms superiority vs. chemotherapy alone in patients with resectable stage IIIA-B NSCLC
Survival of patients with stage IIIA non-small cell lung cancer (NSCLC) remains poor, with a 5-year overall survival (OS) of around 36%. The phase II NADIM II trial compared the efficacy of nivolumab + chemotherapy vs. chemotherapy alone as neoadjuvant treatment for resectable IIIA-B NSCLC. The addition of nivolumab resulted in improved OS, pathological complete response and progression-free survival, demonstrating the superiority of the combination vs. chemotherapy alone in this setting.
Non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases, and approximately 20% of patients with NSCLC are diagnosed with stage IIIA (N2) disease. For these patients, multimodality treatment is necessary. However, the outcomes remain poor, with a 5-year overall survival (OS) of around 36%. Although the use of preoperative chemotherapy (CT) for patients with resectable NSCLC significantly improves OS, the absolute 5-year survival improvement is only 5%. A strong association between pathological complete response (pCR) and survival following neoadjuvant CT-based regimen has been shown. However, the median rate of pCR after neoadjuvant CT is low (4%). Neoadjuvant immunotherapy for resectable NSCLC has previously shown promising activity in several studies. Therefore, the phase 2 NADIM II trial compared the efficacy of nivolumab + chemotherapy vs. chemotherapy alone as neoadjuvant treatment for resectable IIIA-B NSCLC. During the IASCL WCLC 2022 meeting, the efficacy results of this trial were presented.
The phase II open-label, multicentre, randomised NADIM II trial enrolled patients with locally advanced and potentially resectable stage IIIA-IIIB NSCLC and no known EGFR/ALK alterations. Patients were randomised 2:1 to nivolumab (NIVO) 360 mg + paclitaxel 200 mg/m2 + carboplatin AUC5 for three cycles every 21 days as neoadjuvant treatment followed by surgery (experimental arm), or paclitaxel 200 mg/m2 + carboplatin AUC5 for three cycles every 21 days followed by surgery (control arm). After surgery, patients in the experimental arm with R0 resection initiated adjuvant administration of NIVO (480 mg Q4W) within the third to eight weeks from surgery and for six months. Patients with R0 in the control arm initiated a 6-month observation period after surgery. The complete expected follow-up is five years. The primary endpoint was pathological complete response (pCR). Progression-free survival (PFS), overall survival (OS) and biomarker analysis are secondary endpoints of the trial.
In total, 86 patients were randomised to NIVO + chemo (experimental arm, N= 57) or chemo (control arm, N= 29). Median follow-up time was 26.1 months. In total, 92.5% of patients in the NIVO + chemo arm and 65% of patients in the chemo arm achieved an R0 resection degree (p= 0.007). Nodal downstaging was also higher in the experimental arm (69.8% vs. 40.0%, p= 0.04). Median PFS was not reached in the experimental cohort, and was 18.3 months in the control arm (HR[95%CI]: 0.48[0.25-0.91]; p= 0.025]. The 12-month PFS rates were 89.3% vs. 60.7% (p= 0.001) in the NIVO + chemo and chemo arms, respectively. The 24-month PFS rates were 66.6% vs. 42.3% (p= 0.012). Median OS was not reached in the experimental nor control arm (HR[95%CI]:0.40[0.17-0.93]; p= 0.034]. Neoadjuvant nivolumab significantly improved OS rates at twelve months (98.2% vs. 82.1%, p= 0.007) and 24 months (84.7% vs. 63.4%, p= 0.014). The addition of neoadjuvant nivolumab to chemotherapy significantly improved pCR (OR[95%CI]: 7.88[1.70-36.51]; p= 0.0068], and pCR status had a predictive value for PFS and OS. None of the patients showing a pCR has progressed or deceased. In terms of tolerability, the two-year update of the NADIM II trial confirmed a tolerable safety profile for the NIVO + chemo arm, with a moderate increase in grade 3-4 toxicity.
The addition of neoadjuvant nivolumab to chemotherapy (followed by adjuvant nivolumab) improved PFS, OS, and pCR in patients with resectable stage IIIA-B NSCLC, compared to neoadjuvant chemotherapy alone. The safety profile also demonstrated to remain tolerable. NADIM II is the first clinical trial using a neoadjuvant immunotherapy-based combination (nivolumab + chemotherapy) for resectable stage IIIA-B NSCLC to show improved OS.
Provencio M, Serna R, Nadal E, et al. Progression free survival and overall survival in NADIM II study. Presented at IASLC WCLC 2022; Abstract PL03.12.