Results of the phase II LCMC3 trial support the further evaluation of neoadjuvant immune checkpoint inhibition in patients with previously untreated, early-stage NSCLC. Two cycles of neoadjuvant atezolizumab induced a major pathological response in a fifth of patients and resulted in tumour downstaging in 43% of patients. Subsequent resections were feasible within a short time frame with minimal morbidity and a high rate of complete resections.
Previous studies indicated that preoperative, neoadjuvant immune checkpoint inhibitor therapy may provide a clinical benefit in early-stage, untreated NSCLC. To assess this hypothesis in a randomized setting, the phase III IMpower030 trial was set up to evaluate neoadjuvant atezolizumab plus chemotherapy vs. placebo + chemotherapy in patients with resectable stage II, IIIA, or select IIIB NSCLC. In support of this study, the phase II LCMC3 trial also assesses surgical and clinical outcomes with neoadjuvant atezolizumab in early-stage NSCLC. In this study, a total of 181 patients with resectable, untreated, unselected stage IB-IIIA or select IIIB received 2 cycles of atezolizumab followed by surgical resection and surveillance, optional adjuvant atezolizumab for 12 months, or stage-appropriate therapy per investigator. Primary results of this trial were presented during the presidential session at WCLC 2020.
One out of five patients obtained a major pathological response
The median age of the 181 patients in the study was 65 years, 41% had stage IIA or IIB disease, 40% had stage IIIA disease and 90% were current or former smokers. In total, 22 patients (12%) did not undergo surgery, mainly as a result of disease progression (N=10). Subsequently, an additional 8% of patients who did undergo surgery was excluded from the analysis because they were harbouring an EGFR or ALK alteration. At the time of this analysis, a major pathological response (MPR) was achieved in in 21% of patients, with a pathological complete response (pCR) in 7%. Interestingly, in 43% of patients the tumour was downstaged following neoadjuvant atezolizumab (19% was upstaged). This downstaging effect was most prominent in stage IIIA patients with a reduction in the proportion of stage IIIA patients from 39% at baseline to 27% prior to surgery.
The median time-to-surgery, following the 2nd cycle of atezolizumab, was shorter than what was described in other comparable clinical trials. In fact, 88% of patients received surgery within the protocol’s 10-day surgical window. Of the 19 patients who received surgery outside of this time window, the surgical delay was treatment related in only 4 patients. In this study, patients received surgery as early as 8 days post-atezolizumab and as late as 28 days. In comparison, patients in the SWOG 9900 trial, evaluating 3 cycles of neoadjuvant paclitaxel, patients received surgery between 21 and 56 days. In LCMC3, 46% of patients underwent an open thoracotomy surgery, with 79% receiving a lobectomy. Importantly, 92% of patients achieved a R0 resection, which is similar to the resection rate in other comparable trials. Patients in this trial had a median hospitalisation of 7.5 days, which is also in line with historical data. One sudden death occurred within 30 days of surgery, but this event was deemed unrelated to atezolizumab. One additional patient (0.6%) died within 30-90 days post-surgery due to pneumonitis (probably atezolizumab related). With a median follow-up of 2.1 years, the 1-year overall survival (OS) rate was 92% and 95% for stage I/II and stage III disease, respectively (p= 0.45), with a 1-year disease-free survival rate of 85% in both cohorts.
Grade ≥3 treatment-related adverse events (AEs) occurred at a rate of 6% pre-operatively, and 14% post-operatively. Grade ≥3 immune-related AEs occurred in 2% of patients pre-operatively, and 9% post-operatively. The most common post-operative immune related AEs consisted of pneumonitis (6%) and colitis (3%), while hypothyroidism occurred in 5% of pre-operative patients.
Neoadjuvant atezolizumab followed by surgery and optional adjuvant atezolizumab for 12 months resulted in a clinically relevant MPR rate of 21%, and a pCR rate of 7%. Subsequent surgical resections were performed with a low perioperative morbidity and mortality, usually within the narrow protocol window (88%). An R0 resection was achieved in more than 90% of patients. No new safety signals were observed in this study. As such, these results provide further support for the ongoing phase III IMpower30 trial.
Jay Lee et al., Surgical and Clinical Outcomes With Neoadjuvant Atezolizumab in Resectable Stage IB-IIIB NSCLC: LCMC3 Trial Primary Analysis. Presented at WCLC 2020; Abstract PS01.05.