Frontline atezolizumab atop bevacizumab + chemo ups survival in NSCLC
Adding atezolizumab to a combination therapy of bevacizumab plus carboplatin and paclitaxel (CP) significantly improves progression-free survival (PFS) and overall survival (OS) in chemotherapy-naïve patients with metastatic nonsquamous non-small–cell lung cancer (NSCLC), irrespective of PD-L1 expression levels and EGFR or ALK alteration status, according to the IMpower150* trial presented at ASCO 2018.
Bevacizumab is known to have immunomodulatory effects by inhibiting VEGF-related immunosuppression and enhancing T-cell tumour infiltration. The researchers therefore asked the question “does VEGF blockade [with bevacizumab] enhance the efficacy of immunotherapy [with atezolizumab]?”
The global, phase III, open-label study randomized 1,202 patients with metastatic nonsquamous NSCLC 1:1:1 to one of the three arms: atezolizumab 1,200 mg + carboplatin AUC 6 + paclitaxel 200 mg/m2 (ACP), bevacizumab 15 mg/kg + CP (BCP), or atezolizumab + bevacizumab + CP (ABCP) Q3W for four or six cycles depending on investigator’s discretion. [N Engl J Med 2018;378:2288-301; ASCO 2018, abstract 9002]
The current findings, which are concurrently published in the New England Journal of Medicine, compare ABCP vs BCP, while data on ACP vs BCP have yet to be revealed due to prespecified testing hierarchy.
After a median follow-up of 15 months, the addition of atezolizumab doubled the rate of PFS from 18.0 percent in the BCP arm to 36.5 percent in the ABCP arm among patients with a wild-type genotype (WT population; those without EGFR or ALK alterations). The primary endpoint of PFS was 8.3 months (median) in the ABCP arm compared with 6.8 months in the BCP group (hazard ratio [HR], 0.62; p<0.001).
Among patients with high expression of an effector T-cell gene signature in the tumour (Teff-high population), median PFS was also significantly longer with ABCP than with BCP (11.3 vs 6.8 months, HR, 0.51; p<0.001).
Similar results were seen in the entire study population which included those with EGFR or ALK alterations (8.3 vs 6.8 months, HR, 0.61, 95 percent confidence interval, 0.52–0.72).
Furthermore, PFS remained consistently longer with ABCP than with BCP across all subgroups tested, including those with low expression of Teff gene signature (7.3 vs 7.0 months, HR, 0.76), liver metastases at baseline (7.4 vs 4.9 months, HR, 0.42), and regardless of PD-L1 expression levels (8.0 vs 6.8 months, HR, 0.68 for low** PD-L1 levels; 8.0 vs 6.8 months, HR, 0.68 for negative PD-L1 expression; and 12.6 vs 6.8 months, HR, 0.39 for high*** PD-L1 levels).
“High Teff gene signature expression — a surrogate marker of PD-L1 expression and pre-existing immunity — conferred a greater PFS benefit; however, the degree of benefit was similar to that for high PD-L1 expression,” observed the researchers.
“These findings in unselected patients with metastatic NSCLC are particularly relevant because the use of PD-1 inhibitors as first-line monotherapy is currently limited to patients with high PD-L1 expression, and most patients with metastatic NSCLC have tumours with low, negative, or unknown PD-L1 expression,” they explained.
The coprimary endpoint of OS in the WT population was also longer in the ABCP arm than the BCP arm (19.2 vs 14.7 months, HR, 0.78; p=0.02) after a median follow-up of 20 months in an interim analysis.
According to the researchers, the safety profile of the ABCP combination was consistent with those of the individual drugs and there were no new safety signals with the combination. Most of the immune-related adverse events (AEs) in the ABCP arm were grade 1 or 2, with rash, pneumonitis, hepatitis, hypo/hyperthyroidism, and colitis being most commonly reported.
Treatment-related AEs of any grade were reported in similar proportion of patients in both the ABCP and BCP arms (94.4 percent and 95.4 percent), with most being transient and limited to the chemotherapy induction phase. The most common AEs of grade 3 or 4 included neutropenia, febrile neutropenia, decreased neutrophil count, and hypertension. Treatment-related serious AEs were reported in 25.4 percent of the patients receiving ABCP and 19.3 percent of those on BCP. Deaths related to treatment occurred in 11 (2.8 percent) and 9 (2.3 percent) patients in the ABCP and BCP arms, respectively.
According to the investigators, studies on the addition of atezolizumab to other different chemotherapy combinations such as carboplatin + abraxane, carboplatin, or cisplatin are currently ongoing.