Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)

Abstract

PURPOSE In the treatment of non-small cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody following tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase 3 study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel and carboplatin (ABCP) in EGFR or ALK-mutated NSCLC that progressed prior to TKI therapy. METHODS We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC arm) followed by pemetrexed maintenance. The primary endpoint was progression-free survival (PFS). RESULTS A total of 228 patients with activating EGFR mutation (n=215) or ALK translocation (n=13) were enrolled from 16 sites in the Republic of Korea and randomized at 2:1 ratio to either ABCP (n=154) or PC arm (n=74). The median follow-up duration was 26.1 months (95%CI 24.7-28.2). Objective response rates (69.5% vs 41.9%, P <0.001) and median PFS (8.48 vs. 5.62 months, hazard ratio [HR] 0.62 [0.45-0.86], P=0.004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10% and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 vs. 20.27 months, HR 1.01 [0.69-1.46], P=0.975). The safety profile of the ABCP arm was comparable to that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared to the PC arm. CONCLUSION This study is the first randomized phase 3 study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in EGFR or ALK mutated NSCLC who have progressed on relevant targeted therapy.

Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations

“…On the other hand, the generalisability of our results was supported by the fact that the patients were treated by the same team, which provided an unusual homogeneity of patient selection and care; moreover, the real-life nature of the study ensured patients did not need to go through a screening period that would have excluded rapidly growing tumours. Furthermore, a reallife study was the only option available to assess patients with untreated brain metastases in Europe, and the only way to contextualise the degree of patient selection of prospective studies that tested ABCP [23,24,36].…”

“…Recent chemo-immunotherapy studies have shown heterogeneous results in patients with actionable mutations [24,[33][34][35][36]. On the one hand, randomised studies with Pemetrexed-containing combinations [33][34][35] showed disappointing results; on the other hand, studies using Paclitaxel and Bevacizumab [24,36] consistently showed therapeutic efficacy, especially in patients with brain metastases, PDL1 ≥ 1%, and/or ALK translocated lung cancers. This is consistent with our results.…”

“…The only study to use the original Bevacizumab-and Paclitaxel-containing ABCP from IMpower150 was the Korean ATTLAS study [36], albeit with lower chemotherapy doses (Carboplatin AUC5 and Paclitaxel 175 mg/m 2 ). Over 40% of the patients had brain metastases.…”

Multi-omics and artificial intelligence predict clinical outcomes of immunotherapy in non-small cell lung cancer patients

“…However, the ORI-ENT-31 study confirmed that ICI combined with anti-angiogenic therapy and chemotherapy significantly improved PFS in EGFR-mutant non-squamous NSCLC patients who progressed after treatment with EGFR-TKIs [31]. Although the IMpower150 [32], ORIENT-31 and ATTLAS/KCSG-LU19-04 [33] studies have unanimously confirmed that patients with EGFR-TKI-resistant NSCLC can benefit from the four-drug combination therapy of immune + platinumcontaining double-drug chemotherapy + bevacizumab. However, the four-drug combination regimen has a higher incidence of adverse effects and is limited in clinical use.…”

Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant

“…10 Similarly, the ATTLAS study further confirmed the efficacy of atezolizumab plus bevacizumab, carboplatin, and paclitaxel in patients whose illness progressed while receiving TKI treatment. 11 The ORIENT-31 trial showed that sintilimab plus bevacizumab biosimilar IBI305, pemetrexed, and cisplatin resulted in significant improvement in PFS compared with chemotherapy alone for patients whose illness progressed while receiving EGFR-TKI therapy. 12 Although, the IMpower151 study did not meet the primary end point, which also used the 4 drug combination regimen (atezolizumab plus bevacizumab, carboplatin, and pemetrexed or paclitaxel), the subgroup analysis showed that patients who experienced resistance to first-or second-generation EGFR-TKI treatment could benefit more, with a hazard ratio (HR) of 0.55 (95% CI, 0.29-1.02).…”