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9518 Background: Final, mature PFS from the global phase III ALEX study (NCT02075840) of ALC vs CRZ in untreated, advanced/metastatic ALK+ NSCLC have been previously published: ALC 34.8 months (m) (95% CI 17.7–NR) vs CRZ 10.9 m (95% CI 9.1–12.9), (HR 0.43, 95% CI 0.32–0.58). We report 5-year OS and updated safety data from ALEX with a further 12 m follow-up (FU) (cutoff date: Nov 29, 2019). Methods: Patients (pts) with stage IIIB/IV ALK+ NSCLC (by central IHC), ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC were randomized 1:1 to ALC 600 mg BID (n = 152) or CRZ 250 mg BID (n = 151). Asymptomatic CNS metastases (mets) at baseline (BL) were allowed. OS was a secondary endpoint, and no formal statistical testing was planned. Results: Median duration of FU: 48.2 m with ALC vs 23.3 m with CRZ. OS data remain immature (events: 37%; stratified HR 0.67 [95% CI 0.46–0.98]); median OS with CRZ was 57.4 m (95% CI 34.6–not estimable [NE]) vs NE with ALC. The 5-year survival rate was 62.5% (95% CI 54.3–70.8) with ALC vs 45.5% (95% CI 33.6–57.4) with CRZ (Table). In pts with CNS mets at BL the OS HR was 0.58 (95% CI 0.34–1.00) and 0.76 (95% CI 0.45–1.26) in pts without CNS mets at BL. The OS benefit of ALC vs CRZ was generally consistent across all subgroups. Considering the longer treatment duration for ALC (28.1 m) vs the previous analysis (27.7 m), the safety profile of ALC remains consistent; no new safety signals were observed. With ALC, 35% of pts remain on study treatment vs 9% of pts remaining on CRZ. In pts with ≥1 known post-progression treatment (ALC: 32.2%; CRZ: 45.7%), lorlatinib was the most common ALK TKI received after first-line ALC (7.2%), compared with ceritinib after first-line CRZ (15.2%). Conclusions: This is the first global randomized study of a 2nd generation ALK TKI to demonstrate a clinically meaningful improvement in OS vs CRZ in ALK+ NSCLC (5-year survival rate: 62.5%, ALC vs 45.5%, CRZ); longer FU is required as OS data remain immature. Clinical trial information: NCT02075840 . [Table: see text]

9053 Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK inhibitor treatment is poorly understood. Here, we examine the prognostic potential of cfDNA in the phase III ALEX trial of alectinib versus crizotinib in previously untreated patients with advanced ALK+ NSCLC. Methods: Data cutoff was December 1, 2017. Median cfDNA was determined from 276 baseline samples; patients were stratified into ‘≤median’ and ‘ > median’ biomarker-evaluable populations (BEP). Results: Median cfDNA was 11.5ng/mL. Baseline characteristics were mostly balanced between the crizotinib (≤median, n = 72; > median, n = 67) and alectinib (≤median, n = 66; > median n = 71) BEPs. However, the alectinib > median BEP had more active smokers (7.0% vs crizotinib 1.5%), more measurable/non-measurable CNS lesions (47.9% vs 41.8%) and more patients with TP53 short-variant (SV) (44.8% vs 32.8%); the alectinib ≤median BEP had more active smokers (7.6% vs crizotinib 2.8%). Alectinib exposure was not substantially different between relevant BEPs. Higher cfDNA amount was associated with measurable/non-measurable CNS lesions and TP53 SV. Tumor burden positively correlated with normalized cfDNA amount (Pearson correlation 0.204; p < 0.001). Median PFS by investigator in the ≤median BEP was 34.9 months alectinib vs 14.8 crizotinib (HR 0.37, 95% CI 0.22–0.61, p < 0.0001); in the > median BEP it was 14.8 months alectinib vs 8.6 crizotinib (HR 0.43, 95% CI 0.28–0.64, p < 0.0001). Response rates in the ≤median BEP were 82.3% alectinib vs 70.4% crizotinib; in the > median BEP, 70.2% alectinib vs 55.4% crizotinib. Median duration of response in the ≤median BEP was not reached for alectinib vs 21.0 months for crizotinib; in the > median BEP, 33.1 months alectinib vs 7.3 crizotinib. Conclusions: Tumor burden positively correlated with cfDNA amount; patients with ≤median cfDNA at baseline had better prognosis than those with > median cfDNA. Alectinib consistently improved PFS, DOR and ORR versus crizotinib across BEPs, reducing the risk of tumor progression by > 50% compared with crizotinib. Clinical trial information: NCT02075840.

9004 Background: The role of treatment with Bev beyond PD is unclear in the multiline treatment strategy of advanced NSCLC.AvaALL(NCT01351415), a multinational, open-label, randomized phase III trial, assessed continuous Bev and SOC beyond first PD (PD1) in pts with NSCLC following first-line treatment with platinum-based chemo plus Bev. Here we present efficacy and safety data from AvaALL. Methods: Pts with NSCLC who received 4–6 cycles of chemo + Bev and ≥2 cycles of maintenance Bev were randomized after PD1 to second-line SOC therapy (docetaxel, pemetrexed or erlotinib) ± Bev. After second PD (PD2) and third PD (PD3), pts received third-line or fourth-line SOC ± Bev treatment, respectively. Primary endpoint was overall survival (OS). Secondary endpoints were OS rates (6, 12, and 18-months [mos]), progression-free survival (PFS) from PD1 to PD2/from PD2 to PD3, overall response rate (ORR), disease control rate (DCR), and safety. Data cut-off: 24 Jun 2016. Results: Overall, 485 pts were randomized (n = 475 treated). Pt characteristics were well balanced between the two arms. Bev plus chemo resulted in a median OS of 11.9 mos versus 10.2 mos for SOC alone (HR 0.84, 90% CI 0.71–1.00; p = 0.1016; 387 OS events). The primary endpoint was not met (416 OS events were required, at 10% two-sided significance level). OS rates were 10% higher in the Bev arm vs SOC alone at 6-, 12- and 18-mos. Median PFS2 was 4.9 mos with Bev vs 3.8 mos with SOC (HR 0.85, 90% CI 0.72–1.00; p = 0.0907). PFS3 was significantly improved (3.5 mos for Bev, 2.4 mos for SOC; HR 0.65, 90% CI 0.51–0.84; p = 0.0047). ORR and DCR were slightly higher in the Bev arm versus the SOC arm (ORR 9.7% vs 6.7%; DCR 86.2% vs 79.3%, respectively). No new safety signals were identified. Grade ≥3 adverse events were reported in 78.2% of Bev pts and 61.6% of SOC pts. Conclusions: Although the primary endpoint was not met, efficacy data suggest a positive trend for continued Bev plus SOC after PD1 compared with SOC alone. No cumulative safety signals were identified. Clinical trial information: NCT01351415.