Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: Phase 1b results from JAVELIN Lung 101.

Abstract

9008 Background: ALK tyrosine kinase inhibitors (TKIs) are standard of care for patients (pts) with advanced ALK+ NSCLC, and preclinical data suggest potential synergistic activity with checkpoint inhibitors in NSCLC irrespective of ALK status. Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody approved in various countries for treatment of metastatic Merkel cell carcinoma, and in the US for advanced urothelial carcinoma that has progressed following platinum therapy. We report initial results from JAVELIN Lung 101 (NCT02584634), a phase 1b/2 dose-finding trial of avelumab + crizotinib (A+C) or the next-generation ALK TKI lorlatinib (A+L) in pts with advanced/metastatic ALK-negative/wildtype (ALK−) or ALK+ NSCLC, respectively. Methods: In phase 1b, pts with previously treated ALK− NSCLC received A (10 mg/kg Q2W) + C (250 mg BID) while pts with ALK+ NSCLC received A (10 mg/kg Q2W) + L (100 mg QD) (starting dose levels in each group). The primary endpoint was dose-limiting toxicities (DLTs); secondary endpoints included adverse events (AEs) and objective responses. Results: At data cutoff on Oct 27, 2017, 12 ALK− pts had received A+C and 28 ALK+ pts had received A+L. All ALK− pts had received prior anticancer therapy; ALK+ pts had received a median 2 prior ALK TKIs (range 1-3; data not reported for 1 ALK+ pt). DLTs occurred with A+C in 5 ALK− pts (41.7%): ALT and AST increase (2 pts each), febrile neutropenia, hepatitis, QT prolongation, and rash (1 pt each). No DLTs occurred with A+L in ALK+ pts. Grade ≥3 AEs of any causality occurred with A+C in 7 ALK− pts (58.3%; most common [≥10%] was ALT increase [16.7%, n = 2]), and with A+L in 15 ALK+ pts (53.6%; most common were hypertriglyceridemia [14.3%, n = 4] and GGT increase [10.7%, n = 3]). The confirmed objective response rate with A+C in ALK− pts was 16.7% (95% CI, 2.1-48.4; partial response [PR] in 2 pts), and with A+L in ALK+ pts was 46.4% (95% CI, 27.5-66.1; PR in 12 pts; complete response in 1 pt). Conclusions: A+L showed an acceptable safety profile, distinct from A+C, and promising antitumor activity in pts with ALK+ NSCLC, and will be evaluated in treatment-naive pts in phase 2. Clinical trial information: NCT02584634.

How I treat ALK-positive non-small cell lung cancer

“…Similar results were observed in the combination of ceritinib and nivolumab presented at the American Society of Clinical Oncology Annual Meeting in 2017. In contrast, a manageable toxicity profile has been reported with the combinations avelumab with lorlatinib in the phase 1b/2 JAVELIN Lung 101 trial33 and atezolizumab with alectinib34 with no new or unexpected side effects. Encouraging data are emerging with the chemoimmunotherapy combinations, as recently reported in a subset analysis of the IMpower 150 trial,35 although the small sample size of ALK-positive patients included in the study does not allow for definitive conclusions in outcomes.…”

Emerging Roles of ALK in Immunity and Insights for Immunotherapy

“…For example, results from the CheckMate 370 study (NCT02574078) study showed that combination of crizotinib, the first generation of ALK inhibitor, with nivolumab at the respective doses of 250mg twice daily and 240mg every two weeks appeared to exhibit some severe toxicities in advanced ALK-rearranged NSCLC patients [56]. Importantly, studies on ceritinib/nivolumab combination (NCT02393625) showed promising clinical activities in patients [57], and lorlatinib with avelumab (anti-PD-L1 antibody; NCT02584634) showed promising antitumor activities with acceptable safety profiles than crizotinib/avelumab combination [58]. Similarly, alectinib/atezolizumab combination (NCT02013219) [59] also demonstrated promising anti-tumor activity in patients with acceptable safety profiles.…”

Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer

“…In advanced disease, trials exploring optimal administration of both established combinations of checkpoint inhibitors plus chemotherapy, immunotherapy, and targeted therapy are underway. Trial data confirming the activity of checkpoint inhibitor combinations in PD‐L1‐negative, high‐TMB expressing, and EGFR+/ALK+ subpopulations in advanced NSCLC are pending, although the potential for minimal benefit and increased toxicity may prevent the combination of checkpoint inhibitors with TKIs in patients with EGFR+/ALK+ disease . In stage III unresectable disease, durvalumab added as consolidation following chemoradiotherapy has demonstrated improved OS in the phase III PACIFIC trial , leading to its approval in this setting on February 16, 2018 , and additional trials evaluating checkpoint inhibitors in conjunction with chemoradiotherapy are underway .…”