Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy.

Abstract

8034 Background: Nintedanib (N) is an oral inhibitor of VEGFR, FGFR, and PDGFR. This global phase 3 study investigated the safety and efficacy of N + pemetrexed (PEM) vs placebo (P) + PEM in patients (pts) with advanced, non-squamous NSCLC previously treated with chemotherapy. Methods: Pts were randomized 1:1 to N 200 mg po bid + PEM 500 mg/m2 iv q21d (n=353, Arm A) or P + PEM (n=360, Arm B). Continuation until PD or unacceptable toxicity with N, P, PEM, or a combination was permitted. 1° endpoint was centrally reviewed PFS. The null hypothesis was tested on the ITT population after 394 events had occurred (two sided α=5%). 2° endpoints included OS, investigator-assessed PFS, response rate (RR), safety, and QoL. Results: Baseline pt characteristics were balanced between Arm A vs B (median age 59 y, female 45–42%, ECOG PS 1 62-61%, adenocarcinoma 95–93%, prior bevacizumab 8%). Based on a planned DMC futility analysis of investigator-assessed PFS, enrolment was halted after randomizing 713/1300 planned pts (no safety issues identified). Ongoing pts were unblinded and follow-up continued per protocol. Subsequent ITT analysis of the 1° endpoint (centrally reviewed PFS) favored Arm A vs B (median 4.4 vs 3.6 mo, HR 0.83 [95% CI: 0.7–0.99], p=0.04). Disease control was also significantly improved in N-treated pts (61 vs 53%, odds ratio 1.37, p=0.039). No difference in OS (HR 1.03) or RR (9%) was found. Exploratory analyses identified time since start of 1st-line therapy as a predictive marker of improved outcome with N + PEM (ASCO 2013). There was no increase in SAEs or G5 AEs with N + PEM. Addition of N to PEM resulted in a higher incidence of ≥G3 elevated ALT (23 vs 7%), elevated AST (12 vs 2%), and diarrhea (3 vs 1%), but no difference in ≥G3 hypertension, bleeding, thrombosis, mucositis, or neuropathy. Conclusions: The 1° endpoint was met even though the study was stopped prematurely. Treatment with N + PEM significantly improved centrally reviewed PFS vs P + PEM in pts with advanced non-squamous NSCLC previously treated with chemotherapy, and had a manageable safety profile. Clinical trial information: NCT00806819.

The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC

“…Pemetrexed is widely used as a second-line agent for the treatment of nonsquamous NSCLC, and the results showed a significant improvement in independent centrally reviewed PFS with nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months versus 3.6 months; HR ¼ 0.83, 95% CI: 0.70-0.99, p ¼ 0.0435) at the time of the final analysis. 27 On the basis of a preplanned investigator-assessed futility analysis, LUME-Lung 2 recruitment was stopped prematurely, but combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced nonsquamous NSCLC after first-line chemotherapy, with a manageable safety profile.…”

Lung Cancer

“…The trial was stopped after an interim analysis that suggested lack of improvement from the addition of nintedanib. The final analysis of the intention-to-treat population showed a significant although modest improvement of PFS with the experimental combination (median PFS 4.4 versus 3.6 months, p=0.04) [121].…”

International Experts Panel Meeting of the Italian Association of Thoracic Oncology on Antiangiogenetic Drugs for Non–Small Cell Lung Cancer: Realities and Hopes

“…No difference in OS was observed between the two arms. 31 Both studies demonstrated that although more adverse events happened in the combination arm (above all gastrointestinal side effects, a reversible increase in liver enzyme levels, and hematologic toxicities), no differences between the two arms were described in terms of those toxicities usually associated with antiangiogenic agents (such as bleeding, thrombosis, and hypertension).…”