Volasertib Monotherapy vs. Combination with Pemetrexed: A Phase II Trial in Second-Line NSCLC

Introduction

Second-line treatment options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are limited. Volasertib is a potent, selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase 1. This randomized phase II study compared volasertib alone, volasertib combined with pemetrexed, and pemetrexed alone in patients with advanced NSCLC whose disease had progressed after first-line platinum-based chemotherapy.

Patients and Methods

After a safety run-in assessing volasertib plus pemetrexed, eligible adults with stage IV or recurrent NSCLC (nonsquamous or not-otherwise-specified histology), Eastern Cooperative Oncology Group performance status 0-2 and adequate organ function were randomized 1:1:1 to one of three open-label arms: volasertib 300 mg intravenously on day 1 of each 21-day cycle; volasertib 300 mg plus pemetrexed 500 mg/m² (pemetrexed infusion preceding volasertib); or pemetrexed 500 mg/m² alone. Treatment continued until progression or unacceptable toxicity. Early stopping rules were applied for lack of efficacy in the volasertib monotherapy arm. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response, safety and pharmacokinetics. Tumour assessments (RECIST v1.0) were performed every 6 weeks.

Figure 1

CONSORT diagram depicting patient flow: 143 screened and enrolled; 12 treated in run-in; 131 randomized (volasertib 37, volasertib + pemetrexed 47, pemetrexed 47); safety population n = 140.

Results

From May 2009 to July 2011, 143 patients were enrolled (12 in run-in; 131 randomized: volasertib 37, volasertib + pemetrexed 47, pemetrexed 47). Baseline characteristics were balanced. Median cycles received were 2, 4 and 5.5, respectively. In the randomized phase, median PFS was 1.4 months with volasertib, 3.3 months with volasertib + pemetrexed, and 5.3 months with pemetrexed (hazard ratio [HR] volasertib + pemetrexed vs pemetrexed = 1.141; 95% CI 0.73-1.771; HR volasertib vs pemetrexed = 2.045; 95% CI 1.27-3.292). ORR was 8.1% (volasertib), 21.3% (volasertib + pemetrexed) and 10.6% (pemetrexed). No complete responses were recorded. Median duration of response was 17.3, 42.2 and 36.6 weeks, respectively. Recruitment to volasertib monotherapy was halted early because of insufficient activity.

Safety

Treatment-related adverse events (AEs) of any grade occurred in 63.9% (volasertib), 91.3% (volasertib + pemetrexed) and 87.0% (pemetrexed) of patients; grade 3/4 related AEs occurred in 22.2%, 30.4% and 28.3%, respectively. Most common related AEs (all grades) were fatigue, nausea, decreased appetite, neutropenia, rash, vomiting and diarrhea. Serious AEs were reported in 22.2%, 21.7% and 26.1% of patients, respectively; treatment-related serious AEs in 0%, 13.0% and 10.9%. One treatment-related death (septic shock) occurred in the combination arm. Pharmacokinetic analyses showed no interaction between volasertib and pemetrexed.

Discussion

Adding volasertib to standard-dose pemetrexed did not improve efficacy versus pemetrexed alone in second-line advanced or metastatic NSCLC, although toxicity was not markedly increased. Volasertib monotherapy demonstrated inferior PFS and was discontinued for futility. The higher response rate with the combination suggests a possible benefit in a molecularly defined subset; identification of predictive biomarkers for Polo-like kinase inhibition warrants further study.

Conclusion

For second-line treatment of advanced or metastatic nonsquamous NSCLC (Non-small-cell lung cancer), volasertib plus pemetrexed did not confer a progression-free survival (PFS) advantage over pemetrexed monotherapy.

Volasertib is a potent inhibitor of Polo-like kinase 1 (PLK1) (National Institutes of Health), an enzyme essential for cell division. Despite its ability to induce mitotic arrest, clinical data indicated that adding it to standard pemetrexed treatment did not significantly delay disease progression in an unselected patient population.

Consequently, this combination should not replace pemetrexed monotherapy, which remains a standard of care for second-line management of nonsquamous NSCLC.