According to findings from the phase III ALUR and ALEX studies announced ahead of the 2017 ESMO Congress,<sup> </sup>Alectinib demonstrated promising efficacy for patients with <em>ALK</em>-translocated non–small cell lung cancer with central nervous system metastases in both the first- and second-line setting.
Fiona Blackhall, MD, PhD
According to findings from the phase III ALUR and ALEX studies announced ahead of the 2017 ESMO Congress,1,2Alectinib (Alecensa) demonstrated promising efficacy for patients withALK-translocated nonsmall cell lung cancer (NSCLC) with central nervous system (CNS) metastases in both the first- and second-line setting.
In the ALEX trial, which explored the agent in the frontline setting, the CNS-specific objective response rate (ORR) with alectinib was 36% compared with 28.6% with crizotinib (Xalkori) in patients treated with prior radiotherapy. For those without prior radiotherapy, alectinib showed a CNS ORR of 74.4% versus just 24.3% with crizotinib.
In the ALUR study, alectinib was compared with platinum-based chemotherapy in the second-line setting or beyond. In those with measurable CNS disease at baseline, the CNS ORR was 54.2% with alectinib, and none of those treated with crizotinib responded. Across both studies, there were marked improvements in progression-free survival (PFS) with alectinib versus crizotinib or chemotherapy.
“These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care," ESMO spokesperson Fiona Blackhall, MD, PhD, from the University of Manchester and The Christie Hospital, UK, said in a statement. “The results of the ALUR and ALEX trials provide proof of clinically significant CNS efficacy for alectinib and indicate that CNS staging should be routine for optimal care of patients with ALK-positive lung cancer.”
In the open-label ALEX study, patients were randomized to 600 mg of alectinib (n = 152) or 250 mg of crizotinib (n = 151) both twice daily. Of those enrolled, 122 had CNS metastases at baseline: 64 in the alectinib arm and 58 in the crizotinib group. Forty-three patients had measurable lesions at baseline and 47 had received prior radiotherapy (26 in the alectinib group and 21 in the crizotinib arm).
Across the full population of the study, the median PFS was 25.7 months with alectinib versus 10.4 months with crizotinib (HR, 0.47; 95% CI, 0.34-0.65;P<.0001). In those without CNS metastases, the median PFS was not yet reached with alectinib compared with 14.8 months with crizotinib (HR, 0.51; 95% CI, 0.33-0.80;P= .0024). For all patients with CNS involvement, the median PFS was not yet reached with alectinib versus 7.4 months with crizotinib (HR, 0.40; 95% CI, 0.25-0.64;P<.0001).
In those with CNS metastases treated with radiotherapy, the median PFS was not reached with alectinib versus 12.7 months with crizotinib (HR, 0.34; 95% CI, 0.15-0.78;P= .0078). Those without prior radiotherapy had a median PFS of 14.0 months with alectinib versus 7.2 months with crizotinib (HR, 0.44; 95% CI, 0.25-0.78;P= .0041).
Those with CNS disease experienced progressive disease before those without CNS sites in the crizotinib arm. In the alectinib group, however, those with non-CNS sites progressed before those with CNS disease. In those specifically with measurable CNS metastases, the CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib for those pretreated with radiotherapy. In those who did not receive radiotherapy, the CNS ORR was 78.6% with alectinib versus 40.0% with crizotinib.
In the full population of ALEX, grade 3/4 adverse events (AEs) were less frequent with alectinib compared with crizotinib (41% vs 50%, respectively). Moreover, alectinib was associated with a lower incidence of fatal AEs (3% vs 5%) and fewer patients had AEs leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%) or interruption (19% vs 25%).
“Alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib,” ALEX trial lead investigator Shirish Gadgeel, MD, from the University of Michigan. “Clearly this superiority against CNS metastases contributes to the overall efficacy of alectinib. By its superior efficacy in the CNS alectinib limits the morbidity both from these metastases but also from treatments such as whole brain radiation.”
In the open-label ALUR trial, 107 patients were randomized in a 2:1 ratio to alectinib (n = 72) or chemotherapy with pemetrexed or docetaxel (n = 35). Alectinib was administered at 600 mg twice daily, pemetrexed at 500mg/m2 every 3 weeks, and docetaxel at 75mg/m2every 3 weeks. Patients may have received prior platinum-based doublet chemotherapy and crizotinib.
Across the full population of the study, the median PFS by investigator assessment was 9.6 months with alectinib and 1.4 months for chemotherapy (HR, 0.15; 95% CI, 0.08-0.29;P<.001). In an independent review, the median PFS was 7.1 months for alectinib compared with 1.6 months for chemotherapy (HR, 0.32; 95% CI, 0.17-0.59;P<.001).
By independent review, the ORR across the whole group was 36.1% and 11.4%, for alectinib and chemotherapy, respectively. The disease control rate (ORR plus stable disease) was 80.6% with alectinib and 28.6% with chemotherapy. The median duration of response was 9.3 versus 2.7 month for alectinib and chemotherapy, respectively.
Overall, 77.1% of patients treated with alectinib had any AE versus 85.3% for chemotherapy. Grade 3/4 AEs occurred for 27.1% and 41.2% of those treated with alectinib and chemotherapy, respectively. AEs led to dose reductions for 10% of patients treated with alectinib versus 20.6% with chemotherapy.
“[These results] support alectinib as a new standard-of-care for patients with previously treated ALK-positive NSCLC,” noted ALUR senior investigator Silvia Novello, MD, PhD, from the University of Turin, Italy. “This is another important goal reached in the field of thoracic oncology. A drug which has this activity on brain metastases can allow us to modify treatment and reduce the need for whole brain radiotherapy.”
The FDA is currently reviewing an application for alectinib as a frontline therapy for patients with ALK-positive locally advanced or metastatic NSCLC, based on findings from the ALEX trial. The agency is scheduled to decide by November 30, 2017. The agent is approved for patients with ALK+ metastatic NSCLC following prior treatment with crizotinib.