MADRID-Approximately 3-7 percent of lung cancer patients have a mutated form of anaplastic lymphoma kinase (ALK) that serves as an oncogenic driver for their malignancy. Crizotinib, an early ALK inhibitor, has become the standard first-line therapy for ALK-positive non-small cell lung cancer (NSCLC) patients; however, nearly all of these patients will eventually undergo disease progression, often as a result of central nervous system (CNS)-based metastases.
In previous phase II clinical trials, alectinib has shown efficacy in ALK-positive NSCLC patients who had previously received crizotinib therapy. Thus far, no trials have compared alectinib with standard chemotherapies in NSCLC patients who had undergone disease progression while on crizotinib and after receiving platinum-based chemotherapy. To make that comparison, the phase III ALUR trial (MO29750, NCT02604342) was undertaken. Results from this study were recently presented by Silvia Novello, MD, PhD, Assistant Professor, Thoracic Oncology Unit at the University of Turin, San Luigi Hospital, Orbassano, Italy, at the ESMO 2017 Congress (Abstract 1299O).
Trial Design
"Inclusion in this study was limited to ALK-positive advanced or metastatic NSCLC patients who had one prior line of platinum-based chemotherapy and who had disease progression after receiving crizotinib," Novello stated. Additionally, an ECOG performance status (PS) of 0-2 was required.
Enrolled patients were randomized in a 2:1 manner to receive either 600 mg alectinib p.o. BID (alectinib arm) or either 500 mg/m2 pemetrexed IV Q3W or 75 mg/m2 docetaxel IV Q3W (chemotherapy arm). Patients received investigational medications until progressive disease (PD) was noted.
Once PD was noted, patients in the chemotherapy arm were permitted to cross over to alectinib therapy. Those from the alectinib arm who underwent progression were permitted to continue that medication if clinical benefit was noted. Patients were stratified according to the following criteria: ECOG PS (0/1 vs. 2); CNS metastases at baseline (yes vs. no); brain radiotherapy for patients with CNS metastases at baseline (yes vs. no).
The primary objective for this trial was investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) population. The key secondary endpoint was CNS objective response rate (ORR) (defined as the percentage of patients showing complete response (CR) and partial response (PR)) in patients with CNS metastases at baseline as assessed by independent review committee (IRC). Other secondary endpoints including the following: IRC-assessed PFS; disease control rate (DCR) (defined as ORR plus the percentage of patients showing stable disease (SD)) and duration of response (DOR); PFS in patients with baseline CNS metastases; safety; overall survival (OS); time to CNS progression by CNS baseline metastasis status; CNS DCR and CNS DOR in patients with baseline CNS metastases.
Patient Demographics
There were 107 patients in the ITT population, 72 in the alectinib arm and 35 in the chemotherapy arm. All of the patients included in this study had NSCLC with adenocarcinoma histology.
For the alectinib arm (n = 72), the median age was 55.5 years (range: 21-82 years), 83.3 percent were aged 18-64 years, 56.9 percent were male and 84.7 percent were white. In this patient arm, the smoking status was as follows: never smoked-48.6 percent; previously smoked-48.6 percent; currently smokes-2.8 percent. An ECOG PS of 0 was registered in 91.7 percent of these patients, while 8.3 percent had a PS of 1/2. Radiotherapy was already administered in 53 percent of these patients, while 24 percent had surgical therapy. In this group, 34.7 percent of patients had no CNS metastases at baseline, 33.3 percent had baseline CNS metastases without previous radiotherapy, and 31.9 percent had baseline CNS metastases with previous radiotherapy.
Patients in the chemotherapy arm (n = 35) had a median age of 59 years (range: 37-80 years), 71.4 percent were aged 18-64 years, 51.4 percent were female, and 80 percent were white. The smoking status for these patients was as follows: never smoked-45.7 percent; previously smoked-48.6 percent; currently smokes-5.7 percent. Of these patients, 85.7 percent had an ECOG PS of 0 and 14.3 percent had a PS of 1/2. Radiation therapy was described in 60 percent of these patients and 20 percent had surgical therapy. For this arm, 25.7 percent had no baseline CNS disease, 48.6 percent had baseline CNS metastases without prior radiation, and 25.7 percent had baseline CNS metastases with prior radiotherapy.
PFS Data
For the alectinib arm, an investigator-assessed median PFS value of 9.6 months (95% CI: 6.9-12.2 months) was obtained; while for the chemotherapy arm, this figure was 1.4 months (95% CI: 1.3-1.6 months). These afforded a hazard ratio (HR) of 0.15 (95% CI: 0.08-0.29; p < 0.001).
IRC-assessed PFS analysis revealed a median value of 7.1 months (95% CI: 6.3-10.8 months) for the alectinib arm and 1.6 months (95% CI: 1.3-4.1 months) for the chemotherapy arm. For these analyses, a HR of 0.32 (95% CI: 0.17-0.59; p < 0.001) was obtained.
As of the data cutoff date (Jan. 26, 2017), the median follow-up was 5.8 months for the chemotherapy arm and 6.5 months in the alectinib arm. The median time on therapy for the chemotherapy patients was 6 weeks (range: 1.9-47.1 weeks), as compared to 20 weeks (range: 0.4-62.1 weeks) for the alectinib patients.
Subgroup analysis was performed using the investigator-assessed PFS data from the ITT population. When looking at gender stratification, HR values of 0.25 (95% CI: 0.10-0.60) and 0.08 (95% CI: 0.02-0.30) were obtained for male and female patients, respectively. Patients without the presence of CNS metastases at baseline displayed an HR of 0.21 (95% CI: 0.07-0.64), while those having baseline CNS metastases with no prior radiotherapy and those having prior radiotherapy displayed values of 0.12 (95% CI: 0.03-0.45) and 0.12 (95% CI: 0.04-0.37), respectively. Additionally, those having and not having prior radiotherapy (with or without baseline CNS metastases) had HR values of 0.13 (95% CI: 0.05-0.35) and 0.06 (95% CI: 0.02-0.22), respectively.
Response Data
When asked about the response data for patients with baseline CNS disease, Novello noted, "Among these participants, those in the alectinib arm had an ORR of 54.2 percent (95% CI: 33-74%), while those in the chemotherapy group had a value equal to 0 percent (95% CI: 0-21%), meaning that in that subgroup none displayed CR or PR. These figures were obtained from IRC-assessed data."
In the ITT population, the following investigator-assessed response data were obtained for the alectinib participants (n = 72): CR-0 percent; PR-37.5 percent; SD-43.1 percent; PD-5.6 percent. For the ITT chemotherapy arm (n = 35), the following data were obtained: CR-0 percent; PR-2.9 percent; SD-25.7 percent; PD-57.1 percent. These data provided investigator-assessed DCR values of 80.6 percent (95% CI: 70.0-89.0%) and 28.6 percent (95% CI: 15.0-46.0%) for the alectinib and chemotherapy arms, respectively.
An investigator-assessed median DOR value of 9.3 months (95% CI: 6.9 months-not estimable) was obtained for the alectinib patients; for the chemotherapy arm, the median value was 2.7 months (95% CI: not estimable).
Safety Data
"Grade 3-5 AEs were noted in 27.1 percent of the ITT alectinib patients compared to 41.2 percent of the ITT chemotherapy patients," Novello commented. For the alectinib arm, AEs leading to treatment discontinuation, dose reduction, or dose interruption were experienced by 5.7 percent, 4.3 percent, and 18.6 percent of these patients, respectively. Correspondingly, in the chemotherapy arm, AEs leading to treatment discontinuation, dose reduction, or dose interruption were experienced by 8.8 percent, 11.8 percent, and 8.8 percent of these patients.
Conclusions
When asked whether any patients had crossed over to receive alectinib and if any in the alectinib arm had continued that therapy after disease progression, Novello noted, "Crossover from chemotherapy to alectinib was permitted for 22 patients in that arm; continuation of alectinib (in the alectinib arm) beyond progression was permitted in four individuals where clinical benefit was persistent."
Regarding the safety data, Novello commented, "The safety and tolerability of alectinib compared favorably with chemotherapy, despite the treatment duration with alectinib being over three times as long (20 weeks vs. 6 weeks with chemotherapy)."
When Novello was asked about the findings in this study, she stated, "In the immediate future, this suggests a specific role of alectinib in N-line (i.e., non-first-line) therapy for ALK-rearranged patients; but as already specified above, it is possible that we will have alectinib in first line (especially for those patients with brain metastases). It is also important to keep in mind that drug access and drug approvals are not the same across the world, so what is already first line in the U.S. may not be so in Europe or other countries."
In summarizing the results from this trial, Novello stated, "This is another trial supporting the activity of alectinib in ALK-rearranged NSCLC patients as well as its CNS efficacy (as indicated in the ALEX trial). This is potentially a demonstration of this activity also in a third-line setting; however, given the strong data in first-line settings from the ALEX and J-ALEX trials, it is difficult to foresee no changes in the current therapeutic algorithm for ALK-rearranged advanced NSCLC patients."
Richard Simoneaux is a contributing writer.