Alectinib Activity in CNS Metastases in Patients With ALK+ NSCLC

Alexander M. Castellino, PhD

September 08, 2017

UPDATED SEPTEMBER 11, 2017 // MADRID, Spain — Impressive activity against central nervous system (CNS) metastases has been shown again with the targeted agent alectinib (Alecensa, Roche/Genentech) in patients with anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC).

The data come from two studies — ALUR (NCT02604342) and ALEX (NCT02075840) — that were reported here on Monday at the European Society for Medical Oncology (ESMO) 2017 Congress.

Both are phase 3 studies in advanced ALK+ NSCLC. ALEX uses alectinib in the first-line setting and ALUR uses it in the latter lines of therapy.

A subanalysis of ALEX showed that patients with measureable CNS disease at baseline were at a 60% reduced risk for progression with alectinib compared with crizotinib (Xalkori, Pfizer). ALUR showed that in patients with measurable central nervous system (CNS) disease at baseline, CNS overall responses rate (ORR) was 54.2% for patients receiving alectinib and 0% for patients receiving chemotherapy.

"The CNS is a common site of metastases and disease progression in ALK+ NSCLC. Thirty percent of patients with ALK+ NSCLC have CNS metastases at initial diagnosis and CNS is the first site of disease progression in about 50% of patients receiving crizotinib," presenter Shirish Gadgeel, MD, from the University of Ann Arbor, Ann Arbor, Michigan, said.

"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+ lung cancers," Fiona Blackhall, MD, PhD, from the University of Manchester and The Christie Hospital, United Kingdom, said in a statement.

Alectinib is approved for second-line use to treat ALK+ NSCLC that has progressed on crizotinib. But the data from ALEX, which were presented at the American Society of Clinical Oncology (ASCO) 2017 annual meeting, showed impressive findings in the first-line setting. ASCO expert John V. Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, called it "a watershed moment for the treatment of ALK+ lung cancer" and agreed with the study investigators that alectinib presented a new standard for first-line ALK+ NSCLC.

Subanalysis of ALEX in Treatment-Naive ALK+ Advanced NSCLC  

In the original cohort of 303 treatment-naive patients with  ALK+ advanced NSCLC, median PFS was not reached with alectinib vs 11.1 months with crizotinib.

At the ESMO 2017 Congress, new data will be presented from a subanalysis of  patients who did (n = 122 [64 for alectinib and 58 for crizotinib]) and did not (n = 181 [88 for alectinib and 93 for crizotinib]) present with CNS metastases at baseline. Of patients with CNS metastases at baseline, approximately 60% had not received radiation therapy (RT) for treatment.

For patients who did not present with CNS metastases at baseline, median PFS was 14.8 months for those receiving crizotinib and was not reached for those receiving alectinib. Patients receiving alectinib were at a 49% reduced risk for progression compared with the 60% reduced risk reported for patients with CNS metastases at baseline. In these patients, median PFS was 7.4 months for crizotinib recipients and was not reached for patients receiving alectinib.

Because radiation therapy is used to treat brain metastases, the ALEX investigators also report PFS data based on whether patients with CNS metastases at baseline had received prior RT. For patients who had received prior RT (21 for crizotinib  and 25 for alectinib), median PFS was 12.7 months for patients taking crizotinib and was not reached for those taking alectinib (P =.0078). For patients with no prior RT (37 for crizotinib and 39 for alectinib), median PFS was 7.2 months and 14.0 months for crizotinib and alectinib, respectively (P = .0041). Patients receiving alectinib were at a 66% and 56% reduced risk for progression if they had received prior RT and no prior RT, respectively.

Another salient point of the analyses was the site of first disease progression. For patients receiving crizotinib, first disease progression was more common in CNS than in non-CNS sites. For example, of patients without CNS metastases at baseline, 38% and 20% showed CNS vs non-CNS disease progression. However, for alectinib, first disease progression was more frequent in non-CNS sites for patients without baseline CNS metastases: 7% CNS disease progression vs 28% non-CNS disease progression. 

But for patients receiving alectinib with CNS metastases at baseline, first disease progression  in CNS and non-CNS sites was similar (12% and 20%, respectively), but not so for patients on crizotinib, with 52% of patients showing CNS disease progression and 24% showing non-CNS disease progression.

In all cohorts analyzed, the 12-month cumulative incidence rate for CNS disease progression was lower in patients receiving alectinib. In patients with no CNS metastases at baseline, rates of CNS disease progression were 4.6% for patients receiving alectinib and 31.5% for patients receiving crizotinib. Corresponding rates in patients with CNS metastases at baseline were 16.0% and 58.3%, respectively.

Dr Gadgeel also presented CNS response rates. For patients with measureable CNS disease at baseline, ORR was 85.7% for patients receiving alectinib and 71.4% for patients receiving crizotinib among those who had prior RT at study entry. In patients who had not previously received RT, CNS responses were 40% with crizotinib and 78.6% with alectinib.

These responses, based on RECIST 1.1 criteria, were similar to those seen with the Response Assessment in Neuro-Oncology (RANO criteria), which were also presented.

Alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib. Shirish Gadgeel

This analysis suggests that "alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib," commented Dr Gadgeel.

"Overall, these CNS results along with the systemic results consolidate alectinib as the new standard of care for patients with previously untreated, advanced ALK+ NSCLC," Dr Gadgeel concluded.

Summarizing the data, Luis Paz-Ares, MD, from the Hospital Universitario Doce de Octubre, Madrid, Spain, indicated that alectinib is more efficacious because it is a more potent wild-type ALK and ALK mutant inhibitor and has better CNS activity, as seen from pharmacokinetic studies.

Alectinib results in better PFS, particularly in the CNS, he noted. "We don't know what the best sequence will be, but for most cases alectinib should be preferred initial treatment option due to its better efficacy, disease control in the CNS and favorable safety profile," he said. Genomic sequencing should provide guidance in sequencing other therapies, he suggested.

 ALUR in ALK+ Previously Treated Advanced NSCLC

ALUR randomly assigned previously treated patients with ALK+ NSCLC to alectinib, 600 mg twice daily (n = 72), or chemotherapy (pemetrexed or docetaxel; n = 35) until disease progression, death, or withdrawal.

Median follow-up was 6.5 months for patients receiving alectinib and 5.8 months for patients receiving chemotherapy. Investigator-assessed median progression-free survival (PFS) — the primary endpoint — was 9.6 months for patients receiving alectinib and 1.7 months for patients receiving chemotherapy, and alectinib was associated with a significant 85% reduced risk for progression. Median PFS was 7.1 months for alectinib and 1.6 months for chemotherapy based on independent review committee determination, and alectinib was associated with a 68% reduced risk for progression —again significant.

ORRs (independent review committee) were 36.1% and 11.4% for patients receiving alectinib and chemotherapy, respectively. The disease control rate (overall response rate + stable disease) was also significant for patients receiving alectinib: 80.6% vs 28.6% for patients receiving chemotherapy.

Adverse events occurred with a lower frequency in the alectinib group even though patients were taking alectinib for a longer time (20 weeks vs 6 weeks for chemotherapy).

When asked why patients in the chemotherapy group did poorly in the ALUR study compared with other studies, Dr Novella responded: "Most patients received chemotherapy as third-line therapy compared with other studies. Additionally, this is a small sample size for patients in thre chemotherapy arm [n = 35], and only 9 patients received pemetrexed while the others received docetaxel."

Summarizing the information from ALUR, Dr Paz-Ares noted that ALUR reconfirmed the benefits for alectinib in pretreated patients. "Was this trial needed?" he asked. He suggested that "in the era of genomic medicine, a change in the paradigm of developing new drugs is desired especially for targeted agents. Auditable academic registries may become more relevant."

"Patients with NSCLC have a high risk of CNS and brain metastases. These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care," Dr Blackhall said in a statement.

The ALEX and ALUR studies were funded by F. Hoffmann-LaRoche. Dr Novella is on the speaker bereau for Lilly, Bristol-Myers Squibb, MSD, AstraZeneca, and Roche. Dr Gadgeel is a consultant for Ariad, Pfizer, Genentech/Roche, Bristol-Myers Squibb, and AstraZeneca.  Dr Paz-Ares in on the scientific boards of Roche, MSD, Bristol-Myers Squibb, AstraZeneca, Lilly, Boehringer, Novartis, Abbvie, and Celgene.

European Society for Medical Oncology (ESMO) 2017 Congress. Presented September 11. Abstracts 1298O and 1299O.

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