Alectinib Represents Promising Frontline Option for ALK-Positive NSCLC

Tony S. K. Mok, MD, BMSc, FRCPC

Tony S. K. Mok, MD, BMSc, FRCPC

Second-generation ALK inhibitor alectinib (Alecensa) has demonstrated promising activity and tolerability as treatment of patients withALK-positive non—small cell lung cancer (NSCLC), according to findings from the phase III ALEX trial (NCT02075840).

The median progression-free survival (PFS) in the intention-to-treat population was 34.8 months with alectinib versus 10.9 months in the crizotinib (Xalkori) arm. In patients with baseline central nervous system (CNS) metastases, the median PFS was 27.7 months versus 7.4 months with alectinib versus crizotinib, and 34.8 months versus 14.7 months in patients without baseline CNS metastases, respectively (HR, 0.35; 95% CI, 0.22-0.56). For patients without baseline CNS metastases, the median PFS was 34.8 months in the alectinib arm versus 14.7 months in the crizotinib arm (HR, 0.47; 95% CI, 0.32-0.71).

The overall response rate was 82.9% in the alectinib arm versus 75.5% in the crizotinib arm. Overall survival (OS) data were still not mature at the time of analysis.

The safety of alectinib was also comparable to that of crizotinib. Overall, 44.7% of patients in the alectinib arm and 51.0% in the crizotinib arm experienced grade 3 to 5 adverse events (AEs). There were also fewer fatal AEs in the alectinib arm than the crizotinib arm,3.9% versus 4.6%, respectively.Fewer AEs related to alectinib led to dose reductions (16.4%) compared with crizotinib (20.5%).

In an interview withTargeted Oncology, Tony S. K. Mok, MD, BMSc, FRCPC, chairman, Department of Clinical Oncology, Li Shu Fan Professor of Clinical Oncology, The Chinese University of Hong Kong, discussed the final PFS data for frontline alectinib comparted with crizotinib as treatment of patients with advancedALK-positive NSCLC in the ALEX trial. He also highlighted the OS data and provided an update on the safety of alectinib in this patient population.

TARGETED ONCOLOGY: What was the rationale for the ALEX trial?

Mok:The ALEX study is 1 of 3 randomized phase III studies that compare alectinib, which is a second-generation tyrosine kinase inhibitor (TKI) forALK-positive lung cancer, versus the prior standard of crizotinib. In this study, the aim is to look into the differences of PFS between alectinib and crizotinib.

TARGETED ONCOLOGY: What were the PFS data for alectinib compared with crizotinib?

Mok:The initial data that were first published in theNew England Journal of Medicinewas actually not reached in the alectinib arm compared to around 10 months in the crizotinib arm. In this updated data, the median PFS of about 34.8 months versus about 11 months in the crizotinib arm

TARGETED ONCOLOGY: What does the OS look like now?

Mok:The OS of the ALEX study has not yet beenreached. However, we managed to look into the 4-year OS rate, meaning the proportion of patients who are still alive after 4 years. It turned out to be 62.5% with alectinib and about 52% for the crizotinib arm.

TARGETED ONCOLOGY: What makes alectinib unique compared with earlier generation agents?

Mok:This is a second-generation drug, and there are  2 properties that make this agent unique. First, it is able to counteract some of the resistance mutations, and second is the fact that it has high CNS penetration. In fact, in the first of the randomized studies, we are able to document the so-called CNS progression. In about 1 year, about 40% of patients in the crizotinib arm had progressed in the brain as compared to only 9.1% of the patients with alectinib.

TARGETED ONCOLOGY: Did alectinib show consistent safety data in this analysis?

Mok:The safety data of alectinib was compared with crizotinib, and there is no exceeding point of concern. Alectinib had some hepatic toxicity. The incidence of cardiotoxicity is low, and also there is some edema, so compared to crizotinib, there is no significant difference.

TARGETED ONCOLOGY: Are there any implications from these data?

Mok:Based on the original ALEX data published in theNew England Journal of Medicine, we basically demonstrated an improvement in the PFS, and over the past 2 years, we have seen a significant proportion of patients have been using alectinib as a first-line therapy. With the update from the 2019 European Society of Medical Oncology (ESMO) Annual Meeting, this has confirmed its use [in the frontline space]

TARGETED ONCOLOGY: How do brigatinib and ceritinib compare with these data?

Mok:Brigatinib (Alunbrig) had also been compared with crizotinib in a first-line study. It demonstrated a significant improvement in PFS. Certainly, brigatinib is 1 of the choices for first-line therapy. However, we cannot say whether alectinib or brigatinib is better because there is not head to head comparison between the 2. Either brigatinib or alectinib can be used as frontline therapy.

As for ceritinib (Zykadia), it had only been compared to chemotherapy in the ASCEND-4 (NCT01828099) study. In this particular study, the median PFS was about 16 months, or a little bit longer. This is certainly better than chemotherapy. However, the drug is associated with some GI toxicity. It is an option, but it may not be the most favorable option.

TARGETED ONCOLOGY: Where does lorlatinib fit into the treatment landscape?

Mok:Lorlatinib (Lorbrena) is a third-generation TKI againstALK. The drug itself is actually a potent drug, and a randomized phase III study is being conducted now. Hopefully within the next year or 2, we will have that answer. In a sense, lorlatinib has the potential benefit of more potent CNS penetration. However, the most optimal sequence of first- and second-generation agents remains unknown. I am looking forward to the data from this phase III study, and we will adjust at that time.

TARGETED ONCOLOGY: How can we anticipate treatment evolving in theALKspace?

Mok:Right now, we have a total of about 5 different agents that have been approved; crizotinib, brigatinib, ceritinib, alectinib, and lorlatinib [are approved] as second-line therapy. In the near future, there is also ensartinib, which is going to come out in a randomizedstudy.

In this space, I think we will still encounter the question of the optimal sequencing, but more importantly, we must address how we deal with resistance. In thefuture, we will probably have to tailor the treatment paradigm according to the different patterns of resistance.br />

Reference:

Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small-cell lung cancer in the global phase III ALEX study.J Thorac Oncol.2019;14(7):1233-1243. doi: 10.1016/j.jtho.2019.03.007.