Analyst Notes: Optimal sequencing becomes a critical goal in the treatment of ALK-positive advanced NSCLC

Targeting oncogenic driver mutations has proven a moving target in oncology as tumours frequently become resistant to first-line targeted therapy. The treatment of anaplastic lymphoma kinase (ALK)-translocation positive non-small-cell lung cancer (NSCLC) represents a case that exemplifies this scenario.

Until recently, Pfizer's Xalkori (crizotinib) was the only product specifically approved for the treatment of ALK-positive NSCLC. However, a second-line option became available with the US and EU clearance of Novartis' Zykadia (ceritinib) in April 2014 and May 2015, respectively. Close behind these forerunners is Roche's alectinib, which is currently being evaluated in Phase III trials as a therapy for treatment-naïve and previously treated advanced ALK-positive NSCLC. In addition, there are several other ALK inhibitors in early clinical development, including Pfizer's PF 6463922, ARIAD Pharmaceuticals' brigatinib and Xcovery/Betta Pharmaceuticals' X-396.

Newer-generation ALK inhibitors will have an important place in the treatment algorithm for ALK-positive NSCLC, as in almost all cases patients eventually acquire resistance to Xalkori through the development of secondary resistance mutations.

Insights, Analysis & Opinion

Leading key opinion leaders (KOLs) consulted for a new report published by FirstWord – NSCLC: KOL Insight – are optimistic regarding the potential of alectinib to provide a much needed third option for the treatment of ALK-positive NSCLC. However, the debate is still open regarding where it will be best placed within the treatment algorithm.

In the second-line, ALK-positive setting, KOLs consider alectinib to offer a similar level of efficacy as Zykadia, but without gastrointestinal toxicity. KOLs also have high expectations for the ongoing Phase III ALEX trial, which is comparing alectinib against Xalkori in 286 patients with treatment-naïve, ALK-positive, advanced NSCLC. The fact that brain activity will be accurately measured is considered a key strength of the study. Indeed, superior CNS efficacy is cited as a significant potential advantage of alectinib and Zykadia. The brain is one of the most common sites of cancer progression following treatment with Xalkori, making CNS activity a highly desirable attribute.

However, despite KOLs speculating that alectinib's benign toxicity profile and notable CNS activity compare favourably with Xalkori and Zykadia, it's also proffered that there may be no advantage to giving alectinib upfront rather than reserving it for treatment-resistant patients. As with Zykadia, while there are data demonstrating alectinib's efficacy after treatment with Xalkori, there is no such evidence for the use of Xalkori after second-generation ALK inhibitors.

"We treated a few patients with alectinib and it's clearly active in crizotinib failures and even ceritinib failures. In the future, it will be important to know if these newer ALK inhibitors are active after failure of one or multiple ALK inhibitors. The sequencing may be important. Can you start with one of these later generation inhibitors and then still have activity with crizotinib? These are all questions that need to be addressed. It will take some time." - US Key Opinion Leader

Indeed, as the NSCLC targeted treatment armamentarium becomes increasingly crowded, a driving narrative across multiple segments is discerning the optimal sequencing of therapies. There is little doubt that alectinib will have an important role to play, but until more sequencing data and real-world experience become available, the first-line opportunity may remain elusive.

For companies operating in the NSCLC market in Europe and the US, NSCLC: KOL Insight is a must read. The report gives actionable insights and commentary on some of the most critical issues in the NSCLC market, and provides perspectives on how marketed and pipeline drugs could fair in a market ripe for change. For more information, please click here.

To read more Analyst Notes articles, click here.