Novartis sets Alk inhibitors a high bar


Just as the success of Pfizer’s Xalkori in Alk-positive non-small cell lung cancer emboldened numerous other companies to pursue this target, publication of phase I data for Novartis’s ceritinib looks set to cause the window of opportunity to slam shut.

In any case it might be surprising how much interest there is in a genetic mutation that accounts for barely 5% of all NSCLC patients, but then any success in a disease as intractable as lung cancer is bound to focus minds. The question for competitors now is how much room to manoeuvre the Novartis data have left them (see table below).

True, the Swiss firm’s latest results come from a single-arm phase I trial in just 144 patients. But the effect ceritinib has shown in what is a very advanced stage of NSCLC, in patients who had already failed on Xalkori, looks extremely encouraging.

Overall, a 58% response rate was seen, results published in the New England Journal of Medicine show, and median progression-free survival (PFS) reached seven months. Novartis said this was particularly encouraging since patients tend to relapse within a year of starting on Xalkori, and have limited subsequent treatment options.

Responses to ceritinib were seen in untreated regions of the CNS, it said. Bryan Garnier analysts pointed to the molecule’s ability to cross the blood-brain barrier – an important difference versus Xalkori, and one that could open new possibilities in a disease with frequent brain metastases.

Xalkori was approved in 2011, along with a companion diagnostic, for second-line treatment of NSCLC patients with the Alk gene mutation. Ceritinib was filed in the US this year, and has FDA breakthrough therapy designation for Alk-positive patients who have progressed on or are intolerant to Xalkori.

Given the speed with which the FDA has waved through some projects with this designation, approval in the next couple of months is a possibility for ceritinib – and might be a little-appreciated fact given the low-key way in which Novartis disclosed the regulatory submission, in a paragraph buried in its year-end report.

Hotting up

While this therapy area might seem like an obscure niche, Xalkori sold $282m last year, and consensus sellside data compiled by EvaluatePharma see 2018 revenue reaching $788m. Ceritinib is expected to sell $236m in 2018.

And competition is hotting up. Novartis is trying to steal Pfizer’s thunder, running phase III trials in Xalkori-naive patients in addition to a pivotal programme in Xalkori failures; the latter would presumably supplement a conditional approval.

Pfizer itself is trying to move Xalkori upstream in NSCLC treatment, and earlier this week reported results of the phase III Profile 1014 trial in first-line Alk-positive patients. It said PFS was significantly prolonged in this population, and Bryan Garnier said its indication was thus likely to be extended to first line.

The question must now be how much room, if any, these results leave for competing Alk inhibitors further behind in development. 

Alk inhibitors in NSCLC and beyond
Project Pharmacology class Company 2018e sales ($m) Trial ID Note
Xalkori  Alk & c-Met kinase inhibitor Pfizer 788 NCT01154140 Approved for 2nd-line Alk-positive NSCLC
Ceritinib (LDK378) Alk inhibitor Novartis 236 NCT01828099; NCT01828112 US breakthough therapy designation
Alectinib (RG7853) Alk inhibitor Roche 40 NCT02075840 Filed in Japan on phase I/II trial
Phase II
AP26113 Alk & EGFR kinase inhibitor Ariad Pharmaceuticals 28 NCT02094573 Phase II trial started Mar 2014 
PF-06463922 Alk & Ros1 kinase inhibitor Pfizer - NCT01970865 NSCLC with Alk or Ros1 mutation
TSR-011 Alk & TRK inhibitor Tesaro - NCT02048488 Solid tumours and lymphoma
PF-03446962 Anti-Alk-1 MAb Pfizer - NCT01911273 Hepatocellular cancer
RXDX-101 TRK-A/Ros1/Alk inhibitor Ignyta - None listed Company says phase I/II trial ongoing
Phase I
ASP3026 Alk inhibitor Astellas Pharma - NCT01401504 Solid tumours
X-396 Alk inhibitor Xcovery - NCT01625234 Advanced solid tumours

One of the most serious contenders must be Roche’s alectinib. This was filed for approval in Japan last October on the strength of a local phase I/II trial and before phase III data were available. A 286-patient phase III study versus Xalkori should start enrolling in July.

One trial that started recently involves AP26113, a compound under development by the troubled US biotech Ariad Pharmaceuticals. This phase II study, codenamed Alta, plans to recruit 218 post-Xalkori patients, but one has to wonder how much of a market will remain for Ariad once this yields data in 2017.

Pfizer itself has a Xalkori follow-up, PF-06463922, which inhibits Ros1 as well as Alk, and is developing an anti-Alk antibody, PF-03446962. But it is telling that the latter is not in trials for NSCLC, and neither are several other Alk inhibitors, such as Tesaro’s TSR-011.

Perhaps the penny has dropped: the Alk-positive NSCLC space is too small for more than a couple of players, and follow-on competitors will struggle to identify any available patients that are not already treatable with Xalkori or ceritinib.

Given that Xalkori looks set to be used in first-line patients, and ceritinib might – at worst – treat those who fail on it, Pfizer and Novartis look to have this market sewn up. 

To contact the writers of this story email Jacob Plieth or Amy Brown in London at or follow @JacobEPVantage and @AmyEPVantage on Twitter

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