When Pfizer’s Xalkori transformed the treatment of Alk-positive lung cancer it kicked off development of numerous competing assets, and at this week’s World Conference on Lung Cancer the battle for this small market niche continued to play out.
Takeda, the private US biotech Xcovery and even Pfizer itself have all made strong cases for targeting patients who relapse on Xalkori. However, with Roche shortly expected to eat into Pfizer’s first-line stranglehold courtesy of Alecensa – a much better drug – the risk is that showing a benefit in Xalkori failures is about to become irrelevant.
One reason behind Alecensa’s perceived superiority is its ability to cross into the central nervous system – something Xalkori cannot do. This is very important because brain metastases are a major problem in Alk-mutated NSCLC; this is why results specifically in intracranial lesions are now a routine part of every data presentation.
Accordingly, at World Lung Pfizer presented an analysis of a phase II trial of its Xalkori follow-on asset lorlatinib, showing a 68% overall remission rate in 37 post-Xalkori subjects with intracranial lesions. Earlier, Xcovery had reported a 69% remission rate in a phase II study of 13 such patients given ensartinib (ELCC – Xcovery takes on industry giants, 8 May 2017).
Xcovery’s World Lung update concerned 15 Xalkori-naive subjects, three of whom had had intracranial lesions, and all of whom responded to ensartinib, the private group said.
And Takeda, whose Alunbrig was approved in April for patients progressing on or not responding to Xalkori, presented an update of its drug’s pivotal Alta trial; one cut of the data here showed a comparable 67% intracranial response rate in 18 subjects given 180mg, the higher of two Alunbrig doses tested.
This is all very well, but Alecensa itself has demonstrated a 61% CNS response rate in post-Xalkori patients. The Roche drug, approved second-line in 2015, thrashed Xalkori in its head-to-head first-line Alex study, and the US FDA is to decide by November 30 whether to expand its label to include this setting (Therapy focus – Roche looks ready to rule another cancer niche, March 6, 2017).
Approval seems a foregone conclusion. And unless the follow-on agents are tested in subjects who fail Alecensa – something that will take up precious time – they will chase the shrinking market of patients who are initially put on Xalkori. Another Alk inhibitor, Novartis’s Zykadia, already has a first-line label, though its CNS response rate seems lower, at 33%.
Sellside consensus reflects Xalkori’s diminishing importance: 2022 sales forecasts, as compiled by EvaluatePharma, have fallen from $854m in April 2016 to $561m currently. Alecensa’s, meanwhile, have crept up from $532m to $679m in the same period.
In terms of broader data presented at World Lung, lorlatinib showed remission rates of 90% in 30 Alk-naive patients, and 69% in 59 of those who had not responded to Xalkori. The Pfizer follow-on has US breakthrough designation, and the company said it would discuss the new data with the FDA.
Takeda, meanwhile, is turning the focus towards the 180mg Alunbrig dose, which in Alta, a two-arm study, numerically beat 90mg in terms of remission rate (55% versus 46%) and progression-free survival (15.6 months versus 9.2 months). Alunbrig’s approved dose is 90mg daily, with an increase to 180mg “if tolerated”.
Alunbrig’s own first-line Alta-1L trial versus Xalkori will not read out until 2019. By then, of course, Xalkori might no longer be the drug to beat.
|Selected next-generation Alk inhibitor trials|
|Alunbrig||Takeda||Alta||NCT02094573||PFS data comparing 180mg vs 90mg presented at World Lung|
|Alunbrig||Takeda||Alta-1L||NCT02737501||1st-line, vs Xalkori; data due Apr 2019|
|Lorlatinib||Pfizer||Phase II||NCT01970865||ORR data in Alk-naive & post Xalkori pts presented at World Lung|
|Lorlatinib||Pfizer||Phase III||NCT03052608||1st-line, vs Xalkori; data due Feb 2020|
|Ensartinib||Xcovery||Phase I/II||NCT01625234||Data in Xalkori-naive pts presented at World Lung|
|Ensartinib||Xcovery||Exalt3||NCT02767804||1st-line, vs Xalkori; data due Apr 2020|