The biggest concerns from the potentially confirmatory Codebreak-200 trial are a disappointing median progression-free survival benefit, overall survival favouring docetaxel, and two cases of drug-induced liver injury on top of the liver enzyme elevations already disclosed. Individually each might be allayed, but taken together they boost Mirati, whose investors will see fresh doubts about Lumakras’s full approvability.
Full lung cancer approval will be down to the FDA, which will now scrutinise Codebreak-200. Mirati’s rival Kras inhibitor adagrasib faces a December 14 Pdufa date, and depending on timelines full Lumakras approval risks jeopardising Mirati’s chances of obtaining an accelerated green light for adagrasib.
For Codebreak-200’s lead investigator, Dr Melisa Johnson from the Sarah Cannon Research Institute at Tennessee Oncology, this was a highly positive study. “It supports [Lumakras] as a new second-line standard for patients with Kras G12C NSCLC,” she told an Esmo press conference this morning.
Others were not so sure. Another lung cancer doctor, City of Hope’s Dr Jack West, tweeted in light of the abstract that hepatotoxicity concerns and lack of an OS benefit were disappointing given the cost difference between Lumakras and docetaxel, $18,000 versus about $2,000 a month respectively. He also questioned whether docetaxel represented a real comparator, and said few doctors gave this chemotherapy with enthusiasm.
Missing
It is noteworthy that Esmo, having first gone out of its way to let Amgen to present Codebreak-200 as a late-breaker, then allowed an abstract to be published that omitted vital aspects of the data and painted the result in a better light than became evident at today’s full presentation.
Perhaps the biggest red flag is liver toxicity. The abstract had revealed a slightly higher rate of grade 3 or higher ALT elevation versus the earlier Codebreak-100 trial, but today it was disclosed that six patients quit treatment because of this, and another two discontinued owing to drug-induced liver injury.
How close is Hy’s law, the rule suggesting that patients are at high risk of fatal drug-induced liver injury, to being triggered, Evaluate Vantage asked during the press conference? “Not close,” Dr Johnson replied. “The safety signal was pretty similar between [Codebreak-200 and Codebreak-100]. It was amenable to dose reduction.”
It also cannot be denied that docetaxel is fairly toxic, explaining doctors’ reluctance to use it and desire to find something better. The rates of all severe and serious toxicities in Codebreak-200 were higher for the chemo than for Lumakras, though liver enzyme elevation is not an issue for docetaxel.
