In a closely watched competition among KRAS inhibitors, Amgen leads the pack with a randomized trial win in lung cancer. Now, the California drugmaker is giving a first look at the detailed data that could set the bar for all others to come, including Mirati Therapeutics, Roche and Novartis.
Amgen’s Lumakras cut the risk of disease progression or death by 34% compared with the chemotherapy docetaxel in previously treated KRAS G12C-mutated non-small cell lung cancer, according to an abstract released at the European Society for Medical Oncology congress 2022. Lumakras is currently the only FDA-approved. KRAS inhibitor.
At one year, 24.8% of Lumakras takers were alive and did not show any disease worsening, versus 10.1% for docetaxel.
But when it comes to the exact time patients went without disease progression, Lumakras’ performance looks relatively weak. Lumakras only added an extra 1.1 months to patients’ progression-free survival time to a median 5.6 months. That came below the 6.3 months Lumakras had shown in the phase 1/2 CodeBreaK 100 trial that earned its landmark FDA accelerated approval last year. Based on historical data, industry watchers were largely expecting to see a two-month difference between the two treatment arms.
Lumakras’ tumor response rate also appeared to be lower in the new trial than in the early-stage study. In CodeBreaK 200, Lumakras shrank tumors in 28.1% of patients. While that was significantly better than docetaxel’s 13.2%, it came below Lumakras’ own 36% showing in CodeBreaK 100.
Patients in the two studies were slightly different, Jean-Charles Soria, M.D., Ph.D., Amgen’s senior vice president of oncology global development, noted in an interview with Fierce Pharma ahead of the data release. In the phase 3, all patients had previously tried immunotherapy, whereas only 70% in the phase 1/2 had taken such a treatment. Patients in the phase 3 likely had heavier disease burden, he said.
It’s not surprising to see a decline in the efficacy markers as a drug moves from a single-arm trial in a select population to a large, randomized phase 3 trial, study lead author Melissa Johnson, M.D., of Sarah Cannon Research Institute said during a press briefing on Monday. She also noted that the phase 1/2 study was enrolled largely in the U.S., while CodeBreaK 200 was a global trial with representation all over the world.
On whether Lumakras improved how long patients could live, there wasn’t a significant difference between the two treatment arms.
CodeBreaK 200 wasn’t powered for a survival analysis, however, Soria pointed out. Plus, Amgen cut enrollment in the study after discussions with the FDA raised ethical concerns of exposing too many patients to docetaxel when Lumakras had posted strong data in the phase 1/2 CodeBreaK 100 trial, thereby lowering its possibility of showing a definite patient survival signal, both Soria and Johnson noted.
To be fair, industry watchers weren’t really focused on the survival marker because subsequent treatments could muddy the effect. In CodeBreaK 200’s docetaxel group, 34% of patients actually went on to receive Lumakras after disease progression.
Besides calling the 34% progression-free survival benefit “meaningful”, Soria also pointed to Lumakras’ better safety profile as important. In CodeBreaK 200, serious side effects happened in 10.7% of patients, much lower than the 22.5% seen in the chemo group.
Liver enzyme elevation remains a problem for Lumakras, with Grade 3 or above ALT and AST increases appearing in 7.7% and 5.3% of patients, respectively.
Johnson highlighted that Lumakras’ progression-free survival benefit showed up early and was seen over the course of the trial.
Other than being the first randomized study of a KRAS inhibitor, CodeBreaK 200 also has the potential to block Mirati’s accelerated approval path for its rival drug, adagrasib.
Mirati is awaiting an FDA decision by Dec. 14. If the FDA converts Lumakras’ accelerated approval into a full nod before deciding on adagrasib’s application, then the Mirati drug won’t be eligible for an accelerated approval based on tumor shrinkage data.
Amgen is “in formal interactions with the FDA,” Soria said. He wouldn’t offer a timeline for a potential approval, reverting that to the FDA.
The CodeBreaK 200 results “leave room for efficacy differentiation for Mirati’s adagrasib, as well as provide some de-risking of the adagrasib phase 3 trial […] given that the apparent lowered efficacy of Lumakras in in its phase 3 trial still demonstrated superiority over docetaxel,” SVB Securities analysts wrote in a Monday note to clients.
Meanwhile, Amgen and Mirati are also battling it out in a new frontier—colorectal cancer—but in that arena so far, Amgen is falling behind.
Updated data from the phase 1b CodeBreaK 101 trial showed Lumakras’ combination with Amgen’s EGFR inhibitor Vectibix shrank tumors in 30% of KRAS G12C-mutated colorectal cancer, the company showed at ESMO congress 2022.
In comparison, Mirati’s adagrasib, used in tandem with Eli Lilly’s EGFR inhibitor Erbitux, reported a 46% response rate in colorectal cancer, according to the new data from the Krystal-1 trial released at the ESMO meeting.
Mirati’s results appear even better considering patients in adagrasib’s trial had tried a median three prior lines of therapy, whereas Lumakras’ study only had a median two lines.
But these early-stage data should be viewed with caution as they were generated from a small number of patients. Mirati’s data involved 28 patients, and Amgen’s 40.
The “real picture,” as Soria put it, will come from large phase 3 trials with a few hundred patients. Amgen’s phase 3 CodeBreaK 300 trial is now testing the same Lumakras-Vectibix pairing against either Bayer’s Stivarga or Taiho Pharma’s Lonsurf in second-line KRAS-mutated colorectal cancer. Mirati is conducting a phase 3 dubbed Krystal-10 also in the second-line setting.
Editor's Note: The story has been updated Sept. 12 at 10:30 am with more detailed data from CodeBreaK 200 as they are presented at ESMO congress 2022.