NEW YORK – Amgen is taking data from the CodeBreaK 300 trial to regulators to discuss the potential of its KRAS inhibitor Lumakras (sotorasib) plus its EGFR-inhibiting monoclonal antibody Vectibix (panitumumab) to be a new combination treatment option for patients with KRAS G12C-mutant metastatic colorectal cancer.
At the European Society for Medical Oncology Congress earlier this week, researchers reported that Lumakras-Vectibix improved outcomes in this Phase III trial over investigators' choice of two standard-of-care treatments, Taiho Oncology's chemotherapy Lonsurf (trifluridine and tipiracil) or Bayer's multi-kinase inhibitor Stivarga (regorafenib). The trial also explored two dosages of Lumakras, 960 mg and 240 mg. The results were simultaneously published in the New England Journal of Medicine.
In 160 patients in CodeBreaK 300, the median progression-free survival was 5.6 months for those on the higher Lumakras dose plus Vectibix, 3.9 months in the lower Lumakras dosage arm plus Vectibix, and 2.2 months on investigators' choice of treatment. Overall survival data were not mature at the time of data analysis.
The 960 mg Lumakras-Vectibix combination yielded a response rate of 26 percent, with one complete response; 6 percent responded in the lower-dose arm; and no one responded in the control arm. The disease control rate in the high-dose Lumakras arm was 72 percent, compared to 68 percent in the lower-dose arm and 46 percent in the control arm.
Filippo Pietrantonio, a gastrointestinal medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori in Italy, said in a presentation of the CodeBreaK 300 results at the meeting that the 960 mg Lumakras dose with Vectibix demonstrated a "more clinically meaningful benefit," and this data, together with results from studies of Lumakras in non-small cell lung cancer, support using the 960 mg dose in this setting.
"Sotorasib 960 mg plus panitumumab is a potential new standard-of-care therapy for patients with previously treated KRAS G12C-mutated metastatic colorectal cancer," Pietrantonio said.
Vectibix is contraindicated in colorectal cancer patients with RAS mutations in exons 2, 3, and 4. About 3 percent of colorectal cancer patients have KRAS G12C-mutated tumors, which occur in exon 2 and are associated with poor prognosis. However, when Vectibix is combined with a KRAS inhibitor like Lumakras, it appears to overcome tumor resistance in patients with KRAS G12C mutations, as seen in CodeBreaK 300 and in the earlier Phase Ib CodeBreaK 101 trial.
In terms of safety, unlike when Lumakras is paired with chemo or immunotherapy, the Lumakras-Vectibix combination appears more tolerable. About one-third of patients experienced a grade 3 or higher adverse event in both Lumakras-Vectibix arms, compared to 43 percent on investigators' choice of treatment. In the higher-dose Lumakras arm, three patients needed to have their Lumakras dose reduced, while seven patients had a dose reduction for Vectibix.
"In the experimental arms, panitumumab was the main driver of dose reductions and dose delays," Pietrantonio said.
In a discussion of the CodeBreaK 300 results, Miriam Koopman, a professor of medical oncology at the University Medical Center Utrecht in the Netherlands, noted that the results from the study were promising, but maintained that overall survival remains the most important endpoint, even in this late-line setting.
"There are many arguments against the use of progression-free survival in cancer trials, especially in a late-line trial in which there is no risk of imbalances in salvage treatments," Koopman said. "The improvement of progression-free survival alone is not enough in the late-line metastatic setting. We really need the overall survival data."
She concluded that overall survival and quality of life data will determine whether Lumakras-Vectibix becomes the standard last-line treatment for KRAS G12C-mutated colorectal cancer patients.
In a call with investors on Tuesday to discuss the data from ESMO, Jean-Charles Soria, senior VP of R&D at Amgen, said the firm plans to discuss the CodeBreaK 300 data with regulators. Soria also noted that Amgen will initiate a Phase III study of Lumakras in the front-line setting in KRAS G12C-mutant colorectal cancer.
This positive readout comes as Amgen is aiming to convert the accelerated approval of single-agent Lumakras to full approval in previously treated, locally advanced, or metastatic KRAS G12C-mutant NSCLC. Last month, an expert panel convened by the US Food and Drug Administration said data supporting the potential full approval of Lumakras in NSCLC could not be reliably interpreted due to potential bias in the CodeBreaK 200 trial. The FDA is expected to decide whether to grant full approval to Lumakras in NSCLC by Dec. 24.
In the competitive and crowded KRAS inhibitor space, Amgen is still in the lead when it comes to regulatory submissions for KRAS-mutant cancers, though other firms are not far behind. Lumakras competitor Mirati Therapeutics' Krazati (adagrasib) is undergoing testing in a Phase III study with Eli Lilly's EGFR inhibitor Erbitux (cetuximab) in KRAS G12C-mutant metastatic colorectal cancer. At ESMO, other companies also presented data on the activity of their investigational KRAS in colorectal cancer. For example, Jacobio Pharma shared data on its KRAS G12C-SHP2 combination, InventisBio reported on its KRAS-EGFR combination, and Jiangsu HengRui Medicine presented on its G12D inhibitor in this setting.