NEW YORK – Follow-up data from the Phase I/II CodeBreak-100 trial showed that some non-small cell lung cancer patients with KRAS G12C mutations had durable responses to Amgen's Lumakras (sotorasib), and 32.5 percent of patients in the study were alive after two years.
The longer follow-up data, presented at the American Association for Cancer Research's annual meeting on Sunday, included results from more patients than the initial readout that led to Lumakras' accelerated approval in the US last year.
Initial data from CodeBreak-100, presented in June 2021, had a median follow-up of 15 months. The results presented at AACR this week had a median follow-up of 25 months and are the longest follow-up data reported for any KRAS G12C inhibitor, said Grace Dy, chief of thoracic oncology at Roswell Park Comprehensive Cancer Center, during a presentation at the meeting.
The data included results from 174 patients with locally advanced or metastatic NSCLC whose tumors harbored a KRAS G12C mutation and who had received prior systemic therapy. For this readout, the researchers combined the previously reported Phase II data with data from patients in the Phase I portion of the study who received the recommended Phase II dose.
In the pooled analysis, the objective response rate was 40.7 percent, a slight increase from the previously reported data that showed a 38 percent response rate. Among responders, the median duration of response was 12.3 months.
The median progression-free survival was 6.3 months and median overall survival was 12.5 months, both similar to the previous data readout. The one-year overall survival rate was 50.8 percent, and the two-year survival rate was 32.5 percent.
The two-year survival rate "is certainly highly encouraging and sets the benchmark for expectations on the upcoming readout from the confirmatory CodeBreak-200 Phase III trial," Dy said, noting that when patients in this setting receive docetaxel, the two-year survival rate is between 9 percent and 16 percent.
In the Phase III CodeBreak-200 trial, researchers are comparing Lumakras to docetaxel also in KRAS G12C-mutated advanced NSCLC patients. The researchers expect data from that trial to be presented later this year.
In an additional biomarker analysis of CodeBreak-100, the researchers found that long-term responses of greater than 12 months were observed across PD-L1 expression levels. Because of this benefit, the researchers suggested that Lumakras could be an alternative to checkpoint inhibitors in NSCLC patients with low PD-L1 expression who are less likely to benefit from the immunotherapy.
The prolonged clinical benefit on Lumakras was also observed in patients regardless of STK11 co-mutation status. However, patients with a co-occurring KEAP1 mutation were less likely to see a long-term benefit compared to KEAP1 wild-type patients.
Patients with both high and low tumor mutation burden responded to Lumakras in the trial. However, lower plasma circulating tumor DNA at baseline was associated with long-term benefit from the KRAS inhibitor. Dy noted that tumor mutation burden could be used to select patients for monotherapy treatment with Lumakras, however, predictive biomarkers for the drug and its combination approaches need to be studied further.
In a discussion of the CodeBreak-100 results at the meeting, Mark Awad, clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, said that these results represent "significant headway" in the treatment of KRAS-mutant lung cancer. However, he noted that the response rates and duration of progression-free survival of KRAS inhibitors like Lumakras and Mirati's adagrasib remain lower than other classes of drugs, and the rapid onset of acquired resistance presents a challenge for this drug class.
"With adagrasib seeing a comparable response rate of about 45 percent, roughly on par with what we've seen for sotorasib, this raises the question: are we hitting the therapeutic ceiling with G12C inhibitor monotherapy?" Awad wondered.
Combination approaches offer a way to overcome resistance. In fact, Amgen is evaluating several combinations with Lumakras to potentially overcome resistance to KRAS G12C inhibition. In NSCLC, Amgen is evaluating Lumakras with its EGFR inhibiting monoclonal antibody Vectibix (panitumumab) in a Phase I study, and with Verastem Oncology's RAF/MEK inhibitor VS-6766 in a Phase I/II trial.
The company is also eager to expand Lumakras' use to other KRAS G12C-mutant cancers. Last year, Amgen pivoted to Lumakras-based combination regimens in colorectal cancer after results from a colorectal cancer cohort in the CodeBreak-100 study showed limited efficacy with Lumakras monotherapy. An earlier combination study of Lumakras and EGFR inhibitor Vectibix in advanced, KRAS G12C-mutant colorectal cancer showed a 27 percent response rate. In February, Amgen also expanded enrollment in a cohort involving KRAS G12C-mutant advanced pancreatic cancer patients in CodeBreak-100 after initial data showed a 21 percent response rate on Lumakras monotherapy.
Awad also suggested looking for biomarkers to better select patients for KRAS inhibitors, such as low tumor mutation burden, which was associated with better response in the CodeBreak-100 biomarker analysis. He also suggested biomarkers like PD-L1 expression, tumor infiltrating lymphocyte levels, and STK11 mutations could help select patients for KRAS inhibitors versus immunotherapy or chemotherapy.
The CodeBreak-100 biomarker analysis scratched the surface of some of these potential predictive biomarkers for KRAS G12C inhibition. Awad noted that the analysis suggesting that Lumakras was less effective in KEAP1-mutant patients versus KEAP1 wild type needs further study in a larger cohort to determine if KEAP1 mutation status can be a predictive biomarker.
"G12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other tumor types as well, but the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and emergence of complex resistance mechanisms," Awad said. "We will therefore need new approaches to delay drug resistance and choose targeted therapies that are most effective for our patients."