ASCO24: Amgen's Lumakras combo boosts OS prospects in mCRC

A combination therapy involving Amgen's KRAS G12C inhibitor Lumakras (sotorasib) and the EGFR antibody Vectibix (panitumumab) has demonstrated a promising overall survival (OS) trend in patients with chemorefractory metastatic colorectal cancer (mCRC) harboring the KRAS G12C mutation. This is according to new data presented at the American Society of Clinical Oncology (ASCO) annual meeting. The findings were part of the final OS analysis from the Phase III CodeBreaK 300 trial, which had already achieved its primary endpoint of improving progression-free survival (PFS) at both tested doses of Lumakras as compared to the investigator's choice of therapy. These PFS results were initially shared at the European Society for Medical Oncology (ESMO) conference last December.

The study enrolled 160 patients who were randomly assigned to receive Lumakras at dosages of either 960mg or 240mg combined with Vectibix. The control group received the investigator's choice of treatment, which included trifluridine/tipiracil or Bayer's Stivarga (regorafenib).

However, the trial was not designed to demonstrate a statistically significant OS benefit. As of the December 18 cut-off date, 82 deaths had occurred after a median follow-up of 13.6 months. Specifically, there were 24 deaths in the 960mg Lumakras group, 28 in the 240mg group, and 30 in the investigator's choice group. Median OS had not been reached for the 960mg Lumakras dose but was 11.9 months for the 240mg dose and 10.3 months for those who received the investigator's choice of therapy. The hazard ratios for OS were 0.70 for the 960mg dose and 0.83 for the 240mg dose when compared to the control group, indicating a trend toward improved OS for the Lumakras combinations.

Additional efficacy data revealed a 30.2% objective response rate (ORR) for the higher Lumakras dose combination, which included one complete response (CR) and 15 partial responses (PRs). The median duration of response in this group was 10.1 months, and the disease control rate was highest at 71.7% with the 960mg combination. For the lower dose, there was 1 CR and 3 PRs, while the investigator's choice group saw only 1 PR.

Amgen's decision to continue with the higher 960mg dose of Lumakras for its approved labeling has been met with criticism, notably from US Senator Richard Durbin. He has accused the company of prioritizing profits over patient welfare and ignoring concerns regarding severe side effects. Despite this, Amgen is steadfast in its support for the higher dosage. The company pointed out that data from multiple clinical trials across different cancer types, along with real-world evidence, validate the benefits of the 960mg dose for patients with lung cancer.

Lumakras received accelerated approval from the FDA in 2021 for treating KRAS-mutated non-small-cell lung cancer (NSCLC). Nonetheless, a recent bid by Amgen for full approval was rejected by the agency. In response to the criticism, Amgen reiterated its confidence in the efficacy of the higher dose, citing extensive clinical trial data and real-world usage as supportive evidence.

The CodeBreaK 300 trial's results add to the growing body of evidence suggesting that the Lumakras and Vectibix combination could offer a new therapeutic option for patients with KRAS G12C-mutated mCRC who have exhausted other treatment options.