The second time is the charm for Amgen, as it received full approval from the US Food and Drug Administration (FDA) for Lumakras (sotorasib) and Vectibix (panitumumab) combination therapy for the treatment of KRAS G12C-mutated metastatic colorectal cancer (mCRC).

The US regulatory agency approved the therapy in patients who have received prior fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy. In June 2021, the FDA granted accelerated approval to the combination therapy in the same indication.

In 2023, Amgen’s bid to secure full US FDA approval for the Lumakras and Vectibix combo in the mCRC indication failed after the regulatory agency’s Oncologic Drugs Advisory Committee voted against approving the therapies. In a 10-2 vote, the committee noted that the progression-free survival (PFS) data from the confirmatory Phase III CodeBreaK 200 trial (NCT04303780) “could not be reliably interpreted”.

The current approval was based on the data from a second Phase III CodeBreaK 300 trial (NCT05198934). The open-label, active-control study evaluated 160 participants with chemorefractory KRAS G12C-mutated mCRC.

The median progression-free survival (PFS) in the Lumakras (960mg) and Vectibix combination group was 5.6 months, compared to a median PFS of 2 months seen in the patients who received the investigator’s choice of care (active control). The improved overall response rate (ORR) of 26% was reported in the Lumakras and Vectibix combination group, compared to a 0% ORR in the active control arm.

Amgen also noted that the PFS of the low-dose Lumakras (240mg) and Vectibix combination group was not statistically significant compared to the active control group.

The most commonly reported adverse event was rash followed by gastrointestinal adverse reactions and musculoskeletal pain.

The overall survival question remains

 Although, the most serious concern raised by the 2023 Advisory Committee was “multiple sources of systemic bias” in CodeBreaK 200. Pointing to a “much higher rate” of study dropouts in the docetaxel comparator group in comparison to the Lumakras combination group along with an early crossover from the docetaxel to Lumakras group, even before disease progression had been assessed.

The committee’s external panelists did note that there was no significant difference in overall survival (OS), which Amgen noted that the CodeBreaK200 was not statistically powered for. In the CodeBreaK 300 trial, Amgen again stated that the “final analysis of OS was not statistically significant, adding that the study was not statistically powered for OS.

While the OS difference was not observed, there is a need for therapies for mCRC. As per the World Health Organization (WHO), CRC is the third most prevalent cancer worldwide, accounting for approximately 10% of all cancer cases. A 2023 study estimates the prevalence of KRAS G12C mutation in 3% of patients with CRC.

Furthermore, Lumakras is a high-grossing drug for Amgen. It is also approved by the US FDA as a second-line treatment for KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). The US regulatory agency granted accelerated approval to the therapy in NSCLC in 2021. Amgen reported $53m in US sales in the third quarter of 2024, raking in $98m in worldwide sales, as per the company’s financials. Amgen also noted that it represented an 88% year-over-year growth in sales for Lumakras.