After Amgen's stumble, BMS touts KRAS confirmatory trial win for newly bought Krazati

Bristol Myers Squibb looks on track to overtake Amgen as the KRAS leader in lung cancer after following up its rival’s FDA setback with a positive confirmatory trial readout.

BMS’ Krazati significantly reduced the risk of tumor progression or death compared with chemotherapy in patients with pretreated KRAS G12C-mutated non-small cell lung cancer (NSCLC), the company said Thursday. The KRAS inhibitor came to the New Jersey pharma as part of its recent acquisition of Mirati Therapeutics.

The assessment was made by a blinded central review committee of the pivotal phase 3 KRYSTAL-12 study, which serves as the confirmatory trial for Krazati’s accelerated approval as a second-line therapy. BMS said it’s finishing a full evaluation of the data and will share results with regulators.

Besides declaring that the trial met its primary endpoint of progression-free survival, the independent data reviewers noted that Krazati was better than chemo at shrinking tumors, which was one of the trial’s secondary endpoints. The improvements on both endpoints were statistically significant and clinically meaningful, according to BMS.

The trial remains ongoing to evaluate whether Krazati can extend patients’ lives. BMS didn’t specify which direction Krazati’s survival outcomes are trending right now. Progression-free survival has typically been an approval-worthy endpoint in second-line NSCLC, unless there’s a negative trend in overall survival.

As for Amgen, the California drugmaker recently applied for full approval of its first-to-market KRAS inhibitor, Lumakras, based on progression-free survival data from the phase 3 CodeBreaK 200 trial. The study would have served its purpose had it been done properly. But the FDA figured its results couldn’t be reliably interpreted, and a group of external advisers agreed.

The agency and its advisory committee experts voiced concerns about disproportionate patient dropout rates between the two trial arms in Lumakras’ CodeBreaK 200 study as well as a bias for investigators to be more likely to call tumor progression early for patients on chemo so that they could cross over to receive Lumakras.

Both problems were chalked up to the enthusiasm around Lumakras as the first FDA-approved KRAS inhibitor.

By comparison, Krazati’s KRYSTAL-12 requires confirmation from a blinded central review to determine tumor progression before crossover.

Despite the compromised trial results, the FDA has let Lumakras stay on the market while Amgen runs another confirmatory trial to be completed no later than February 2028. The recently launched phase 3 CodeBreaK 202 trial is comparing Lumakras against Merck’s Keytruda in their respective combinations with chemotherapy for patients with newly diagnosed, advanced, PD-L1-negative, KRAS G12C-positive nonsquamous NSCLC.

Lumakras’ setback gives Krazati an opportunity to catch up. Before the BMS buyout, Krazati in the third quarter posted $16.4 million in sales, coming in below analysts’ expectations. Lumakras generated $52 million sales during the same period.

BMS' Krazati also appears to hold more potential in the first-line setting. While Amgen was forced to combine Lumakras with chemo alone, a better liver toxicity profile has allowed BMS to pair Krazati with drugs in the PD-1 inhibitor class. A phase 3 trial is testing the Krazati-Keytruda combo in first-line KRAS G12C-mutated PD-L1-high NSCLC. And the company expects phase 2 results this year to guide its development path in PD-L1-low disease.

Both BMS and Amgen are also gunning for approvals in colorectal cancer, which is a smaller market than NSCLC. Amgen recently reported that Lumakras, at its currently approved 960-mg dose and used in combination with Vectibix, extended the median progression-free survival to 5.6 months versus 2.2 months for standard treatments in patients with chemo-refractory KRAS G12C colorectal cancer. The result came from the phase 3 CodeBreaK 300 trial.

A regulatory submission based on the study was planned in the first half of 2024, Amgen said during its fourth-quarter report. The company recently also launched a phase 3 trial for Lumakras in combination with Vectibix and chemo in first-line colorectal cancer.

For its part, BMS has the phase 3 KRYSTAL-10 study for Krazati and Eli Lilly’s Erbitux in second-line colorectal cancer, with a readout expected this year.