A newer KRAS G12C drug beat the first two in a head-to-head lung cancer trial

The KRAS G12C mutation was, for decades, considered undruggable. Then two oral drugs, sotorasib and adagrasib, were approved to block it in lung cancer — a genuine breakthrough, but one with modest durability, as responses tend to fade within months. A phase 3 trial published in the New England Journal of Medicine on 25 October did something those first drugs were never tested against: it put a newer KRAS G12C inhibitor head-to-head with them [s1].

What is being compared

KRAS G12C is a specific misspelling in the KRAS gene that drives a slice of non-small-cell lung cancers. Divarasib is a next-generation oral inhibitor of it, designed to be more potent and more selective in the laboratory than the first-generation drugs sotorasib and adagrasib [s1]. Potency and selectivity in a test tube do not automatically translate into benefit for patients, which is the whole reason a comparative trial was needed.

Rather than testing divarasib against a placebo or against chemotherapy, Krascendo 1 compared it directly with the existing targeted drugs — the more demanding and more informative design, because it answers the question a clinician actually faces: among the drugs that hit this target, which works best?

How the trial was built

Krascendo 1 was an international, open-label, randomised phase 3 trial in patients with previously treated KRAS G12C-mutated advanced or metastatic NSCLC, registered as NCT06497556 [s1][s2]. In all, 338 patients were randomly assigned: 167 to divarasib at 400 mg once daily, and 171 to control treatment — of whom 156 received sotorasib at 960 mg once daily and 15 received adagrasib at 600 mg twice daily [s1]. Treatment continued until the disease progressed, side effects became unacceptable, the drug stopped helping, or the patient withdrew [s1].

The primary endpoint was progression-free survival, judged by blinded independent central review — an outside panel reading the scans without knowing which drug a patient was on, which guards against bias in an open-label trial [s1]. Overall survival, response rate, duration of response and safety were secondary [s1].

What it found

Divarasib came out ahead on every efficacy measure. Over a median follow-up of 14.3 months, median progression-free survival was 9.8 months with divarasib against 5.7 months with the first-generation drugs, a hazard ratio for progression or death of 0.58 (95% CI 0.44–0.76; P<0.001) [s1]. Median overall survival was 17.7 months versus 12.0 months, a hazard ratio for death of 0.56 (95% CI 0.41–0.78; P<0.001) [s1].

The response figures tracked the same way. Among the 328 patients who could be evaluated, a confirmed tumour response occurred in 58.4% on divarasib versus 32.3% on control — nearly double [s1]. And the responses lasted longer: a median duration of response of 11.9 months with divarasib against 6.9 months with sotorasib or adagrasib [s1].

Unusually for a more potent drug, divarasib was also easier to tolerate on the measure reported. Grade 3 or 4 treatment-related adverse events occurred in 24.6% of patients on divarasib versus 34.5% on control treatment [s1]. More effective and less toxic is not the usual trade-off in oncology.

What is, and is not, established

What Krascendo 1 supports is clear: in previously treated KRAS G12C-mutated NSCLC, divarasib produced longer progression-free and overall survival, more and more durable responses, and fewer severe treatment-related side effects than the first-generation inhibitors it was tested against [s1]. For patients whose cancer carries this mutation, that is a meaningful step up from the current targeted options.

The qualifications are worth keeping in view. The trial was open-label, which is why the central, blinded scan review matters — it is the part of the design that the lack of blinding could not distort [s1]. The comparison was overwhelmingly against sotorasib; only 15 patients received adagrasib, so this is not a clean three-way contest between all three drugs [s1]. And the population was specifically patients whose disease had already been treated, not those receiving a KRAS G12C inhibitor first [s1]. Divarasib is investigational and not yet approved; these results describe a trial, not a treatment available in clinic.

Red flags: patients on any targeted lung cancer drug who notice new breathlessness, persistent nausea or vomiting, or signs of liver trouble should contact their oncology team. This article describes research and is not medical advice. Choices among KRAS G12C inhibitors are for patients and their treating oncologists.