KRAS, the most common oncogene across all tumor types, was historically considered undruggable until 2013, when researchers from the University of California, San Francisco, found the key to developing molecules against that target. Since then, a number of drug development programs aimed at inhibiting KRAS G12X mutations have emerged, led by Amgen and Mirati Therapeutics with inhibitors of KRASG12C. Amgen’s sotorasib (branded as Lumakras in the United States and Lumykras in Europe) received an accelerated approval from the FDA in May 2021 for the second-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), and the drug has also been approved in that indication throughout most of Europe, Japan, and a number of other regions. Mirati’s adagrasib is under FDA review for a possible accelerated approval in the same indication, with an FDA PDUFA date of December 14.
Amgen’s Phase 3 CODEBREAK-200 trial results were intended to confirm sotorasib’s clinical benefits, potentially spurring the FDA to change the drug’s status from accelerated approval to fully approved. If that change in status is accomplished before December 14, sotorasib’s full approval will block an accelerated approval for adagrasib. However, Amgen’s presentation of the full CODEBREAK-200 trial data at the European Society for Medical Oncology (ESMO) in September unexpectedly raised new questions about sotorasib that could possibly leave the road clear for adagrasib’s accelerated approval next month.
Both sotorasib and adagrasib are oral, selective inhibitors of KRASG12C, the most common mutation in NSCLC with 12-15% of patients affected. KRASG12C mutations are also important in other tumor types, including colorectal tumors. However, Mirati has optimized adagrasib for sustained target inhibition, giving the molecule a half-life of 23 hours versus 5 hours for sotorasib.
Sotorasib’s accelerated approval in metastatic KRASG12C NSCLC was based on 12-month data from the Phase 1/2 CodebreaK-100 trial that showed an overall response rate (ORR) of 37% in the 124 evaluable patients and a median progression-free survival (PFS) of 6.8 months. The CodebreaK-200 trial followed on as a phase 3 controlled randomized study comparing sotorasib to docetaxel in patients with previously treated, advanced, metastasized or unresectable KRASG12C-mutated NSCLC.
ESMO audiences were expecting CodebreaK-200 to confirm the benefit seen for sotorasib in CodebreaK-100. However, the full data from the trial showed only a median PFS of 5.6 months for sotorasib versus 4.6 for docetaxel, which was less than the 6.3 months PFS that earned sotorasib its accelerated approval. In addition, overall survival, a key trial secondary endpoint, was not significantly different between sotorasib and docetaxel (10.6 versus 11.3 months, respectively). Experts have speculated this was possibly due to the study being underpowered to show overall survival benefits, and to extensive patient crossover of docetaxel non-responders to sotorasib. Amgen originally intended the trial to include 650 patients but after the positive CodebreaK-100 results, was permitted by the FDA to halve the number of patients and allow crossover of non-responding docetaxel patients to sotorasib. Indeed, the patients participating in CodebreaK-200 had a heavier burden of disease than those in CodebreaK-100 and had all previously tried immunotherapy, versus only 70% of patients in CodebreaK-100 having done so. For these reasons, direct comparisons between the results of CodebreaK-100 and CodebreaK-200 could be difficult.
The safety profile in CodebreaK-200 was consistent with that observed in the previous trial. Liver enzyme elevations were already known to be associated with sotorasib. While two cases of liver injury were seen in the Phase 3 patients receiving the drug, six patients quit the study due to Grade 3 or higher liver enzyme elevations. However, experts believe this safety issue could be effectively addressed by dose reduction. Amgen remains in discussion with the FDA regarding the CodebreaK-200 results, with hopes they will still support sotorasib’s full approval.
Meanwhile, the FDA’s consideration of an accelerated approval for adagrasib in December is based on the results of Mirati’s Phase 1/2 KRYSTAL-1 trial in patients with KRASG12C-mutated NSCLC who had been previously treated with a platinum-based chemotherapy and a PD-1/PD-L1 inhibitor. At a median follow-up of 12.9 months, the ORR for the 112 evaluable patients was 41%, including one complete response, and the disease control rate was 81% (improved or stable disease). Median PFS in the trial was 6.9 months and at data cut-off in January 2022, the median overall survival was 14.1 months (with a median duration of follow-up at 15.9 months). Adverse events for the adagrasib-treated patients also included liver enzyme elevations. Mirati is currently running a confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients with a KRASG12C mutation who have been previously treated for metastatic NSCLC. That study is expected to complete in August 2023.
While direct comparisons between Amgen and Mirati’s KRAS inhibitors remain to be seen, the results to date suggest similar safety profiles for the two treatments and possibly somewhat greater efficacy for adagrasib, based on its higher reported ORR and OS.
Will the results achieved in CodebreaK-200 be sufficient to secure Amgen a full approval for sotorasib? If so, what is the likelihood of that happening before Mirati’s PDUFA date of December 14? If sotorasib does achieve full approval, how will that affect Mirati’s development and commercialization plans for adagrasib? We’ll be watching this space.