Tony Mok, MD, The Chinese University of Hong Kong, Hong Kong, China, discusses results from the phase 3 KRYSTAL-12 trial comparing adagrasib and docetaxel among patients with previously treated KRAS^_G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Study results demonstrated that adagrasib improved survival and response in this patient population.

Transcript: 

Hi, I'm Professor Tony Mok from the Chinese University of Hong Kong. It's a great pleasure and honor of mine to present KRYSTAL-12 at ASCO 2024. KRYSTAL-12 is a randomized phase 3 study that compares adagrasib with docetaxel in patients with advanced-stage lung cancer after failing chemotherapy and immunotherapy. Those patients must harbor KRAS^G12C.

 It is common knowledge that KRAS is a tough mutation to treat and only recently we managed to have an inhibitor for KRAS^G12C, which accounts for about 14% of the lung adenocarcinoma. With this group of patients, we right now have previously had a drug called sotorasib but now the second drug is called adagrasib. Adagrasib is actually a covalent bonding inhibitor that had a very good efficacy in the phase 2 single-arm study with promising response rate, good progression-free survival, and overall survival. Based on that, both FDA in the United States and EMG from Europe have approved it in a conditional manner. To get this further, we need a randomized phase 2 study and therefore we have KRYSTAL-12. 

In KRYSTAL-12, it is a randomized study that compares these 2 drugs looking for progression-free survival as a primary end point. We enrolled a total of 453 patients, the patient must be confirmed to have advanced-stage non-small cell lung cancer that have the KRAS^G12C, either central laboratory or approved local laboratory.  We have to have good performance status, brain mets have to be stable, but then for chemotherapy, they can receive either sequentially or concurrently. For the stratification, we stratified according to either the geographic region, Asia versus non-Asia, and also sequential versus concurrent chemotherapy. It is a 2-to-1 randomization, 2/3 will receive adagrasib, 600 mg BID, the other 1/3 will receive single-agent chemotherapy of docetaxel, 75 mg/m². The primary end point is BIRC-assisted progression-free survival. 

We're glad to share with everybody that it is a positive study with a median of about 5.5 months versus 3.8 months and hazard ratio of .52. On top of that, at 6 months the progression-free survival rate is 45% versus 30%. We also demonstrated improvement in the response rate, a total of 32% of patients responded in the adagrasib arm comparing to 9% in the docetaxel arm. The depth of response as well as the duration of response are also significantly different. We have evidence of intracranial response of 24% versus 11% favoring the adagrasib. The most common toxicity of GI related diarrhea is common and it occurred above 53% but, majority are actually grade 1, about more than 20% of that grade 1. There is also the GI problem of nausea and vomiting but again, it can be controlled with oral antiemetic. 

Overall, I think the KRYSTAL-12 is a positive study demonstrating improvement in progression-free survival response rate and overall response rate associated with a limited and manageable toxicity. It will become one of the treatment options for patients with KRAS^G12C mutation. 

Source: 

Mok TSK, Yao W, Duruisseaux M, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at the 2024 ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract #LBA8509