Tony S.K. Mok, MD, on NSCLC: Adagrasib vs Docetaxel in KRAS G12C–Mutated Disease

Crystal-XII is a randomized phase three study that compare adagrasib with docetaxel in previously treated non-small cell lung cancer, that harbored KRAS-G2LC mutation. Now this study is important. Now, as you probably know, KRAS-G2LC accounted for about 14% of all lung adenocarcinoma. And then the adagrasib, which is a covalent bonded inhibitor of the KRAS-G2LC, as demonstrated in the early phase two data, that there is actually promising response rate, progression-free survival and over-survival. And also NCCN had approved that this is a category 2A agent for patient with this mutation, and brain metastasis. However, we still need to prove it with the randomized study, and is the time that we can share with you the result. So a bit of the design. This is designed to enroll the patient with the KRAS-G2LC stage four. The patient can receive chemotherapy, and also immunotherapy either concurrently or sequentially. It's a randomized in a two-to-one fashion, total above 453 patient. Now with that, there is actually, the patient actually was able to dispose, and majority of the patient received the targeted drug, meaning at aggressive of 99% of patient, and the dosage absolute arm is about 92% patient. And overall, the progression pre-survival is much improved, with the actually median of 5.5 versus, 3.8 months, hazard ratio 0.58. And also there is a difference in the response rate. 32% versus 9%, and this is also translated into a duration of response of about 8.4 months versus about 5.3 months. There's another feature that's important, which is the intracranial response. So for a patient with the known brain metastasis, we have a intracranial response rate of 24% versus about 11%. Safety wise, actually the most common toxicity is diarrhea. And then with this, actually the patient is mostly grade one and two. And also there's some nausea and vomiting, which is actually well controlled. One toxicity that's not so clear is that there's a slight elevation of the blood creatinine. However, most of this, patient will be reversible upon c-section of the drug. So as a conclusion, I think the Crystal-12 study had confirmed the role of the adagrasib as a second line therapy for patient with the lung cancer, with the KRAS-G2LC, after failing the chemotherapy and immunotherapy. In the future, there is also the Crystal-7 study, which actually put adagrasib in the first line. It will be in combination with pembrolizumab, comparing to pembrolizumab alone in patient with actually a PTPS score of over 50%.