1. Goodwin, Peter M.

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The drug adagrasib-a binding inhibitor for the G12C mutant form of the Kirsten rat sarcoma (KRAS) oncogene-brought promising clinical responses, including in brain metastases, for patients whose non-small cell lung cancers (NSCLC) had already been treated with chemotherapy and immunotherapy. A lively first day of the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting heard this news from the KRYSTAL-1 study (Abstract 9002), simultaneously published in the New England Journal of Medicine (2022; doi: 10.1056/NEJMoa2204619).

Lung Cancer. Lung Ca... - Click to enlarge in new windowLung Cancer. Lung Cancer

"For a long time we didn't have any KRAS drugs. It was deemed the undruggable target. Now we have a second drug that apparently works," said senior author of the study, Alexander I. Spira, MD, PhD, FACP, Medical Oncologist with Virginia Cancer Specialists. "It's also important because there is preliminary evidence of brain activity-which is super important because a lot of these patients will have brain metastases.


"The challenge that we have right now is [that], in this population, we don't have anything that really works in the brain very well," he told Oncology Times. "And for the first time, we presented some preliminary data today with active and treated metastases. We're starting to see some activity and efficacy in central nervous system (CNS) metastases-which is important because this is a huge unmet need for these patients."

Alexander I. Spira, ... - Click to enlarge in new windowAlexander I. Spira, MD, PhD, FACP. Alexander I. Spira, MD, PhD, FACP

When he was asked why adagrasib should have this ability to treat brain metastases, Spira said it wasn't about the KRAS mutation itself (even though patients with the mutation had a tendency to develop more brain metastases). But it was about the drug's ability to reach the brain.


"The challenge is getting the drugs into the central nervous system: How do you get the drugs into the brain? That's the key thing that we've been lacking," he stated. Although, he acknowledged that there had been hopes such a small molecule drug would work in the brain. "It's become almost an assumption that a lot of these small molecules do have CNS activity. But that's not necessarily the case. We have to prove it first."


Spira said that, although another KRAS inhibitor, sotorasib, had already been found to be effective in the brain, there were good reasons for looking at an alternative molecule. "It's always good to have two. It gives patients opportunities [and] they do have slightly different side effect profiles. One of the things people are going to be looking at is: Does one work after the other one? Does one work if the other one is not tolerated?" KRAS inhibition could also potentially be combined with other medicines such as checkpoint inhibitors, he noted.


Study Details

In the KRYSTAL-1 study, 116 patients who had already been treated for their lung cancers (with chemotherapy and immunotherapy) each had 600 mg of adagrasib twice a day. The response rate was 43 percent. There was preliminary evidence of CNS activity in patients with stable, treated brain metastases. "And it worked," Spira noted. "A lot of patients did require a dose reduction. But most important: The discontinuation rate was only about 7 percent."


Adagrasib inhibits the KRAS G12C oncogene by irreversibly binding to it and locking it in its inactive state. Before the study, adagrasib had already shown clinical activity and an acceptable adverse event profile, the researchers wrote.


All patients had been previously treated with platinum-based chemotherapy and anti-programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) immunotherapy. The primary endpoint in KRYSTAL-1 had been objective response, and secondary endpoints included the duration of any response, the progression-free survival, overall survival, and safety.


A total of 116 patients with NSCLC and the mutation had been treated-nearly all of them previously having received both chemotherapy and immunotherapy. Out of the 112 patients who had measurable disease at baseline, 48 had a confirmed objective response. The median duration of response was 8.5 months, and the median progression-free survival was 6.5 months. After median follow-up of 15.6 months, the median overall survival was 12.6 months.


Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3 percent. Treatment-related adverse events (AEs) had occurred in 97.4 percent of the patients. Half of whom had Grade 1 or 2 AEs, and just less than half had Grade 3 or higher AEs (including two deaths). But only 7 percent of patients opted for drug discontinuation.


Although KRYSTAL-1 had not been a randomized study, treatment with adagrasib appeared to have been superior to standard of care with docetaxel, Spira said. The biggest side effects had been gastrointestinal and were managed-including by dose reductions. So, he noted that the remaining questions had been to discover whether adagrasib could be combined with other agents such as checkpoint inhibitors. He also said they needed to optimize doses and to see if it could bring benefits in the frontline setting.


"KRAS is no longer an undruggable target: We have two drugs. And we've just got to get them to more patients," Spira concluded.


Peter M. Goodwin is a contributing writer.