KRYSTAL-1 May Fill Unmet Needs in KRAS G12C mutated GI Cancers


Tanios S. Bekaii-Saab, MD, FACP, discusses the unmet needs that are hoped to be filled by the phase 1/2 KRYSTAL-1 study.

Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the unmet needs that are hoped to be filled by the phase 1/2 KRYSTAL-1 study (NCT03785249).

To be enrolled in the KRYSTAL-1 study, patients need to have a solid tumor with a KRAS G12C mutation and unresectable or metastatic non-small cell lung cancer which progressed on or after treatment with a PD-1/PD-L1 inhibitor in combination with or following chemotherapy.

In part 1 of the study, the dose escalation of adagrasib (MRTX849) was reviewed, determining the maximum-tolerated dose to be 600 mg twice a day. Adagrasib at this dosage demonstrated a clinical benefit rate of 96% in the phase 1/1b trial and progressed to be the recommended phase 2 dose.

Because adagrasib showed promising clinical activity in this patient population, Bekaii-Saab hopes this study will help to fill some of the unmet needs that continue to exist in this space.


0:08 | KRYSTAL-1 is a study that's built as a phase 1, phase 1B and phase 2 study. The key criteria for entry on the study is essentially to have a KRAS G12C mutation. Phase 1 was essentially dose escalation that primarily looked at trying to determine the maximum tolerated dose, 600 mg twice a day. That ultimately went into expansion and included some rational combinations. Phase 2 was monotherapy and combination. Phase 1B for example, had an added grasp for all solid tumors and for brain metastases, since it has that CNS penetration. They looked at lung cancers, both treatment naive and those that were exposed to prior KRAS G12C.

1:06 | In colon cancer, these G12C inhibitors don't appear to have much activity on their own. That is because of a feedback loop mechanism that essentially creates that adaptive resistance and activates EGFR. In colon cancer, most of the follow through development was with adagrasib and cetuximab (Erbitux), which is what's being developed right now in a large study called KRYSTAL-10, a phase 3 randomized study looking specifically at adagrasib plus cetuximab plus chemotherapy in second-line colon cancer.

1:45 | In pancreas cancer, they expanded from a single agent which is still ongoing but also to look at cetuximab plus. The phase 2 had a single agent in colon cancer plus cetuximab in colon cancer, then pancreas cancer plus cetuximab. The data I presented was on the other solid tumor basket. At the time, we presented with 42 patients with adagrasib, a single agent, and then there are lung cancer lung cancer cohorts, both single agents and one that includes the SDK11 mutations. There’s quite a bit of data that has been presented prior to the presentation I did at ASCO GI that included showing activity in lung cancer, colon cancer, the few patients with pancreas, ovarian, endometrial, phalangeal, you name it. Every cancer where this agent has been looked at, as long as they harbor the KRAS G12C mutation, there has been evidence of activity.

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