The KRYSTAL-1 Study: Expanding Options in KRAS-Mutated Lung Cancer

Lung cancers tend to be more highly mutated than other solid organ malignancies. Over the past decade, an increasing number of targeted therapies have been developed against specific mutations that drive tumor growth. Their use is largely responsible for the recent improvement in survival in patients with advanced stage non-small cell lung cancer (NSCLC). Consequently, current best practice mandates testing for these mutations in patients with advanced disease with non-squamous sub-type. Efforts to assess the utility of targeted therapies in earlier stages of disease are being actively investigated.

From a practical perspective, molecular analysis necessitates that sufficient tumor tissue is available after a histological diagnosis is made. Thus, it is not uncommon for small diagnostic biopsies to be insufficient and will become increasingly prevalent as the number of mutations with corresponding targeted therapies increase. A role for liquid biopsies that use cell-free DNA from blood for tumor genotyping has been recognized as an option in such cases.

Kirsten rat sarcoma viral oncogene (KRAS) mutations have long been recognized as drivers of cancer. In NSCLC, KRAS mutations are associated with cigarette smoke exposure and increased tumor mutational burden. However, an effective targeted therapy for KRAS has remained elusive until recently. In May 2021, sotorasib, an oral selective covalent inhibitor of KRAS^G12C, was the first drug to be approved as a second-line treatment, based on the Phase II CodeBreaK100 study of 126 patients with previously treated, but relapsed KRAS^G12C-mutated disease. An objective response was observed in 37% of patients with a median duration of response of 11 months. This durable clinical benefit was confirmed in an updated analysis with follow up at 2 years.

Adagrasib, like sotorasib, selectively inhibits KRAS^G12C, with reported differences in pharmacokinetics and ability to penetrate the blood-brain barrier. In the KRYSTAL-1 phase 1-1b study, adagrasib showed clinical activity and an acceptable adverse-event profile in patients with previously treated advanced NSCLC harboring the KRAS^G12C mutation. Furthermore, in the follow-on phase 2 KRYSTAL-1 study cohort of 112 patients, 43% had a confirmed objective response, with an intracranial objective response rate of 33% in patients with central nervous system metastases (n=33). These results appear consistent with the earlier CodeBreaK100 trial and argue for the role of selective KRAS^G12C inhibition in patients with KRAS^G12C-mutated NSCLC.

Adagrasib is currently being assessed by the FDA for accelerated approval. If approved, adagrasib will join sotorasib as a second-line treatment in KRAS^G12C-mutated advanced NSCLC. An awareness of the rapidly changing landscape of targeted therapies in patients with lung cancer will empower you and your patient to make the best treatment decisions.

The following NEJM Journal Watch summary provides more details of the study.

Jyoti D. Patel, MD, FASCO, reviewing Jänne PA et al. N Engl J Med 2022 Jul 14

Mutations in KRAS occur in about one quarter of patients with non–small-cell lung cancer (NSCLC), and approximately 14% of lung adenocarcinomas and 0.5%–4% of squamous NSCLCs harbor KRAS^G12C mutations. KRAS had long been considered an “undruggable” target until the FDA approved sotorasib in 2021 for previously treated KRAS^G12C-mutant NSCLC based on a phase 2 trial showing a response rate of 37% (NEJM JW Onc Hem 2021 Sep and N Engl J Med 2021; 384:2371).

Now, in an industry-sponsored, phase 2 study, 115 patients with unresectable or metastatic NSCLC with a KRAS^G12C mutation who had previously been treated with platinum-based chemotherapy and checkpoint inhibitor therapy received the KRAS^G12C inhibitor, adagrasib (600 mg orally twice daily) until disease progression, unacceptable adverse events, withdrawal of consent, or death.

During a median follow-up of 13 months, the primary outcome — objective response — was noted in 43% of 112 patients with measurable disease at baseline. One patient had a complete response and 47 had a partial response. The median duration of response was 8.5 months. Furthermore, in a post hoc analysis of 33 patients with central nervous system (CNS) metastases at baseline, the rate of intracranial objective response was 33%.

Treatment-related adverse events occurred in nearly all patients, most commonly gastrointestinal events and fatigue. Just over half of treatment-related events were grade 1 or 2 in severity; 45% were grade 3 or higher.

Comment: Adagrasib, like the recently approved drug sotorasib, is a selective covalent inhibitor of KRASG12C that leads to a clinically significant and durable reduction in tumor burden. In addition, adagrasib has been optimized for favorable properties, including a long half-life and the ability to penetrate the central nervous system, and this is a very promising therapy for patients.

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Robert Smyth, MD, MSc, is a 2022–2023 NEJM Editorial Fellow. He is currently an Assistant Professor of computational biomedicine at the Boston University School of Medicine.