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lung cancer drugs: lung cancer drugs
Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations occur in approximately 30 percent of non-small cell lung cancers (NSCLCs) and KRASG12C is the most common mutation in KRAS-mutant NSCLC. Despite advances in the treatment of NSCLC, there are limited treatment options for patients with this debilitating and difficult-to-treat condition. Thus, KRASG12C-mutated NSCLC is an area of critical unmet need.
Recently, the FDA granted accelerated approval for adagrasib, a targeted treatment option for adult patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior treatment for their cancer. Adagrasib is a highly selective KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive, GDP-bound state. Adagrasib has been previously reported to have favorable pharmacokinetic properties, including a long half-life (23 hours), extensive tissue distribution, and central nervous system (CNS) penetration.
The FDA based the accelerated approval of adagrasib on its positive benefit-risk profile from the multicenter, single-arm, open-label KRYSTAL-1 trial (NCT03785249), with continued approval contingent upon verification and description of a clinical benefit in a confirmatory trial (N Engl J Med 2022; doi: 10.1056/NEJMoa2204619).
In this registrational Phase II cohort, the researchers evaluated adagrasib in 112 patients with KRASG12C-mutated NSCLC who were previously administered a platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 (PD-L1) therapy either concurrently or sequentially. Adagrasib was given at 600 mg orally twice daily until disease progression or unacceptable toxicity. Primary efficacy endpoints were confirmed objective response rate (ORR) and duration of response (DOR) as evaluated by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
Of the 112 patients with measurable disease at baseline in the KRYSTAL-1 study, adagrasib elicited an ORR of 43 percent (95% CI: 34-53%) in patients with locally advanced or metastatic KRASG12C-mutant NSCLC, with 80 percent (95% CI: 71-87%) of patients achieving disease control. Median DOR was 8.5 months (95% CI: 6.2-13.8) among the responders and the median PFS was 6.5 months (95% CI: 4.7-8.4). The intracranial confirmed ORR was 33.3 percent (95% CI: 18.0-51.8%) among 33 patients with previously treated, stable central nervous system metastases.
A pooled efficacy analysis (n=132) included Phase I/Ib NSCLC and registrational Phase II NSCLC cohorts from the KRYSTAL-1 study of adagrasib as a single agent at 600 mg capsules orally twice daily demonstrated an ORR of 44 percent and a disease control rate of 81 percent based on BICR. Moreover, the therapy produced a median DOR of 12.5 months (95% CI: 7.3-NE) and a median OS of 14.1 months (94% CI: 9.2-19.2).
Regarding safety, adagrasib was evaluated in a pooled patient population with NSCLC and other solid tumors as a single agent at 600 mg orally twice daily in 366 patients enrolled in KRYSTAL-1 and KRYSTAL-12 (NCT04685135). The most common (≥ 25%) adverse events (AEs) in the trial included diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, and decreased appetite. Permanent discontinuation of adagrasib due to AEs occurred in 13 percent of patients.
The FDA also simultaneously approved the Resolution ctDx FIRST Assay for plasma and a therascreen KRAS RGQ PCR kit for tissue. These companion diagnostics are intended to aid in patient treatment selection. The FDA advises that plasma should be evaluated first; the ctDx FIRST assay delivers a significantly quicker turnaround time, potentially allowing physicians to accelerate treatment decisions. If no mutation is detected in the plasma, then the tumor tissue should be assessed. Adagrasib is available as 200 mg tablets. The recommended dose is 600 mg orally twice daily until disease progression or unacceptable toxicity.
In an interview with Oncology Times, Shirish M. Gadgeel, MD, Chief of the Division of Hematology and Oncology in the Department of Internal Medicine at the Henry Ford Cancer Institute/Henry Ford Health System, discussed how the FDA approval of adagrasib potentially changes the treatment strategy for patients with NSCLC harboring KRASG12C mutations.
Oncology Times: Despite advances in the treatment of NSCLC, few effective treatment options are available for patients with KRASG12C-mutated NSCLC. What are some of the treatment challenges for patients with advanced NSCLC harboring the KRASG12C mutation?
Gadgeel: “Patients with NSCLC harboring KRASG12C mutations and other KRAS mutations have historically had few effective treatment options for reasons, including those involved in the biology of KRAS as well as clinical features. The KRAS protein is rather small with a smooth surface that does not contain deep binding pockets for small molecules, which led historically to many challenges for developing direct inhibitors.
“In addition, data suggest that the presence of co-mutations such as STK11 and KEAP1 may limit the activity of immune checkpoint inhibitors. Therefore, a proportion of KRAS mutation NSCLC patients has derived the benefits of advances in immunotherapy. Finally, we know patients with NSCLC harboring KRASG12C mutations have distinct clinical characteristics that have been historically challenging for clinical management, such as presentation with CNS metastases at diagnosis.”
Oncology Times: How does the approval of adagrasib change the treatment paradigm for this patient population?
Gadgeel: “Adagrasib was selected for particular properties, including a long half-life allowing for sustained inhibition of KRASG12C and CNS penetration. The approval of adagrasib provides an additional therapeutic option in providing a targeted therapy option for patients with NSCLC harboring a KRASG12C mutation, which was historically thought to be undruggable.
“In addition, the drug has shown that it could have efficacy against CNS metastases. Recent data also shows that adagrasib could be administered with immune checkpoint inhibitors without significant hepatic or other toxicities, though at this time point, the drug has been only approved as a single agent following initial systemic therapy.”
Oncology Times: What potential value do the blood- and tissue-based companion diagnostics provide to both patients with KRASG12C-mutated NSCLC and their clinicians?
Gadgeel: “By having both tissue and blood-based tests available as a companion diagnostic for identifying KRASG12C mutations, clinicians are not limited on how they can test for identification of KRASG12C mutations and can select a test that best fits the needs of each patient, including turnaround time and tissue availability.”
Oncology Times: Are there any studies that are evaluating adagrasib as a monotherapy, in combination with other therapies in NSCLC, or in other advanced solid cancers that you are excited about?
Gadgeel: “Adagrasib is being evaluated as a monotherapy and in combination with other agents across lines of therapy, tumor types, and tumor-specific populations of interest. We look forward to additional forthcoming data. There is quite a bit of excitement around recently presented datasets, including efficacy of adagrasib in patients with NSCLC and untreated CNS metastases, the combination of adagrasib and pembrolizumab in treatment-naïve NSCLC that showed initial indications of tolerability, the clinical activity of adagrasib both as monotherapy and in combination with cetuximab in previously treated CRC, as well as preliminary activity in other solid tumors (i.e., PDAC, other GI tumors, etc.).
Dibash Kumar Das is a contributing writer.
