FDA Approves Companion Diagnostic for Sotorasib in KRAS G12C–Mutated Advanced NSCLC

The FDA has approved the Guardant360 CDx assay as a companion diagnostic for tumor mutation profiling to identify patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) whose tumors harbor the KRAS G12C mutation and may derive benefit from sotorasib (Lumakras), according to an announcement from Guardant Health, Inc.¹

The decision was based on clinical validation findings from the phase 2 CodeBreaK 100 trial (NCT03600883), which examined the drug in patients with locally advanced or metastatic NSCLC. Data from the trial supported the May 2021 FDA approval of the KRAS G12C inhibitor for use in patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.

Participants who had progressed following treatment with an immunotherapy and/or chemotherapy and were identified to harbor the KRAS G12C mutation using the diagnostic test, experienced an objective response rate (ORR) of 36% (95% CI, 28%-45%).^2,3 This rate proved to be consistent with the rate observed in patients who were identified using traditional tumor-based testing.

“The approval of [sotorasib] represents a significant medical advancement for patients with advanced NSCLC who harbor the KRAS G12C mutation because it is the first and only targeted therapy now available to them,” Darryl Sleep, MD, chief medical officer and senior vice president of medical affairs at Amgen, stated in a press release. “However, patients can only benefit from targeted therapies, or personalized treatments, if they are tested for biomarkers. Today’s FDA approval of Guardant360 CDx, offers an important development in biomarker testing by providing a high-quality, blood-based testing option for patients.”

The diagnostic assay provides comprehensive genomic data through a simple blood draw, and results are returned within 7 days. According to Guardant Health, Inc., the test allows for oncologists to move beyond existing limitations with tissue biopsies, in that clinically relevant information can rapidly be obtained to optimize treatment decisions for patients. Notably, the diagnostic covers all genes that have been recommended by the National Comprehensive Cancer Network, including those that are relevant to treatment guidelines for the disease.

The phase 2 trial enrolled 126 patients with locally advanced or metastatic NSCLC and a KRAS G12C mutation; 124 of these patients were determined to have centrally evaluable lesions at baseline per RECIST criteria.⁴ To be eligible to participate, patients needed to have progressed on previous standard treatments. Patients who had active brain metastases were excluded.

Patients were given oral sotorasib at a dose of 960 mg until progressive disease. Radiographic scans were performed every 6 weeks up to week 48 and then once every 12 weeks thereafter.

The primary objective of the trial was ORR per RECIST v1.1 criteria and blinded independent central review, while secondary objectives focused on duration of response (DOR), disease control rate (DCR), time to recovery, progression-free survival, overall survival, and safety. Investigators also evaluated biomarkers as an exploratory end point.

Additional data from the trial showed that sotorasib resulted in a median DOR of 10 months, with 58% of patients experiencing a response that persisted for 6 months or longer. The agent also resulted in a DCR rate of 81% (95% CI, 73%-87%) in this patient population.

Results from the exploratory biomarker analyses revealed that the efficacy of the KRAS G12C inhibitor was observed across a range of biomarker subsets, including patients who had PD-L1–negative or –low status, and those whose tumors were STK11 mutated.⁵

Regarding safety, the most common adverse effects reported with sotorasib include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage, and cough. If a patient develops symptoms associated with interstitial lung disease (ILD), the FDA recommends that the agent be withheld; if ILD is confirmed, the agent should be permanently discontinued. Moreover, liver function tests should be monitored before treatment with the agent is started. If the patient goes on to develop liver damage, the drug should be withheld, dose reduced, or discontinued.

“In the CodeBreaK 100 phase 2 clinical trial, which was the basis for the FDA approval, sotorasib demonstrated compelling efficacy and tolerability in patients with KRAS G12C–mutated NSCLC. This approval represents a historic milestone for patients with this mutation,” Vamsidhar Velcheti, MD, director of thoracic oncology at NYU Langone Health Perlmutter Cancer Center, added in the release. “This new targeted therapy, reinforces once again why comprehensive results from a simple blood test, clinicians can have greater confidence using the test, and patients benefit from less invasive testing and shorter wait times to see whether they are eligible for a targeted therapy such as [sotorasib].

References

1. Guardant260 CDx receives FDA approval as first and only liquid biopsy companion diagnostic for Amgen’s LUMAKRAS (sotorasib) KRASG12C inhibitor for use in advanced non-small cell lung cancer. News release. Guardant Health, Inc. May 28, 2021. Accessed June 1, 2021. https://bit.ly/3vHxPtb
2. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. May 28, 2021. Accessed June 1, 2021. https://bit.ly/3c172Ah
3. FDA approves LUMAKRAS (sotorasib), the first and only targeted treatment for patients with KRAS G12C–mutated locally advanced or metastatic non-small cell lung cancer. News release. May 28, 2021. Accessed June 1, 2021. https://prn.to/3yLuxqY
4. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.
5. Bauml JM, Li BT, Velcheti V, et al. Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Poster CT181.