Sotorasib Flips the Switch for Patients With KRAS G12C-Mutant NSCLC

Ferdinandos Skoulidis, MD

Sotorasib (Lumakras), a small molecule inhibitor of KRAS, has been approved as a targeted treatment option for patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer (NSCLC). KRAS G12C is a driver mutation that is found in about 13% of patients with nonsquamous NSCLC in the United States.

In May, the FDA granted accelerated approval specifically for patients who have progressed on or after at least 1 systemic therapy.¹ The decision was based on data from the phase 2 CodeBreaK 100 (NCT03600883) trial, a multicenter, singlearm, open-label clinical study evaluating sotorasib as a therapy for patients whose disease presented with KRAS G12C mutations.²

In an interview with OncLive^®, Ferdinandos Skoulidis, MD, PhD, assistant professor of thoracic/head & neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston, discussed the necessity for targeting and screening patients for KRAS G12C mutations.

OncLive: Please discuss the rationale for targeting KRAS G12C mutations and what was noteworthy about the efficacy data.

This specific KRAS G12C mutation is detected in approximately 13% of all patients with metastatic nonsquamous NSCLC. Following failure of standard of care systemic therapies with PD-1/PD-L1 inhibitors and platinum-based chemotherapy administered either in combination or sequentially, clinical outcomes with second-line chemotherapy with docetaxel or docetaxel in combination with ramucirumab for patients bearing KRAS-mutant tumors are generally poor. In addition, chemotherapy is often poorly tolerated and associated with significant toxicities.

Among the most impressive findings of the study were the durability and depth of responses and it should be noted that 4 patients (3.2%) achieved a complete response. The reported overall disease control rate of 80.6% with median progression-free survival of 6.8 months and median overall survival of 12.5 months further support the activity of sotorasib in this heavily pretreated patient population and appear superior to historical data with docetaxel or docetaxel and ramucirumab. The confirmatory phase 3 randomized CodeBreak 200 clinical trial will shed further light on the relative benefit of sotorasib compared to docetaxel.

Finally, it is important to highlight that the clinical activity of sotorasib extended across a broad range of patient subgroups, including difficult-to-treat molecular subsets such as tumors that harbor co-alterations in STK11. This is notable, because STK11 comutations are prevalent in KRAS G12C-mutant NSCLC and are associated with worse clinical outcomes with standard-of-care systemic therapies, including PD-1 axis inhibitor monotherapy, chemoimmunotherapy, platinum-doublet chemotherapy, and chemotherapy with docetaxel.

What adverse effects do clinicians need to be aware of when prescribing sotorasib?

Reported adverse events are generally low-grade and manageable with standard supportive measures, treatment-interruption and, where necessary, up to two dose reductions to 480 mg and 240 mg once a day.

Prescribing physicians need to be aware of 2 specific warnings that are included in the FDA label. The first is the potential for hepatotoxicity, with a requirement for liver function test monitoring every 3 weeks for the first 3 months of treatment and every month thereafter as clinically necessary. The second is the risk of pneumonitis/interstitial lung disease, an infrequent but potentially life-threatening adverse event. It is important to advise patients to immediately withhold sotorasib if they experience new or worsening respiratory symptoms with prompt initiation of diagnostic work up to evaluate for pneumonitis. If drug-related pneumonitis is confirmed, treatment with sotorasib should be permanently discontinued.

How do these data and subsequent approval impact the importance of screening patients for these mutations?

The approval of sotorasib underscores the critical importance of offering molecular profiling to every patient with metastatic nonsquamous NSCLC. We now have a well-tolerated approved oral therapy at our disposal that confers durable clinical benefit in about 13% of patients with nonsquamous NSCLC, yet we will only be able to harness its full potential if we can expeditiously identify patients that are candidates for therapy. There is an urgent need to expand and promote equitable access to screening across the US, particularly among underserved patient populations.

With regards to screening for KRAS G12C somatic mutations, both single-gene testing and comprehensive molecular profiling can support treatment with sotorasib. However, broad profiling may offer the additional advantage of simultaneously screening for multiple oncogenic drivers as well as emerging biomarkers.

Finally, initiatives to offset the cost of screening for eligible patients, such as the industry supported Amgen Biomarker Assist program, are an important additional component of the effort to boost the uptake of molecular testing and should be further rolled out.

What does the future hold for sotorasib?

We are eagerly awaiting the results of the confirmatory phase 3 randomized CodeBreaK 200 clinical trial comparing sotorasib with docetaxel for patients with previously treated advanced KRAS G12C-mutant NSCLC. In this context, an immediate scientific and clinical priority is to comprehensively characterize molecular determinants of response and mechanisms of both innate and acquired resistance to sotorasib to optimally tailor combination regimens. Based on the clinical development paradigm of EGFR tyrosine kinase inhibitors, clinical trials exploring the utility of sotorasib in early-stage, surgically resectable disease are expected to follow.

References

1. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed July 9, 2021. bit.ly/3e00LpA
2. Lumakras. Prescribing information. Amgen Inc; 2021. Accessed July 9, 2021. bit.ly/3r3NgKP