Sotorasib Shows Promise in Non-Small Cell Lung Cancer Subset

Data from the phase 2 CodeBreaK 100 trial demonstrated that treatment with sotorasib, a KRAS G12C inhibitor, induced rapid responses and encouraging survival outcomes in previously treated patients with KRAS G12C–mutated advanced non–small cell lung cancer (NSCLC).

“Because of the way that mutant RAS protein interacts with some of the proteins in the cell, it is a really hard target for drug development,” study author Dr. Vamsidhar Velcheti, director of thoracic medical oncology and NYU Langone’s Perlmutter Cancer Center, said in an interview with CURE®. “Because of that, a lot of efforts by several cancer researchers over several decades have failed because we could not develop good drugs against this RAS gene.”

However, as Velcheti noted, recent advancements have helped develop novel therapies that target the RAS mutation. However, according to Velcheti, the story has been different for patients with the KRAS G12C mutation (which occurs in approximately 10% to 15% of all lung cancers).

“Previously, we've not had any targeted therapy treatment options for these patients,” he said. “And the CodeBreaK 100 trial demonstrates that this drug, sotorasib, can shrink cancers and is extremely well tolerated compared to traditional chemotherapy.”

Data from a prior phase 1 trial of the investigational therapy showed similar results in 35 previously treated patients with KRAS G12C–mutated advanced NSCLC. At the time, the study results demonstrated sotorasib induced a 50% response rate in these patients.

In the phase 2 CodeBreaK 100 trial, 126 patients were treated with oral sotorasib at 960 mg once daily.

Eighty-one percent of patients had progressed after receiving platinum-based chemotherapy and PD-1/PD-L1 inhibitors; the remainder had progressed after having received one of these therapies. The data cutoff date was December 1, 2020.

The results of the phase 2 trial, which were presented at the 2020 World Conference on Lung Cancer, showed that sotorasib induced a 6.8-month median progression-free survival (the time from treatment to disease progression or worsening) in patients with KRAS G12C–mutated advanced NSCLC.

Moreover, results from the phase 2 cohort demonstrated that 80% of patients achieved disease control after treatment with sotorasib. After a median follow-up of 12.2 months, patients who received study drug achieved a 37.1% confirmed objective response rate (the proportion of patients who had a complete or partial response to treatment) and a disease control rate of 80.6% in this patient population. The median duration of response was 10 months.

The median best tumor shrinkage among all responders (46 patients) was 60%, with a median time to objective response of 1.4 months.

Aside from its efficacy, the study drug also was associated with a favorable benefit-risk profile. Most treatment-related adverse events (TRAEs) were of grades 1 or 2, and no treatment-related deaths occurred. Grade 3 and 4 (considered more serious or severe) TRAEs occurred in 25 (19.8%) patients and one patient (0.8%), respectively.

The most common all-grade TRAEs patients reported experiencing included, but were not limited to, diarrhea (31%) and nausea (19%). Some patients (7.1%) discontinued treatment because of TRAEs.

These data, according to Velcheti, represent a new approach for this population of patients with NSCLC.

“Patients who have already progressed on chemotherapy and immunotherapy, if they have a KRAS G12C mutation, right now, the standard treatment option for these patients is docetaxel or gemcitabine, a salvage chemotherapy option,” he said. “Unfortunately, the response rate and the side effect profiles for these drugs are not that great. So, patients essentially have a lot of side effects and the response from these drugs is very modest. This treatment (sotorasib) is definitely a big advance for those patients who have that KRAS G12C mutation because the response rates are much higher, and patients respond better.”

Sotorasib was recently granted breakthrough therapy designation from the Food and Drug Administration (FDA) for use in patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, as determined via an FDA-approved test, following at least one prior systemic treatment.

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