Lumakras Improves Outcomes, Quality of Life in Patients With Lung Cancer Subtype

Lumakras outperformed chemotherapy in reducing the risk of progression or death and improving quality of life for patients with KRAS G12C-mutated non-small cell lung cancer, study results showed.

Lumakras (sotorasib) decreased the risk of disease progression or death by 34% in patients with previously treated non-small cell lung cancer (NSCLC), and the drug led to more patients being alive without disease progression at 12 months (a statistic known as progression-free survival) compared to the chemotherapy docetaxel, according to findings from the phase 3 CodeBreaK 200 clinical trial.

The study results, which were presented at the 2022 European Society of Medical Oncology Congress, showed that at a median follow-up of 17.7 months, the 12-month progression-free survival rate was 24.8% with Lumakras compared with 10.1% with docetaxel. On average, patients lived for 5.6 months on Lumakras before their disease progressed, compared to 4.5 months for those given docetaxel.

Of note, there were fewer severe side effects with Lumakras, a KRAS G12C inhibitor, compared with the chemotherapy agent, docetaxel (33.1% compared to 40.4%, respectively). Additionally, serious side effects were less common with Lumakras than docetaxel (10.7% versus 22.5%).

“The (progression-free survival) rate doubled and the (progression-free survival) benefit was seen across all subgroups tested. Likewise, the secondary end points of objective response rate (which measures how much tumors shrink from treatment), disease control rate, time to response and duration of response were all significantly improved in favor of (Lumakras),” said study author Dr. Melissa L. Johnson, director of the Lung Cancer Research Program Sarah Cannon Research Institute in Nashville, Tennessee. “In my opinion, this supports (Lumakras) as a new second-line standard for patients with KRAS G12C–mutated NSCLC.”

Based on findings from the earlier phase 1/2 CodeBreaK 100 trial, the Food and Drug Administration (FDA) granted Lumakras an accelerated approval in May 2021 for patients with KRAS G12C–mutated locally advanced or metastatic NSCLC. In this study, the objective response rate was 36% for a median duration of 10 months.

CodeBreaK 200 Continues to Show Efficacy With Lumakras

The global phase 3 CodeBreaK 200 study enrolled 345 patients with locally advanced, unresectable, or metastatic KRAS G12C–mutated NSCLC. The study was originally designed to enroll 650 participants but was reduced to approximately 330, based on guidance from the FDA. The agency requested that patients in the docetaxel group be able to crossover to receive Lumakras following disease progression.

The median overall survival, which is the time from treatment until death of any cause, was 10.6 months with Lumakras, compared with 11.3 months with docetaxel, though these findings were not statistically significant, meaning that the researchers could not say for certain that the separate treatment regimens led to the difference in survival time.

Thirty-six percent of patients in the Lumakras group received a subsequent therapy at crossover compared with 42% in the docetaxel group. A subsequent KRAS G12C inhibitor was received by 34% of patients in the docetaxel group. The most common treatment at crossover for those in the Lumakras group was chemotherapy (21%).

“The trial was initially twice as big and when the CodeBreaK 100 data read out, the FDA suggested strongly that the trial be amended to reduce the number of patients enrolled by half, so it would decrease the number of patients randomized to docetaxel,” Johnson said.

Patients with active brain metastases were excluded from the study, although a history of brain metastases was allowed, Johnson noted. A brain metastasis occurs when cancer cells spread from their original site to the brain. According to the Mayo Clinic, lung cancer is one of a few cancers that are most likely to cause brain metastases.

The objective response rate with Lumakras was 28.1%, compared with 13.2% with docetaxel. When also considering patients with stable disease, the overall disease control rate was 82.5% for Lumakras compared with 60.3% with docetaxel.

Any degree of tumor shrinkage was seen in 80.4% of patients treated with Lumakras compared with 62.8% in those treated with docetaxel.

The median percent change in tumor size for responders was 58.8% with Lumakras, compared to 48.5% with docetaxel. Median time to response was 1.4 months and 2.8 for Lumakras and docetaxel, respectively. Median duration of response was 8.6 months with Lumakras compared with 6.8 months for docetaxel.

“Secondary end points were all significantly improved in favor of (Lumakras),” said Johnson. “Response, disease control, time to response, and duration were all positive in favor of (Lumakras).”

Lumakras Side Effects, Quality of Life

Side effects leading to treatment discontinuation were experienced by 9.5% of patients in the Lumakras group compared with 11.3% with docetaxel. The most common side effects between Lumakras and docetaxel, respectively, were diarrhea (33.7% versus 18.5%), nausea (14.2% versus 19.9%), alanine aminotransferase (ALT) increase, which could indicate liver damage (10.1% versus 0%), aspartate aminotransferase (AST) increase, which is also indicative of liver disease (10.1% versus 0%) and fatigue (6.5% versus 25.2%).

The most common severe side effects observed with Lumakras were diarrhea (11.8%), ALT increase (7.7%) and AST increase (5.3%).

“In CodeBreaK 100 as well as 200, the safety signals are pretty similar,” Johnson said. “There were 10% to 20% of patients who hit grade 3 (liver toxicity) but it was amenable to dose reduction and dose hold followed by restarting.”

According to information from the National Cancer Institute, a grade 3 side effect is considered to be severe.

Patient-reported outcomes were improved with Lumakras compared to docetaxel, including time to deterioration in global health status, physical function and cancer-related symptoms. For quality of life, there was a 31% reduction in the risk of quality-of-life deterioration with Lumakras. The drug also delayed physical functioning deterioration by 31% over docetaxel.

The worsening of key cancer-related symptoms were also delayed significantly with Lumakras. There was a 37% reduction in the risk of dyspnea (difficult or labored breathing) and the risk of cough worsening was delayed by 45% with Lumakras. Chest pain deterioration was numerically delayed with Lumakras, with lower scores seen with docetaxel (27.3 compared to 34.9); however, this finding was not statistically significant.

“(Lumakras) is oral daily, versus IV for docetaxel every three weeks. You lose your hair with docetaxel. Patients don’t lose their hair with (Lumakras), for example,” Johnson said. “There are a lot of subtle ways this data shows how much better quality of life is for patients, and the patient-reported outcomes also show that.”

Continued Study of Lumakras

The phase 1/2 CodeBreaK 101 trial continues to enroll patients to explore potential Lumakras combination therapies for solid tumors with KRAS G12C mutations. There are also several phase 1/2 studies exploring various Lumakras combinations across settings. Additionally, the phase 3 CodeBreaK 300 trial (NCT05198934) is exploring Lumakras with Vectibix (panitumumab) for patients with KRAS G12C–mutant colorectal cancer.

“We look at (CodeBreaK 200) as the first step. There are more studies ongoing adding other drugs to it,” Johnson concluded. “It is well tolerated, so it will pair nicely with other drugs inhibiting MAP kinase, EGFR, even PD-L1.”

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