KRAS Inhibitor Shrinks Tumors in Over 40% of NSCLC Patients

CHICAGO — More than 40% of patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) responded to treatment with adagrasib, findings from a phase II trial showed.

Among 112 evaluable patients in the KRYSTAL-1 study, all of whom were previously treated, the confirmed objective response rate (ORR) was 42.9% with the investigational KRAS G12C inhibitor, reported Alexander Spira, MD, PhD, of Virginia Cancer Specialists Research Institute in Fairfax.

Median time to response was 1.4 months, while median duration of response (DOR) was 8.5 months (95% CI 6.2-13.8), he said here at the American Society of Clinical Oncology (ASCO) annual meeting.

“Adagrasib demonstrated promising clinical activity,” said Spira, “as well as what we would characterize as a manageable safety profile.”

Median progression-free and overall survival in the cohort were 6.5 months (95% CI 4.7-8.4) and 12.6 months (95% CI 9.2-19.2), respectively.

Most responders had a partial response (one complete) and 37% achieved stable disease, for a disease control rate of 80%.

“Based upon this data, a new drug application for adagrasib has been accepted and is currently under review at the FDA,” Spira noted, adding that an ongoing confirmatory trial is testing the drug versus docetaxel in previously treated NSCLC patients with KRAS G12C mutations.

“It’s important to see how this drug weighs against sotorasib [Lumakras], which is our currently approved KRAS G12C inhibitor in this line,” said ASCO-designated discussant Sukhmani Padda, MD, of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center in Los Angeles.

She noted that while most efficacy endpoints — response, disease control rate, time to response, DOR, as well as survival endpoints — were similar in both drugs’ registrational trials, high-grade toxicity was higher in the current adagrasib study.

As a result, dose interruptions (61%) and reductions (52%) with adagrasib were higher compared to what was seen in the phase II sotorasib trial (22% for both), said Padda. However, treatment discontinuation for toxicity was a similar 7% with both drugs.

While adagrasib has activity, Padda said she was “curious about a lower optimal starting dose. We talk about this all the time as it relates to targeted therapy, even with sotorasib.”

KRYSTAL-1 enrolled 116 NSCLC patients with a KRAS G12C mutation who were treated with adagrasib from January to December 2020 (data cutoff was Oct. 15, 2021 for the current analysis). Nearly all (98.3%) had previously received both chemotherapy and immunotherapy.

In an exploratory analysis examining co-occurring alterations, the confirmed ORR was 40.5% in those with STK11, 28.6% with KEAP1, 51.4% with TP53, and 58.3% with CDKN2A co-alterations. Only one of seven patients with a KEAP1 co-mutation and STK11 wild-type responded to treatment. Responses were similar in patients assessed for their PD-L1 status (41.7-46.8%).

For the subgroup of 33 patients with treated and stable central nervous system metastases, 33.3% (95% CI 18.0-51.8) had a confirmed intracranial response to adagrasib, and the median DOR of intracranial response was 11.2 months.

In the overall cohort, patients had a median age of 64, about two-thirds were women, 89% had metastatic disease, and adenocarcinoma was the predominant histology (97.4%).

Most of the patients were white (83.6%), while 7.8% were Black and 4.3% were Asian. The vast majority of patients were either former (86%) or current (9.5%) smokers. For PD-L1 expression, 40.5% had a tumor proportion score (TPS) of <1%, while 23.3% had a score of 1-49% and 10.3% had a TPS of 50% or greater.

Treatment-related adverse events (AEs) were reported in nearly all patients (97.4%), with the most common including diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), and fatigue (40.5%), as well as increased levels of alanine transaminase (ALT; 27.6%), blood creatinine (25.9%), and aspartate aminotransferase (AST; 25.0%).

Grade ≥3 treatment-related AEs occurred in 44.8%, the most common of which included anemia (14.7%), pneumonia (12.1%), dyspnea (10.3%), hyponatremia (8.6%), hypoxia (7.8%), fatigue (6.9%), acute kidney injury (6.9%), and increased levels of ALT and AST (5.2% for each). There were also two treatment-related deaths.