Olomorasib plus Keytruda was proven to be safe and well tolerated for patients with KRAS G12C-mutant non-small cell lung cancer.
The novel drug, olomorasib, when given with Keytruda (pembrolizumab), was safe and effective in treating KRAS G12C-mutant non-small cell lung cancer (NSCLC), according to data from the phase 1/2 LOXO-RAS-20001 trial presented at the 2024 ASCO Breakthrough Conference.
Study Highlights:
In efficacy-evaluable patients with metastatic disease being treated in the first line (17 patients), the objective response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) with the combination was 77% and was composed entirely of partial responses (PR; disease shrunk but did not disappear). The best responses to treatment included stable disease (SD; 12%) and progressive disease (PD; 6%), although 6% of patients were not evaluable (NE). At a median follow-up of 5.5 months, the median progression-free survival (PFS; time patients live without their disease worsening) was NE. The estimated six- and 12-month PFS rates were both 72.8%.
In patients with previously treated KRAS G12C-mutant NSCLC (43 patients), the ORR was 40% and included all PRs. PD and SD were the best responses in 42% and 16% of patients, respectively. The best response was NE in 2% of patients. Notably, 81% of previously treated patients had received prior immunotherapy.
Across both groups, the median time on treatment was 3.5 months (range, 0 to 17 months), the median time to response was 1.4 months and the median duration of response was NE.
“Olomorasib in combination with pembrolizumab demonstrates promising antitumor activity,” lead study author Dr. Yutaka Fujiwara, chief of the Department of Thoracic Oncology at Aichi Cancer Center Hospital in Aichi, Japan, stated in an oral presentation of the data. “We have responses at both the 50-milligram and 100-milligram dose level regardless of PD-L1 score and previous treatment, including immunotherapy and KRAS G12C inhibitor.”
PD-L1 is a protein that immunotherapy agents, like Keytruda, target. Higher PD-L1 scores are typically associated with a better response to these agents, according to the American Cancer Society.
Immunotherapy remains the cornerstone of first-line treatment for patients with KRAS G12C-mutant NSCLC; however, outcomes for these patients remain suboptimal.
“Prognosis for [patients with] KRAS G12C-mutant NSCLC remains poor, despite the approval of first-generation KRAS inhibitors, which are currently limited to second or later line use. Further progress may be achieved with the addition of targeted therapy to immunotherapy in NSCLC,” Fujiwara added.
Olomorasib, a potent and selective second-generation inhibitor of GDP-bound KRAS G12C, is emerging as a candidate to address these unmet needs. Previously reported data from the LOXO-RAS-20001 study showed that olomorasib, when given alone, demonstrated a favorable safety profile, with treatment-related side effects being predominantly grade 1 (mild). Notably, this safety profile was consistent even in patients who had discontinued previous KRAS G12C inhibitors due to toxicity, indicating a manageable toxicity profile.
Moreover, efficacy for olomorasib monotherapy was consistent across a range of KRAS G12C-mutant solid tumors. Among patients with NSCLC who were previously treated with a KRAS G12C inhibitor (39 patients), the agent produced an ORR of 41%, with 63% having received a KRAS G12C inhibitor as their immediate prior therapy. The median PFS was 8.1 months.
Notably, preliminary central nervous activity (CNS) activity was seen, with CNS responses observed in patients with NSCLC and measurable brain metastases.
LOXO-RAS-20001 is an open-label, multicenter, study evaluating the safety, tolerability and preliminary efficacy of olomorasib in patients with advanced solid tumors harboring KRAS mutations.
The study begins with a phase 1a dose escalation phase evaluating olomorasib monotherapy in KRAS G12C-mutant solid tumors, as well as a phase 1b dose expansion and optimization phase assessing olomorasib as both monotherapy and in combination with other agents. The dose expansion phase is further divided into the following five parts:
Patients at least 18 years of age with locally advanced or metastatic solid tumors harboring a KRAS G12C mutation were enrolled in the study. Other eligibility criteria included measurable disease, an ECOG performance status of 0 or 1 (meaning that they could independently perform all daily tasks), and no prior exposure to a KRAS G12C inhibitor except where indicated. In part B4, patients were permitted to have prior exposure to chemotherapy, anti-PD-L1 therapy, or a KRAS G12C inhibitor. No prior therapy for metastatic disease was permitted in part G.
The study’s main goals were to establish safety and tolerability, as well as the maximum tolerated dose and recommended phase 2 dose of the agent. Key secondary end points included pharmacokinetics (how the body and drug interact); and ORR and duration of response.
The current analysis features patients with KRAS G12C-mutant NSCLC who were enrolled in part B4 (48 patients) and part G (16 patients) of the study and received Keytruda plus olomorasib. The data cutoff was March 18, 2024. Patients in this population were treated with Keytruda plus oral olomorasib at a twice-daily dose of 50 milligrams (15 patients) or 100 milligrams (49 patients).
The median age was 67 years of age (range, 42 to 83 years old), and the majority of patients were male (53%), White (47%), and had an ECOG PS of 1 (75%; no restrictions on daily tasks). Brain metastases were observed in 38% of patients and 31% had first-line metastatic disease.
Regarding PD-L1 expression score, 28%, 27%, 27% and 19% had a score of 50% or greater, less than 1%, between 1% to 49%, and unknown, respectively.
“When we look at the PD-L1 scores, there was a well-balanced distribution,” Fujiwara added.
The median number of prior systemic lines of therapy was two (range, 0 to eight prior lines of therapy), and 69% of patients received either platinum-based chemotherapy plus a PD-L1 inhibitor (82%); platinum-based chemotherapy alone (18%); or a KRAS G12C inhibitor (39%). Among patients who were previously exposed to a KRAS G12C inhibitor, patients discontinued treatment due to disease progression (76%), toxicity (18%), and other reasons (6%).
Regarding safety, any grade side effects were observed in 70% of patients across all dose levels and populations; 86% experienced any grade treatment-emergent side effects. Side effects led to dose holds in 25% of patients and olomorasib dose reductions in 17% of patients in the overall population. Only 3% and 11% of patients permanently discontinued olomorasib versus Keytruda, respectively, due to side effects; 5% discontinued both drugs due to side effects.
Common side effects in 10% or more of patients included diarrhea (any grade, 23%; grade 3, 13%), fatigue (16%, 0%), alanine transaminase (ALT) increase (20%; 6%), pruritis (19%; 3%), aspartate transaminase (AST) increase (16%; 8%) and nausea (14%; 0%).
The incidence of side effects in at least 10% of patients included diarrhea (any grade, 28%; grade 3 or higher, 13%), fatigue (27%; 0%), ALT increase (25%; 8%), pruritis (25%; 3%), nausea (23%; 0%), joint pain/stiffness (19%; 0%), AST increase (17%; 8%), vomiting (17%; 0%), anemia (16%; 2%), decreased appetite (14%; 2%), cough (13%; 0%), difficulty breathing (11%; 5%), hypokalemia (11%; 3%) and headache (11%; 0%).
Investigators noted that grade 2 or higher diarrhea was unusually brief, with a median duration of nine days. These events resolved to grade 1 or baseline with dose modification and antidiarrheals in 92% of patients. All grade 3 ALT/AST (indicating liver issues) resolved to grade 1 or baseline after a median of six days following dose modification and/or corticosteroids. No grade 2 or higher ALT/AST elevation had high-risk features.
“Given these promising results, we are currently conducting a global, registrational, phase 3 trial called SUNRAY-01”, Fujiwara concluded. The study will compare first-line olomorasib plus Keytruda with Keytruda plus placebo in KRAS G12C-mutant, locally advanced or metastatic NSCLC with a PD-L1 expression of at least 50%; or first-line olomorasib versus placebo in combination with Keytruda, pemetrexed and platinum-based chemotherapy in patients with this tumor type regardless of PD-L1 expression. The trial is currently open to enrollment.
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