Olomorasib Plus Pembrolizumab Generates Antitumor Activity in KRAS G12C+ NSCLC

Treatment with the second-generation KRAS G12C inhibitor olomorasib plus pembrolizumab (Keytruda) produced favorable safety in KRAS G12C–mutant non–small cell lung cancer (NSCLC), supporting the continued development of this combination in the first-line setting, according to data from the phase 1/2 LOXO-RAS-20001 trial (NCT04956640) presented during the2024 ASCO Breakthrough Conference.¹

In efficacy evaluable patients with metastatic disease being treated in the first line (n = 17), the objective response rate (ORR) with the combination was 77% and was composed entirely of partial responses (PR). 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) was NE (95% CI, 3.6-NE). The estimated 6- and 12-month PFS rates were both 72.8%.

In patients with previously treated KRAS G12C–mutant NSCLC (n = 43), the ORR was 40%, and included all PRs. PD and SD were the best responses in 42% and 16% of patients, respectively; 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, 0-17), the median time to response was 1.4 months, the median duration of response was NE.

“Olomorasib in combination with pembrolizumab demonstrates promising antitumor activity,” lead study author Yutaka Fujiwara, MD, PhD 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 mg and 100 mg dose level regardless of PD-L1 score and previous treatment, including immunotherapy and KRAS G12C inhibitor.”

Immunotherapy remains the cornerstone of first-line treatment for patients with KRAS G12C–mutant NSCLC; however, outcomes for these patients remain suboptimal.¹

“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 monotherapy demonstrated a favorable safety profile, with treatment-related adverse events (TRAEs) being predominantly grade 1. Notably, this safety profile was consistent even in patients who had discontinued previous KRAS G12C inhibitors due to toxicity, indicating a manageable toxicity profile.²

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 (n = 39), 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 (95% CI: 5.6-15.6). Notably, preliminary 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 5 parts: NSCLC (part B), CRC (part C), other solid tumors (part D), NSCLC with prior KRAS G12C inhibitor exposure (part E) and first-line NSCLC (part G).^1,3

Patients at least 18 years of age with locally advanced or metastatic solid tumors harboring a KRAS G12C mutation were enrolled onto the study. Other eligibility criteria included measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, 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 primary objectives 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; and ORR and duration of response per RECIST 1.1 criteria.

The current analysis features patients with KRAS G12C-mutant NSCLC who were enrolled onto part B4 (n = 48) and part G (n = 16) of the study and received pembrolizumab plus olomorasib.¹ The data cutoff was March 18, 2024. Patients in this population were treated with pembrolizumab plus oral olomorasib at a twice-daily dose of 50 mg (n = 15) or 100 mg (n = 49).

The median age was 67 years of age (range, 42-83), and the majority of patients were male (53%), White (47%), and had an ECOG PS of 1 (75%). 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 2 (range, 0-8), 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 treatment-related adverse effects (TRAEs) were observed in 70% of patients across all dose levels and populations; 86% experienced any grade treatment-emergent effects (TEAEs). TRAEs required 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 vs pembrolizumab, respectively, due to TRAEs; 5% discontinued both drugs due to TRAEs.

Common TRAEs 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 TEAEs 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%), arthralgia (19%; 0%), AST increase (17%; 8%), vomiting (17%; 0%), anemia (16%; 2%), decreased appetite (14%; 2%), cough (13%; 0%), dyspnea (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 9 days. These events resolved to grade 1 or baseline with dose modification and antidiarrheals in 92% of patients. All grade 3 ALT/AST resolved to grade 1 or baseline after a median of 6 days following dose modification and/or corticosteroids. No grade 2 or higher ALT/AST elevation had high-risk features. Elevated liver function tests were also less than 10x ULN without total bilirubin elevation and otherwise asymptomatic.

“Given these promising results, we are currently conducting a global, registrational, phase 3 trial called SUNRAY-01 [NCT06119581]”, Fujiwara concluded. The study will compare first-line olomorasib plus pembrolizumab with pembrolizumab plus placebo in KRAS G12C-mutant, locally advanced or metastatic NSCLC with a PD-L1 expression of at least 50%; or first-line olomorasib vs placebo in combination with pembrolizumab, pemetrexed and platinum-based chemotherapy in patients with this tumor type regardless of PD-L1 expression. The trial is currently open to enrollment.

Disclosures: Dr Fujiwara disclosed honoraria from Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo/UCB Japan, Lilly Japan, Merck, MSD, Nihonkayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, Yakult Pharmaceuticals; serving in a consulting or advisory role for AstraZeneca, Chiome Bioscience, Daiichi Sankyo, MSD, Ono Pharmaceutical, Otsuka; and institutional research funding from Abbvie, Amgen, Anheart Therapeutics, AstraZeneca, Bristol-Myers Squibb Japan, Chugai Pharma, Incyte, Lilly Japan, Merck Serono, MSD (Inst)

References

1. Fujiwara Y, Burns TF, Dragnev KH, et al. Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. J Clin Oncol. 2024, 42(suppl 23):195.doi:10.1200/JCO.2024.42.23_suppl.195
2. Updated data from the phase 1/2 study of olomorasib in KRAS G12C-mutant advanced solid tumors presented at the 2024 ASCO® Annual Meeting. News release. Lilly. June 1, 2024. Accessed August 8, 2024. https://investor.lilly.com/news-releases/news-release-details/updated-data-phase-12-study-olomorasib-kras-g12c-mutant-advanced
3. Study of LY3537982 in cancer patients with a specific genetic mutation (KRAS G12C). Clinicaltrials.gov. Updated July 29, 2024. Accessed August 8, 2024. https://clinicaltrials.gov/study/NCT04956640