Greenlight for launching KRAS inhibitors for lung cancer

Lilly and MSD are developing new 2nd-generation drugs…selective KRAS G12C inhibitors

Clinical trials for olomorasib·MK-1084 are showing progress…overcoming resistance and expanding combination therapy strategies are gaining attention

Next-generation KRAS inhibitors are emerging as a new game-changer in the lung cancer treatment market.

 

While first-generation KRAS inhibitors, such as Amgen's Lumakras and BMS's Krazati, have been commercialized, concerns have risen regarding their limitations in terms of resistance and restricted indications.

 

As a result, global pharmaceutical companies are now jumping into the competition with their next-generation pipelines.

 

KRAS is a protein that plays a key role in cell growth, differentiation, and survival, and it induces tumor formation through various mutations.

 

Although it is frequently found in non-small cell lung cancer (NSCLC) and colorectal cancer, existing drugs have failed to provide a clear therapeutic benefit to most patients, except for specific types of lung cancer patients.

 

Consequently, the development of 2nd-generation KRAS inhibitors is rapidly emerging as a key project in global oncology research.

 

Lilly's olomorasib in Phase 3 Trials...Combination with Keytruda·Chemotherapy

Eli Lilly unveiled the clinical results of its 2nd-generation KRAS inhibitor, olomorasib, at the World Conference on Lung Cancer (WCLC 2025), held in Barcelona, Spain, from September 6-9 of this month.

 

Olomorasib is classified as a next-generation KRAS inhibitor candidate as it shows anti-tumor activity even in patients with a history of treatment with existing KRAS G12C inhibitors.

 

It was also designated as a 'Breakthrough Therapy' by the U.S.

 

Food and Drug Administration (FDA) earlier this month.

 

The clinical results presented at WCLC 2025 are based on data from the Phase 1 (LOXO-RAS-20001) and the early cohort of the Phase 3 (SUNRAY-01) studies.

 

The studies were conducted in first-line NSCLC patients stratified by their PD-L1 expression level.

 

The goal of the SUNRAY-01 study is to prove superiority in first-line NSCLC treatment with a PD-L1 expression level of 50% or more, by comparing olomorasib + Keytruda with placebo + Keytruda.

 

According to Lilly, 85 patients received the olomorasib and Keytruda combination therapy, and 17% of them had already started Keytruda treatment for one cycle before enrollment.

 

The clinical results showed an objective response rate (ORR) of 71%.

 

Notably, the patient group with PD-L1 expression of 50% or more who received 100mg of olomorasib (26 patients) showed an 85% response rate.

 

The median duration of response (DOR) has not yet been reached.

 

The progression-free survival (PFS) rate was 77% at 6-month.

 

In terms of safety, diarrhea (29%) and elevated liver enzyme levels (AST/ALT 25-26%) were reported as the most common adverse events.

 

Grade 3 or higher adverse events were elevated ALT (18%), AST (14%), and diarrhea (7%).

 

Most adverse events were manageable through dose reduction (29%) or steroid treatment.

 

Treatment discontinuation occurred in 9% of patients, but an overall manageable safety profile was maintained.

 

Olomorasib also yielded notable results in the Phase 1 combination trial with chemotherapy (LOXO-RAS-20001).

 

A total of 78 patients received olomorasib + Keytruda + chemotherapy combination therapy, with PD-L1 expression distribution of 35% for less than 1%, 40% for 1-49%, and 22% for 50% or more.

 

A high proportion of high-risk patients was included.

 

The ORR in this patient group was 59%, and it was 64% in patients who received a high dose (100mg).

 

The median DOR was 10.5 months, and PFS was 11.6 months, showing a significant therapeutic effect even when combined with chemotherapy.

 

The safety profile overlapped with the characteristics of chemotherapy.

 

Anemia (35%), nausea (37%), fatigue (32%), and diarrhea (30%) were the most commonly reported symptoms.

 

Grade 3 or higher adverse events included anemia (14%), neutropenia (12%), and elevated liver enzymes (12%).

 

These were also manageable through dose adjustments (15%) and treatment discontinuation (6%).

 

Based on this data, Lilly is accelerating Phase 3 studies such as SUNRAY-02.

 

SUNRAY-02 is evaluating olomorasib + Keytruda + chemotherapy in the entire PD-L1 patient population.

 

The industry is paying attention to the possibility of Lilly positioning olomorasib as a first-line NSCLC treatment regardless of PD-L1 expression levels.

 

There are high expectations that it could become a new option for patient groups with limited treatment opportunities due to resistance issues.

 

MSD Also Developing Next-Generation KRAS G12C for NSCLC Treatment

MSD

MSD is also aiming to enter the KRAS inhibitor market by putting MK-1084 at the forefront.

 

MK-1084 is currently in Phase 1/2 trials for solid tumors, including NSCLC and CRC.

 

MSD's strategy is to combine it with Keytruda for lung cancer and with Erbitux for colorectal cancer.

 

To address the issues of resistance and limited duration of treatment for KRAS inhibitor monotherapies, MSD's goal is to improve response rates and survival by synergizing with PD-1 inhibitors and targeted therapies.

 

In the Phase 1 KANDLELIT-001 study, MK-1084 demonstrated positive anti-tumor activity in both colorectal cancer and NSCLC as a monotherapy and in combination therapies.

 

In the colorectal cancer patient group, MK-1084 monotherapy showed an ORR of 38%, 46% when combined with cetuximab, and 38% when combined with cetuximab + chemotherapy (mFOLFOX6).

 

Including unconfirmed responses during the follow-up period, the ORR reached as high as 66%.

 

The results were even more pronounced in lung cancer patients.

 

MK-1084 monotherapy had an ORR of 38%, but it achieved a high response rate of 77% when combined with Keytruda, and 53% when combined with Keytruda + chemotherapy.

 

The safety was also reported to be manageable.

 

Elevated liver enzyme levels and hematological abnormalities were the main side effects, but most were controlled through dose adjustments and adjuvant therapy.

 

MSD is accelerating the commercialization of MK-1084 through subsequent Phase 3 studies, KANDLELIT-004 (lung cancer) and KANDLELIT-012 (colorectal cancer).