The current market of NSCLC harboring KRAS mutations comes with major challenges and limited treatment options. KRAZATI (adagrasib) is a highly selective and potent oral small molecule inhibitor of KRASG12C and Mirati’s flagship product being investigated for multiple indications. KRAS mutations are seen most frequently in pancreatic cancer, followed by colorectal cancer and NSCLC. The most frequent KRAS variant observed in NSCLC is G12C. In addition, the most common KRAS variation in CRC and pancreatic cancer is G12D. In the United States, KRASG12C is present in ~40% of KRAS NSCLC cases. Mirati Therapeutics made waves in the market when they secured approval for their KRAS inhibitor KRAZATI last year. The drug was approved in December 2022 for adult patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one systemic therapy. KRAZATI’s response data is best-in-class so far in G12C in NSCLC, with no black box warning of QTc prolongation. KRAZATI's second-line NSCLC label is better than LUMAKRAS. KRAZATI's debut coincided with LUMKRAS' sequential sales fall.  Mirati is now planning to enter the first-line setting in combination with pembrolizumab for patients with PD-L1 TPS ≥50%.

The Phase II/III KRYSTAL-7 trial (NCT04613596) is examining the safety and efficacy of KRAZATI (adagrasib) as a monotherapy and in combination with pembrolizumab in patients with advanced NSCLC whose tumors harbor a KRAS G12C mutation. In patients with PD-L1 TPS ≥50%, the combination demonstrated an ORR of 63% and a DCR of 84% as of June 2023. The median DOR was not reached and the median PFS was also not reached. 

The most common treatment-related adverse events (TRAEs) were nausea and diarrhea (any grade 51% and 44%, respectively). Looking specifically at liver TRAEs, 16% of patients had grade ≥ 3 treatment-related alanine aminotransferase (ALT) and raised aspartate aminotransferase (AST) increase. This is notable because, for LUMAKRAS (sotorasib), 27% to 37% of patients had severe grade ≥ 3 treatment-related ALT/AST increase when the KRAS inhibitor was given in sequence or concurrently with a PD-L1 inhibitor. 

These compelling findings have spurred Mirati to plan the initiation of a Phase III trial evaluating the concurrent use of KRAZATI and pembrolizumab vs. pembrolizumab alone in treatment-naïve KRAS G12C patients. The Phase III KRYSTAL-7 trial plans to begin enrollment at the end of this year.

KOL insights

“The results of the KRYSTAL-7 phase II trial found adding adagrasib to pembrolizumab in patients with advanced, unresectable, or metastatic NSCLC with KRASG12C mutation showed “encouraging preliminary activity”, especially in patients with high PD-L1 expression (Tumor Proportion Score [TPS] ≥ 50%).”-Associate professor, Thoracic Oncology & Phase-I, USA

“KRYSTAL-7: Excellent results of adagrasib + pembrolizumab 1st line KRAS G12C NSCLC in PD-L1 >50% (ORR 63%) with low rate of TRAEs leasing to discontinuation.” -MD, PhD, Head of Thoracic Oncology & Clinical Trials, Spain

“I am interested in KRYSTAL-7, [which is] looking at adagrasib (Krazati) and pembrolizumab, as there have been a lot of challenges with combining TKIs and immuno-oncology [IO] historically, and both adagrasib and IO are active in KRAS-mutant NSCLC.”-MD, Stanford Medicine, USA

Conclusion

The synergy between KRAZATI and pembrolizumab has yielded highly promising results, paving the way for a Phase III trial. While further data is required to solidify the efficacy signals from the KRYSTAL-7 trial, including its performance in low PD-L1 expressers, this combination is projected to enter the first-line treatment landscape in the United States by 2027, capturing a substantial market share. The company is optimistic about the prospects of its developmental product, as indicated by the imminent Phase III initiation in the first-line setting. 

KRAZATI got approval in the second line in the United States but the story seems to be different for Europe. Mirati’s optimism was dampened when, earlier this year (July 2023), the Committee for Medicinal Products for Human Use gave a negative opinion on their Conditional Marketing Authorisation Application. Mirati intends to continue supplying KRAZATI under early access in EU Member States in alignment with applicable laws and regulations. 

KRAZATI has an safety edge over LUMAKRAS’s safety profile. Its lower hepatotoxicity in combination with PD-L1 inhibitors sets it apart from the competition. In patients with therapy-naïve NSCLC, LUMAKRAS has previously demonstrated  hepatotoxicity when used in combination with immune checkpoint inhibitors (such as pembrolizumab) as a first-line treatment. Because of its low peak-to-trough ratio and steady-state pharmacokinetics, KRAZATI, however, does not appear to be as hepatotoxic as LUMAKRAS. KRAZATI is poised to capture a significant market share, worth millions in KRAS-mutated NSCLC. Bristol Myers Squibb recently made headlines when it revealed that it will purchase Mirati for up to USD 5.8 billion, diversifying its oncology business. This move signifies a significant shift in the pharmaceutical landscape and opens new doors of opportunity for both companies. 

Prior to the approval of the first drug LUMAKRAS (licensed for KRAS G12C mutant NSCLC), KRAS mutations were historically thought to be undruggable. DelveInsight estimates that the total metastatic KRAS-mutated NSCLC market size in the 7MM is expected to reach around USD 8 billion by 2032 and KRAZATI will capture roughly 15-20% of the market share by 2032. The most frequent KRAS variant in NSCLC is G12C. Since the majority of treatments for NSCLC now target the G12C variant, this variant type is likely to become crowded and competitive. Future opportunities in G12C may be found in R/R patient’s pool of approved KRAS drugs and in the first-line setting.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the KRAS-mutated NSCLC Market Insight, Epidemiology And Market Forecast Report.

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.