Leading Players in Undruggable KRAS Mutation

Undruggable KRAS Mutation

Amgen and Mirati – Leading Players With High Hopes for the Undruggable KRAS Mutation?

ASCO 2021 Annual Meeting will be conducted virtually for the second year in a row and holds impressive new developments just as last year. As Amgen is also set to present its overall survival and exploratory subgroup analyses along with patient-reported outcomes (PRO) from its Phase II CodeBreaK 100 trial in the upcoming conference, DelveInsight analyzes key players striving to meet the extraordinary unmet need of establishing KRAS as a druggable target.

It has taken decades of research to finally target KRAS mutation. KRAS is an oncogene that impacts the growth of lung, pancreatic, and colorectal cancers, and as the mutation is extremely heterogeneous, the first approval is expected for KRASG12C; KRASG12C mutation is prevalent in 14% of NSCLC, 3–4% of colorectal cancer, and 2% of pancreatic cancer patients.

Amgen’s much-hyped Lumakras (sotorasib) is on track to make the home stretch leaving behind Mirati’s Adagrasib. Amgen is conducting one of the broadest global KRASG12C programs with eight regulatory submissions for advanced NSCLC evaluating Lumakras as monotherapy and in combination with docetaxel or an anti-PD-1/L1. The company is also evaluating Lumakras in combination with other targets that inhibit MEK, SHP2, EGFR, mTOR, CDK mutations etc. It has been assessed in a Phase II CodeBreak 100 trial in second line NSCLC. Interestingly, the study showed a durable response rate of 37.1%, a disease control rate of 80.6%, and a median progression-free survival of 6.8 months. Based on these results, Amgen filed an NDA to the FDA and EMA in December 2020. Not only the drug has received a priority review through its breakthrough designation, but the FDA is also reviewing its NDA under its Real-time Oncology Review (RTOR) pilot program too. Apart from NSCLC, Amgen and Mirati move head-to-head, targeting metastatic colorectal cancer (mCRC) as their second indication. However, Amgen again takes the lead with Phase II mCRC trial data expected in the first half of 2021 and submission in the following year. Considering these achievements, along with a speedy review process, Amgen is definitely moving at an accelerated pace and has already started enrolling for its confirmatory Phase III CODEBREAK 200 trial, making it a probable historic milestone in lung cancer therapy.

Despite all the progress made, we cannot overlook the fact that recently in April, the FDA proposed a postmarketing requirement and requested Amgen to study a lower dose of Lumakras at 240 mg, as the agency is concerned about the safety and efficacy of Lumakras at the current high dose of 960mg. On the other hand, the FDA has not requested a similar study from Mirati, as the company wisely evaluates several clinical trials at different doses. Can there be a dosing related issue with Lumakras, and will it impact its approval? As of now, the company does not expect any impact on the approval timelines; however, the news has created suspicion in our minds, and we eagerly look forward to the trial results at higher dosing.

In comparison, competitor Mirati remains in hot pursuit with adagrasib monotherapy, as the company expects to share monotherapy data from its Phase I/II KRYSTAL-01 trial in the second half of 2021 simultaneously preparing to file an NDA during the same time in second/third line NSCLC. Mirati is also evaluating adagrasib along with Novartis’ experimental SHP-2 inhibitor, TNO155, in both NSCLC and mCRC patients, and is expected to provide an update later in 2022. Interestingly, Novartis is also presenting its initial results from a dose finding study of TNO155, in adults with advanced solid tumors during the upcoming ASCO 2021.

 When compared with Lumakras’ 37% response rate, Adagrasib has triggered responses in 45% of patients in its Phase I/II study, although in a relatively smaller clinical trial. When evaluating the percentage of tumor responses, there were almost 70% of adagrasib responders who had tumor responses greater than 40% from baseline, while only 47% of Phase I study patients on Lumakras could say the same; however, the number of clinical trials assessed were higher in Lumakras.

Moreover, we also believe that Adagrasib’s stronger efficacy has been weighed down by side effects such as increased incidence of a serious heart rhythm problem (QT prolongation), which comes as an advantage for Lumakras. We need to be more vigilant when comparing cross trials as it largely depends on the trial designs and profiles of the patients. Excitingly, both Mirati and Amgen have initiated physician marketing campaigns to spread awareness about the importance of genetic testing and the role of KRAS activity in lung cancer among oncologists. We assume this move to be fruitful for both the competitors in the long run, as both have colorectal and pancreatic cancer in their future bucket list too.

The battle to become the foremost market entrant with its KRAS inhibitor remains between Amgen, which has already filed Lumakras in the US, and Mirati’s adagrasib, likely to be filed in the second half of 2021. However, we believe that Amgen will likely be the first company to enter the KRAS market as Lumakras is set for a decision from the FDA on its first indication in NSCLC in August 2021. In addition, there is a list of pharma companies queuing up to Amgen and Mirati, including Eli Lilly, Boehringer Ingelheim, Cardiff Oncology, Revolution Medicines, along with Moderna/Merck, working to advance their respective KRAS inhibitors already in clinical trials.