Mirati's KRAS drug shrinks 45% of NSCLC tumors, putting it in Amgen's slipstream on race to FDA

Mirati CEO Charles Baum, M.D., Ph.D. (Mirati)

Mirati Therapeutics’ KRAS drug MRTX849 has triggered responses in 45% of patients with non-small cell lung cancer (NSCLC). The result, which beats the 35% reported by KRAS rival Amgen, sets Mirati up to file for FDA approval of the drug in the second half of next year.

Excitement about the potential of medicines that hit KRAS, a target once considered undruggable, has driven Mirati’s share price up around 900% since the start of 2018. The surge is underpinned by evidence that the alteration targeted by Mirati and Amgen, KRAS G12C, drives resistance to existing medicines in around 14% of NSCLC patients, plus smaller numbers of people with colorectal and pancreatic cancers. 

Amgen showed its hand last month, revealing 35% of NSCLC patients responded to its KRAS prospect sotorasib. Now, Mirati has released data on 51 advanced NSCLC patients who received MRTX849 in phase 1/1b and phase 2 clinical trials. The update on MRTX849, also known as adagrasib, impressed observers.

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“It looks good so far,” Michael Yee and other analysts at Jefferies wrote in a note to investors. 

The objective response rate in the cohort was 45%. Among the 23 responders, 16 patients had a best tumor response of 40% or more. One patient had progressive disease. One patient was not evaluable as they underwent tumor imaging too early for the response to be assessed. The other 49 patients either had stable disease or partial responses. 

One of the partial responders initially had a complete response, only to have to stop treatment due to hypoxia. The patient had a second complete response when treatment resumed, and 100% tumor regression in target and non-target lesions was seen in two consecutive scans. 

Mirati only has 3.6 months median duration of follow-up on the 51 patients in the pooled analysis. As it stands, 65% of patients remain in treatment, including the complete responder, and 83% of the responders are yet to progress. The durability data on the 14 phase 1/1b patients, on whom Mirati has 8.2 months of follow-up, are similar. Four responders have been on treatment for 11 months. Amgen has more durability data.

Two patients in the 110-subject safety analysis died of treatment-related adverse events, one of pneumonitis and another of cardiac failure. Almost 5% of treatment-related adverse events led to the discontinuation of treatment. Around one-third of participants experienced grade 3 or 4 treatment-related adverse events, most commonly fatigue or increased levels of liver enzymes. The data suggest Amgen may have an edge over Mirati in terms of safety and tolerability. 

"Some questions remain regarding MRTX849's safety profile. Compared to AMG 510, MRTX849 had a higher rate of serious treatment-related adverse events," analysts at SVB Leerink wrote in a note to investors. "From Amgen’s point of view, the new data from '849 throw down the gauntlet on efficacy, but leave a window on safety and tolerability."

Mirati is continuing to enroll NSCLC patients in the phase 2 clinical trial with a view to having the data to file for accelerated approval in the second half of next year. That puts Mirati a little behind Amgen, which shared top-line phase 2 findings and plans to discuss them with the FDA earlier this month. The lead is another the advantages Amgen holds over Mirati. 

“While [Mirati] has shown slightly higher response rates ... we also think this is generally expected on the [Amgen] side, and [Amgen] is already preparing to file to FDA,” the Jefferies analysts wrote. 

Amgen and Mirati are both already looking past the initial data needed to win FDA approval to the additional evidence that will influence their commercial prospects. Buoyed by a reduction in the size of brain metastases in one patient, Mirati is now enrolling additional NSCLC patients with secondary brain tumors to assess the efficacy of MRTX849 in a population with high unmet needs. 

Both companies are also assessing the effect of giving their drugs in combination with other cancer medicines. Mirati saw a 60% reduction in the tumor volume of a heavily pre-treated NSCLC patient who received MRTX849 and Novartis’ experimental SHP-2 inhibitor TNO-155. Having also safely tested MRTX849 with Keytruda and Erbitux, Mirati has combination options as it seeks to establish its KRAS drug in earlier lines of treatment in NSCLC and colorectal cancer patients. 

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