Encouraging early data for Mirati's KRAS inhibitor adagrasib in lung, other cancers

Pooled efficacy data from Phase I/Ib and Phase II trials demonstrated that monotherapy with Mirati Therapeutics' adagrasib was associated with a 45% confirmed objective response rate (ORR) in previously treated patients with advanced non-small-cell lung cancer (NSCLC), the company announced. CEO Charles Baum said the preliminary findings, which were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics (ENA), "showed deep and durable anti-tumour activity" in NSCLC, as well as in colorectal cancer (CRC) and other solid tumours, "providing renewed hope for patients that harbour a KRAS G12C mutation."

According to Mirati, adagrasib is a selective inhibitor of KRAS G12C optimised for a long half-life and significant volume of tissue distribution, which the company says helps to "maintain continuous inhibition of KRAS-dependent signalling for the complete dose interval to maximise efficacy."

No progression for 83% of NSCLC responders

One of the analyses presented at the conference involved 51 advanced NSCLC patients across the Phase I/Ib and Phase II monotherapy cohorts who had received a median of two prior systemic treatments. All patients had previously been prescribed platinum-based chemotherapy regimens, while 92% had received prior treatment with an anti-PD-1/L1 inhibitor. Aside from the 45% ORR, results showed that the disease control rate (DCR) was 96%. Among responders, Mirati noted that 70% of subjects had a best tumour response that surpassed 40%, while 83% have not experienced disease progression and are still on treatment.

Mirati also reported findings from an early analysis of KRAS G12C plus STK11 co-mutations in advanced NSCLC, showing that nine out of 14 of these patients achieved ORR across the pooled cohorts. "Approximately 30% of all KRAS G12C-mutant NSCLC patients have a STK11 co-occurring mutation…[which has] been shown to be significantly correlated with poor clinical outcomes when treated with immunotherapy and platinum-based chemotherapy regimens," the company noted.

In addition, in one case study involving a heavily pre-treated NSCLC patient whose cancer spread to the brain, Mirati said adagrasib led to a 67% reduction in tumour volume, including the disappearance of a metastatic brain lesion. The drugmaker stated that the Phase II cohort of adagrasib as a monotherapy is currently enrolling additional NSCLC patients with active brain metastases to further explore the compound's effect in this population.

CRC, other solid tumours

Meanwhile, pooled efficacy data from Phase I/Ib and Phase II cohorts involving 18 patients with advanced CRC, who had received a median of four prior systemic treatments, showed that 17% achieved confirmed ORR, while the DCR was 94%. Further, 12 of the 18 patients remain on treatment, and 10 of these have been on it for over four months.

Mirati also presented early findings from a Phase I/Ib cohort involving patients with other types of advanced solid tumours, including one patient each with pancreatic, ovarian, endometrial and cholangiocarcinoma tumours. Data showed that all of these had a confirmed partial response to therapy, while two appendiceal cancer patients had stable disease. According to the company, all six eligible patients remain on treatment.

Filing slated for 2021

Baum remarked "this is a positive result any way you look at it, especially if you compare it to the current standard of care." He noted that adagrasib, formerly MRTX849, has also been well tolerated as a monotherapy and in combination with Merck & Co.'s Keytruda (pembrolizumab) and Eli Lilly's Erbitux (cetuximab), as well as the investigational SHP-2 inhibitor TNO-155. "Enrolment is complete in the Phase II cohort of adagrasib as a monotherapy treatment for patients in second- and third-line NSCLC, and we anticipate submitting a new drug application for accelerated approval in the second half of 2021," he said.

Wall Street observers expect that Mirati, as well as Amgen, which is developing the KRAS G12C inhibitor sotorasib, are both likely to receive accelerated approval for their respective treatments. For Mirati's drug, Bloomberg analysts are projecting annual sales to hit $2.3 billion by 2027.

Setting the bar against Amgen

Amgen recently released top-line Phase II results from the CodeBreaK 100 study, evaluating sotorasib, which is also known as AMG 510, in 126 patients with KRAS G12C-mutant advanced NSCLC who have failed a median of two prior lines of treatment, including immunotherapy and/or chemotherapy. However, the company provided few details, saying only that on the primary endpoint of ORR, sotorasib was "consistent with previously reported Phase I data in patients with advanced NSCLC taking the 960-mg daily dose." It said other measures of efficacy, including duration of response, were "promising," while over half of responders were still on treatment and continuing to respond as of the data cut-off.

For related analysis, see ViewPoints: Amgen keeps investors guessing with latest KRAS update, and ESMO ViewPoints: Amgen’s KRAS update looks good for regulators, and middling for investors.

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