Two Ways to Target Tumors with KRAS Mutations

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Tumors with KRAS mutation are notoriously difficult to treat. Early data presented at the 2020 American Association for Cancer Research virtual annual meeting suggest 2 new routes for the treatment of cancers with KRAS mutation, including (1) the combination of a RAF/MEK inhibitor and a FAK inhibitor, and (2) the use of onvansertib, an investigational competitive inhibitor of the PLK1 enzyme, together with chemotherapy.

Clinical Activity of RAF/MEK plus FAK Inhibitors

In a poster presentation, investigators led by Udai Banerji, MBBS, MD, DNB, PhD, FRCP, Drug Development Unit, Institute of Cancer Research and the Royal Marsden, London, England, described data from a phase 1 ongoing clinical trial with several investigational agents. In this study, VS-6766, a RAF/MEK inhibitor, used as monotherapy or in combination with defactinib, an FAK inhibitor, was explored in patients with advanced solid tumors and KRAS mutations.

MEK is downstream of KRAS, but “very frustratingly, previous MEK inhibitors have not worked,” said Dr Banerji. He noted that evidence supports FAK as part of a MEK signaling feedback loop that confers resistance to MEK inhibition, reinforcing the addition of the FAK inhibitor to the combination.

Treatment with the combination of VS-6766 and defactinib demonstrated a 67% overall response rate (ORR) in low-grade serous ovarian cancer with KRAS mutation.

In this combination study, VS-6766 was administered 3 weeks of every 4 weeks using a twice-weekly dose-escalation schedule. Defactinib was administered using a twice-daily dose-escalation schedule and was also given 3 weeks of every 4 weeks.

Among the 8 patients in the study with low-grade serous ovarian cancer, 4 patients showed responses, for an ORR of 50%. Among the 6 patients with KRAS mutation–positive low-grade serous ovarian cancer, 4 patients were responders, for an ORR of 67%. Of the 4 patients who responded, 3 received a previous MEK inhibitor and at the time of data analysis (November 2019) had been in the study for a median of 20.5 months.

Phase 3 clinical trial data show an ORR to MEK inhibition alone of 20% to 30% in solid cancers with KRAS mutation, said Dr Banerji. “And although the numbers are very small, we’re looking at much higher response rates with the addition of the FAK inhibitor,” he said.

“In this study, there were a couple of patients who had previously had MEK inhibitors and then became resistant, and they responded, so it’s possible that the FAK inhibitor is adding something,” Dr Banerji added.

The treatment was less effective in non–small-cell lung cancer (NSCLC) with KRAS mutation. All 10 patients with NSCLC had KRAS mutations, 1 of whom achieved a partial response and 8 of whom had disease control. One patient had a reduction in tumor size of 22% and was still receiving treatment at the time of data analysis. The median time on treatment for this cohort was approximately 18 weeks.

Based on an observation of higher response rates seen in patients with KRAS G12V mutations in the phase 1 combination study, a combined analysis was performed using data from the combination study and a previous single-agent study that used a twice-weekly dosing schedule of VS-6766. This combined analysis had a 57% ORR (4 of 7 patients), including 2 of 5 patients with NSCLC and KRAS G12V mutation who received VS-6766 as a single agent achieved a response and 2 of 2 patients who responded to combination treatment with defactinib.

The combined analysis had an ORR of 60%, as a single agent and in combination with defactinib in KRAS G12V mutation–positive gynecologic cancers.

Onvansertib Promising in Colon Cancer with KRAS Mutation

An ongoing phase 1b/2 trial of 12 patients with metastatic colorectal cancer and KRAS mutation demonstrated consistent tumor regression and durable response with oral onvansertib, a competitive inhibitor of the PLK1 enzyme, when combined with FOLFIRI chemotherapy and bevacizumab (Avastin), reported Afsaneh Barzi, MD, PhD, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles.

Of 12 patients enrolled in the study, 7 of 8 evaluable patients have had a partial response (N = 3) or stable disease (N = 4).

At the April 1 data cutoff, the onvansertib combination induced a median progression-free survival of 6.5 months, and 6 patients with responses are continuing treatment, said Dr Barzi.

The 8 evaluable patients received the 2 lowest doses of onvansertib, 12 mg/m2 and 15 mg/m2, in the dose-escalation phase. One of the 3 patients who were receiving the highest dose (18 mg/m2) had life-threatening neutropenia.

Changes in KRAS mutation blood levels during cycle 1 of treatment were highly predictive of tumor regression, said Dr Barzi. In all, 5 patients had a decrease in KRAS mutational burden to nondetectable levels in cycle 1 (28 days) and had subsequent tumor regression at 8 weeks, whereas 2 patients had detectable KRAS mutational burden at the end of cycle 1 and showed tumor growth at 8 weeks.

“So far we are observing what we had hoped for in this trial—lack of toxicity and positive signs of efficacy. We remain optimistic, because we are observing antitumor effects of onvansertib, which could present the opportunity for a new treatment designed to attack KRAS-mutated tumors and act synergistically with standard-of-care chemotherapy,” Dr Barzi said.

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