Two Distinct Ways to Target KRAS-Mutant Tumors Hint at Efficacy

August 2020 Vol 11, No 8

KRAS-mutant tumors are notoriously difficult to treat. Early data presented at the 2020 virtual meeting of the American Association for Cancer Research suggest 2 new routes to treating KRAS-mutated cancers: (1) the combination of a RAF/MEK inhibitor and a FAK inhibitor, and (2) onvansertib, a competitive inhibitor of the PLK1 enzyme, together with chemotherapy.

Clinical Activity of RAF/MEK and FAK Combination

Udai Banerji, MD

In a poster presentation, investigators led by Udai Banerji, MD, described phase 1 data from an ongoing study in which VS-6766, a RAF/MEK inhibitor, as either monotherapy or in combination with defactinib, a FAK inhibitor, was explored in patients with KRAS-mutant advanced solid tumors.

MEK is downstream of KRAS, but “very frustratingly, previous MEK inhibitors have not worked,” said Dr Banerji, professor of molecular cancer pharmacology, The Royal Marsden and The Institute of Cancer Research, London. He said that evidence supports FAK as part of a MEK signaling feedback loop that confers resistance to MEK inhibition, supporting the use of the FAK inhibitor in the combination.

Combined treatment with VS-6766 and defactinib demonstrated a 67% overall response rate (ORR) in KRAS-mutant low-grade serous ovarian cancer (LGSOC).

In the combination study, VS-6766 was administered 3 of every 4 weeks using a twice-weekly dose-escalation schedule. Defactinib was administered using a twice-

daily dose-escalation schedule, also 3 of every 4 weeks. In cohort 1, VS-6766 was administered at 3.2 mg and defactinib at 200 mg. In cohort 2a, VS-6766 was dosed at 4 mg and defactinib at 200 mg; and in cohort 2b, VS-6766 was dosed at 3.2 mg and defactinib at 400 mg.

In the 8 patients with LGSOC, there were 4 responses, for an ORR of 50%. Among the 6 patients with KRAS-mutant LGSOC, there were 4 responders, for an ORR of 67%. Of the 4 patients who have responded, 3 had a prior MEK inhibitor and at the time of data analysis (November 2019) had been on study for a median of 20.5 months.

Randomized phase 3 data show an ORR to MEK inhibition alone of 20% to 30% in KRAS-mutant cancers, 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]. 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.”

The treatment was less effective in KRAS-mutant non–small-cell lung cancer (NSCLC). All 10 patients with NSCLC had KRAS mutations; 1 patient achieved a partial response and 8 had stable disease. One patient had a reduction in tumor size of 22% and was still on treatment at the time of data analysis. 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 prior single-agent study that used a twice-weekly dosing schedule of VS-6766. This combined analysis showed a 57% ORR (4/7 patients): 2 of 5 patients with KRAS G12V–mutant NSCLC who received VS-6766 single agent achieved a response, and 2 of 2 patients responded to combination treatment with defactinib.

The combined analysis showed a 60% ORR (3/5 patients); as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRAS G12V–mutant gynecologic cancers.

Early Onvansertib Data Offer Hope for KRAS-Mutant Colon Cancer

An ongoing phase 1b/2 trial of 12 patients with KRAS-mutated metastatic colorectal cancer demonstrated consistent tumor regression and durable response with oral onvansertib, a competitive inhibitor of the PLK1 enzyme, when combined with FOLFIRI chemotherapy and bevacizumab, reported Afsaneh Barzi, MD.

Of 12 patients enrolled, 7 of 8 (88%) evaluable patients have had either 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, associate professor of clinical medicine, Keck School of Medicine of the University of Southern California, Los Angeles.

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

Changes in KRAS mutation blood levels during cycle 1 of treatment were highly predictive of tumor regression, said Dr Barzi. Five patients had a decrease in KRAS mutation to nondetectable levels in cycle 1 (28 days) and had subsequent tumor regression at 8 weeks, while 2 patients had detectable KRAS mutation 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-mutant tumors and act synergistically with standard-of-care chemotherapy,” she said.

Related Articles
Keynote: Genetic Therapies Will Explode, Better Access to Data Will Drive Value
June 2022 Vol 13, No 6
Over the past 5 years, there have been 20 FDA approvals of novel genetic medicine technologies – and this is just the beginning. Here’s a glimpse of what’s coming ahead.
Empowering the Patient Voice: Genomic Testing and Cancer Care Decisions
Frank dela Rama, RN, MS, AOCNS, Sara Campbell, BS, BSN, OCN, Jim G.
|
Video Library
In this roundtable discussion presented by AONN+ and supported by Exact Sciences, a panel of experts discuss the critical role of nurse navigators in educating cancer patients about genomic testing and how to interpret the results.
AONN+ 2020 CEU Monograph: Early Detection, Vaping, Fertility Preservation, and Genetic Testing
Meg Barbor, MPH
|
December 2020 Vol 11, No 12
Proceedings from key sessions from an AONN+ conference are presented in this CEU activity.
Last modified: August 10, 2023

Subscribe Today!

To sign up for our print publication or e-newsletter, please enter your contact information below.

I'd like to receive:

  • First Name *
    Last Name *
     
     
    Profession or Role
    Primary Specialty or Disease State
    Country