Two Novel Agents Target Emerging Molecular Alterations in Patients With Solid Tumors

In solid tumors, targeted therapies are scarce for patients with mutations likeKRASor fusions likeNRG1. Two clinical trials are investigating novel agents targeting these alterations to improve outcomes in patients with these particular genetic drivers of disease. The research was recently presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

TargetingKRASG12C

In a press release, Pasi A. Jänne, MD, PhD, director, The Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, stated, "There are currently no effective targeted therapies for patients withKRAS-mutant cancers.KRASmutations are the most common oncogenic alteration in all of the human cancers, and as such, finding a therapeutic approach for this subset of cancers would have tremendous clinical impact for [patients with] cancer."

Investigators set out to find such a therapeutic approach in the phase I/II study of investigational KRAS inhibitor MRTX849 in patients with advanced solid tumors who have aKRASG12C mutation (NCT03785249). Clinical activity was seen in patients with non—small cell lung cancer (NSCLC) and colorectal cancer (CRC). Partial responses (PRs) were seen in 50% of patients with NSCLC, and in 25% of the patients with CRC. In the group of patients who received the highest dose (600 mg twice daily), 75% of patients with NSCLC had PRs, as did 50% of the patients with CRC. Among the evaluable patients, the disease control rate (DCR) was 100% (6/6) for patients with NSCLC and 75% (3/4) for those with CRC. In all other solid tumors, the DCR was 100% (2/2).¹

The primary endpoints of the ongoing study are safety, pharmacokinetics, pharmacodynamics, and clinical activity.

Among all patients, most of the treatment-related adverse events (AEs) were grade 1. There was one patient who experienced dose-limiting toxicity (DLT) with the 1200 mg once-daily dose and another who experienced a DLT with the 600 mg twice-daily dose. The study continues to look into dose escalation to determine the maximum tolerated dose (MTD).

The criteria for this trial included patients with solid tumors harboring aKRASG12C mutation who had either unresectable or metastatic disease for whom no standard treatment exists or for those who showed a decline with standard treatment. Patients with brain metastases, history of gastrointestinal disease, previous gastric surgery, or the inability to swallow medication were excluded. The trial also omitted patients with other active cancers.

TargetingNRG1Fusions

In an AACR presentation, Alison Schram, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, reported the cases of 3 patients who were enrolled in the phase I/II study of MCLA-128, targeting solid tumors that harborNRG1fusions (NCT02912949).²

Two patients withATP1B1-NRG1—fusion,KRASwild-type pancreatic cancer who previously progressed on chemotherapy responded to MCLA-128 in the study. The 52-year-old patient who stopped irinotecan/oxaliplatin due to an increase in tumor size and intolerable AEs had a PR to zenocutuzumab with a 54% reduction in tumor size. On MCLA-128, his highest toxicity was no higher than grade 2. The 34-year-old patient withKRASwild-type pancreatic cancer had stable disease on zenocutuzumab with 25% tumor shrinkage. Both received treatment with MCLA-128 750 mg intravenously every 2 weeks for at least 7 months.

A third patient who responded hadCD74-NRG1NSCLC and had previously received several different treatment regimens. The patient was treated for at least 4.5 months with MCLA-128 and achieved a PR with 41% tumor shrinkage.

These 3 responding patients were selected from 29 patients with solid tumors upon which next-generation sequencing was performed to findNRG1fusions.²All were continuing treatment with MCLA-128 as of the data cutoff.

“We have an ongoing phase II basket trial that opened recently and is enrolling NRG1 fusion-positive patients. We are very excited about that option based [on our] preliminary experience with these 3 patients. I feel that this a new and novel paradigm for targeting these rare genomic alterations,” said Schram.³

The trial has several primary objectives. The study aims to characterize the safety and tolerability of zenocutuzumab inNRG1fusion—positive solid tumors and find the objective response rate, and duration of response to the drug. Additionally, the study intends to find the correlation between antitumor activity and biomarkers.

Patients withNRG1fusion—positive solid tumors with an ECOG performance status of 0 or 1 who had an estimated life expectancy of at least 12 weeks were eligible to enroll. The study’s key exclusions were pregnant women, presence of uncontrolled infection, symptomatic of unstable brain metastases, congestive heart failure, or concurrent malignancy.

The investigators note that the approach used in this study requires further testing in the study ofNRG1fusion—positive solid tumors. Both trials are ongoing and recruiting patients in accordance with the eligibility criteria.

References

1. Mirati therapeutics presents first clinical data of phase 1/2 trial of mrtx849 at the 2019 aacr-nci-eortc international conference on molecular targets and cancer therapeutics [press release]. San Diego, CA: Mirati Therapeutics Inc.; October 28, 2019. https://bit.ly/34hicea. Accessed October 31, 2019. r portraits of human breast tumors.Nature.2012;490:61-70. doi: 10.1038/nature11412.
2. Bispecific Antibody MCLA-128 Shows Clinical Activity in Patients With Solid Tumors Harboring NRG1 Gene Fusions [press release]. Boston, MA: American Association for Cancer Research; October 27, 2019. https://bit.ly/2qdfPKk. Accessed October 31, 2019.
3. Schram A. Clinical proof-of-concept for MCLA-128, a bispecific HER2/3 antibody therapy, in NRG1 fusion-positive cancers. Presented at: the 2019 AACR-NCI-EORTC International Conference; October 26-30, 2019; Boston, MA.