Varlitinib therapy for solid organ tumours shows promise in phase I study

Varlitinib demonstrate good antitumour activity and an acceptable safety profile in patients with advanced or metastatic solid organ tumours, according to a recent Singapore study.

For phase II trials, an intermittent dosing regimen of 300-mg varlitinib twice daily is recommended. Moreover, adding subcutaneous trastuzumab to this regimen appears to be safe, showing no dose-limiting toxicities (DLT).

“Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers,” the researchers said.

Thirty-seven eligible cancer patients (median age 56.8 years, 83.7 percent women) participated in the phase Ib dose-finding study. Most of them (n=28, 75.6 percent) had breast cancer, of which 20 were HER2+. All participants were heavily pretreated, having undergone a median of four prior lines of palliative systemic treatment.

Patients were divided into three treatment cohorts: cohort A (n=18; varlitinib + carboplatin + paclitaxel), cohort B (n=16; varlitinib + paclitaxel), and cohort C (n=3; varlitinib + paclitaxel + trastuzimab). Cohort A patients were started on a 500-mg varlitinib dose, de-escalating to 400 and 300 mg depending on DLTs.

All cohort A doses were deemed intolerable. Grade 3/4 neutropaenia emerged as the most common DLT, observed in six (33.3 percent) patients. [Target Oncol 2022;doi:10.1007/s11523-022-00867-0]

“As it was deemed not clinically meaningful to reduce the dose of varlitinib to less than 300 mg intermittently, the triplet combination of varlitinib, carboplatin, and paclitaxel was declared intolerable and could not be developed further,” the researchers said.

In cohort B, patients were initiated on a 300-mg intermittent varlitinib dose (4 days on, 3 days off) with weekly paclitaxel. This regimen did not result in any DLTs and was thus deemed tolerable. Dosing was then escalated to either 400 mg intermittent varlitinib or 300 mg continuous varlitinib; both regimens were deemed intolerable, yielding high rates of DLTs.

Therefore, the researchers noted that when given in combination with paclitaxel, varlitinib had an MTD of 300 mg twice daily, administered intermittently.

Of note, all three patients in cohort C were given additional subcutaneous trastuzumab at 600-mg doses, administered on the first day of each 3-week cycle. No DLTs were reported, suggesting the safety of add-on trastuzumab.

In terms of tumour response, all patients with metastatic cancer showed disease progression at the recommended dosing regimen. Thirty-one patients were available for the assessment of treatment response, of whom 35.5 percent (n=11) achieved confirmed partial response, while 41.9 percent (n=13) reached stable disease.

Among the 20 patients with HER2+ breast cancer, 16 were available for assessment. More than half (56.3 percent; n=3) achieved partial response, while stable disease was the best response in 25.0 percent (n=4). The clinical benefit rate was 81.3 percent.

“The manageable toxicity profile, pharmacokinetic properties, and encouraging antitumour activity in patients with advanced solid tumours, particularly HER2+ breast cancer, warrant further evaluation of varlitinib in larger phase studies,” the researchers said.