Necitumumab/Abemaciclib Combo Fails in Stage IV NSCLC

Benjamin Besse, MD, PhD

A phase Ib study of necitumumab (Portrazza) in combination with abemaciclib (Verzenio) failed to meaningfully improve outcomes in patients with stage IV non—small cell lung cancer (NSCLC), said Benjamin Besse, MD, PhD, at the 2018 European Lung Cancer Conference in Geneva, Switzerland.

Outcomes were measured by progression-free survival (PFS) and objective response rate (ORR).

The 2-part, single-arm trial with an expansion cohort was designed to evaluate the safety and efficacy of necitumumab in combination with abemaciclib in comparison with historical data. The primary endpoint was PFS at 3 months.

Median PFS was 2.14 months (95% CI, 1.41-2.76) and median overall survival (OS) was 6.93 months (CI 95%, 4.96-12.85). The PFS rate at 3 months was 32.3% and 22.2% at 6 months. OS at 6 months was 57.3%. The trial was initiated to determine the dose-limiting toxicity (DLT) of abemaciclib administered twice a day at doses ranging from 100 mg to 200 mg when combined with necitumumab in patients with stage IV NSCLC. The optimal dose was measured by the number of patients with a DLT in the first cycle of treatment. Necitumumab was delivered at a standard 800 mg on days 1 and 8 of a 21-day cycle.

“If you compare these results with what is available in the literature, you have to compare with single agent erlotinib in non-mutated NSCLC patients, and, in fact, the activity is quite similar to this monotherapy, so we can consider that this trial is negative.” said Besse, presenting author and head of the thoracic cancer unit, Department of Medicine, Institut Gustave Roussy, Villejuif, France. “The combo should not be developed further unless a predictive biomarker could be found, either for necitumumab or for abemaciclib, and then we could reexplore the combination—but in a molecularly-selected NSCLC population,” he added.

Investigators determined that necitumumab at 800 mg and abemaciclib at 150 mg was the maximum tolerated dose in cycle 1 of the treatment. During the dose experimentation phase, 3 patients developed a DLT in cycle 1. One patient assigned to 150 mg of abemaciclib (n = 3-6) experienced grade 3 diarrhea. In the cohort receiving 200 mg of abemaciclib (n = 3-6), there was 1 case of grade 3 stomatitis and 1 case of grade 4 thrombocytopenia.

The second part of the study was the dose extension with 50 patients added—25 with nonsquamous NSCLC and 25 with squamous NSCLC. Besse said the challenge in stage IV NSCLC is to find effective third-line treatment. “Today, we have 2 lines of chemotherapy, and we have immunotherapy, but in the third line there is no approved agent but erlotinib, which in an unselected population has poor activity.”

Necitumumab, which targets the epidermal growth factor receptor (EGFR), is approved for first-line treatment in combination with cisplatin and gemcitabine in squamous lung cancer patients. “We know that it has activity in lung cancer, and the goal was to combine necitumumab with [CDK4/6 inhibitor] abemaciclib, which has a completely different mechanism, and there is some biological rationale for combining these 2 drugs,” he said.

Sixty-six patients were enrolled and the median patient age was 61 years (range, 37-85); 26 patients (39.4%) were aged 65 years or older. Men (n = 47) outnumbered women (n = 19), and 83.3% of patients were current or former smokers. Patients with nonsquamous stage IV NSCLC (n = 35) outnumbered those with squamous histology (n = 27).

Treatment-related adverse events (TRAEs) occurred in 20% or more of patients. The most common instances of grade ≥3 TRAEs included fatigue (n = 8), diarrhea (n = 4), decreased appetite (n = 4), dyspnea (n = 5), vomiting (n = 4), and hypokalemia (n = 4).

No new clinically significant safety concerns emerged from this study, and the safety profile of necitumumab and abemaciclib in combination was consistent with the safety profiles of individual study drugs.

Besse B, Barlesi F, Demedts I, et al. A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non—small cell lung cancer. Presented at: the 2018 European Lung Cancer Conference; April 11-14; Geneva, Switzerland. Abstract 1350.