MEDI5752 Plus Chemotherapy Produces Long DOR, But High Dose Comes With High Toxicity

Myung-Ju Ahn, MD, PhD

Chemotherapy added to 1500 mg of MEDI5752, a PD-1/CTLA-4 bispecific monoclonal antibody, led to a doubling in duration of response (DOR) compared with pembrolizumab (Keytruda) and chemotherapy in patients with treatment-naïve nonsquamous non–small cell lung cancer (NSCLC). Findings from the phase 1b/2 trial were presented at the 2022 ESMO Congress.

However, the regimen resulted in high rates of discontinuation and toxicity, leading investigators to explore a 750-mg dose of MEDI5752. The reduced dose of the agent demonstrated a similar overall response rate (ORR) and improved tolerability, but investigators need longer follow-up to assess progression-free survival (PFS), overall survival (OS), and DOR.

“The 1500-mg MEDI5752 plus chemotherapy showed improved antitumor activity—almost double the duration of response compared [with] pembrolizumab plus chemotherapy in the first-line setting, and the clinical benefit of [MEDI5752] in patients with PD-L1–negative [status] was consistent with the previous data,” said Myung-Ju Ahn, MD, PhD, a professor in the Department of Hematology and Oncology with Sumsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, South Korea.

At the 1500-mg dose, MEDI5752 plus chemotherapy (n = 20) induced an ORR of 50.0% vs 47.6% in patients assigned to pembrolizumab plus chemotherapy (n = 21). The median DOR was 20.5 months (95% CI, 4.1-not evaluable [NE]) in the MEDI5752 arm compared with 9.9 months (95% CI, 2.8-NE) with pembrolizumab.

The median PFS (15.1 vs 8.9 months) and OS (not reached vs 16.5 months) also favored the MEDI5752 arm.

Among patients who were PD-L1–negative (< 1% expression on tumor cells), ORR again favored the experimental arm, 55.6% (95% CI, 21.2%-86.3%) vs 30.0% (95% CI, 6.7%-65.2%). Similarly, the median PFS was superior with MEDI5752 vs pembrolizumab, 13.4 vs 9.0 months.

Investigators also assigned 64 patients to 750-mg MEDI5752 plus chemotherapy in a single-arm cohort. These data include the first 50 patients who had at least 8 weeks of follow-up. One patient was not evaluable for response.

In this group, the ORR was 40.8% and 49% of patients had at least 30% reduction in target lesions. Among PD-L1–negative patients (n = 36), the ORR was 44.4% and 55.6% of patients had at least 30% reduction in target lesions.

At the July 12, 2022, data cutoff, the median follow-up was 22.8 months in the experimental arm (range, 0.8-26.9) and 14.5 months (range, 1.6-27.9) with the control.

The median patient age in the MEDI5752 arm was 63.0 years (range, 50-86) and men made up 70% of the cohort. The median age in the pembrolizumab arm was 70.0 years (range 48-78) and 81% of the cohort was male. Approximately 60% of patients in both groups had an ECOG performance score of 0.

Sixteen patients (80.0%) in the experimental arm were current or former smokers compared with 90.5% in the control arm. All patients in the MEDI5752 arm and 90.5% in the pembrolizumab arm had stage IV disease.

Four patients (20.0%) in the MEDI5752 arm had brain metastases and 2 (10.0%) had liver metastases compared with 3 (14.3%) and 4 (19.0%), respectively, in the pembrolizumab arm.

Nine patients (45.0%) in the experimental group were PD-L1 negative compared with 10 (47.6%) with the control. Investigators identified 5 oncogenic drivers in the MEDI5752 arm and 2 in the pembrolizumab arm.

In the 750-mg cohort, the median age was 67.0 years (range, 36-83) and 72.0% of group were men. Thirty-eight patients (76.0%) had an ECOG status of 1 and 88% were current or former smokers. Ninety-six percent had stage IV disease, 16.0% had brain metastases, 16.0% had liver metastases, and 72.0% were PD-L1 negative. Investigators identified 2 oncogenic drivers in this group.

Patients received 1500 mg MEDI5752 plus 5 area under the curve (AUC) carboplatin and 500mg/m2 pemetrexed every 3 weeks for 4 cycles followed by maintenance therapy MEDI5752 or pembrolizumab every 3 weeks until unacceptable toxicity, progression, or withdraw of consent. Patients in the single-arm cohort received 750 MEDI5752 plus pemetrexed on the same schedule.

Fourteen patients (70.0%) in the 1500-mg group discontinued treatment compared with 6 (28.6%) in the pembrolizumab arm and 10 (20.0%) in the 750-mg group. Eighty percent of patients in the high-dose group experienced grade 3/4 treatment-related adverse events (TRAEs) compared with 61.9% in the pembrolizumab group and 50% in the low-dose group.

As expected, incidence of grade 3/4 TRAEs was much greater in the 1500-mg group compared with the 750-mg group. The most common grade 3/4 TRAEs were rash (10% vs 2%, respectively), alanine transaminase increased (30% vs 2%), aspartate transaminase increased (20% vs 2%), pneumonitis (5% vs 0%), and diarrhea (5% vs 2%).

“The emerging data of 750 mg plus chemotherapy showed a similar overall objective response with the improved tolerability less [and a lower] rate of discontinuation,” Ahn said. “[These] data suggests that MEDI5752 provides the potential options to improve the standard of care in first-line [for patients with] NSCLC, especially in those who have PD-L1–negative tumors.”

Invited discussant, Laura Mezquita, MD, PhD, a medical oncologist at Hospital Clínic de Barcelona in Spain, said it will be necessary to identify predictive biomarkers to determine which dose of MEDI5752, or possibly even a lower dose, is most appropriate for patients.

“This dose, 1500 mg, improves efficacy also in the PD-L1–negative population, however with very high toxicities and discontinuations,” she said. “Probably [the 750-mg dose] will be better, but we only have emerging activity…the safety profile is favorable, but longer follow-up is what is needed.”

_Reference

_{Ahn MJ, Kim SW, Carcereny E, et al. MEDI5752 or pembrolizumab plus carboplatin/pemetrexed in treatment-naïve non-small-cell lung cancer: a phase 1b/2 trial. Presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.}