The invited discussant of the two trials in cervical and endometrial cancers presented at the ESMO Congress 2019 was Nicoletta Colombo, MD, of the University of Milan-Bicocca in Italy, who commented on what she called “exciting results in cancers with unmet needs.”
Dr. Colombo noted: “The studies evaluated different immunotherapy combinations, and in both, there were high response rates and deep and durable responses in unselected populations…. Immunotherapy has changed the face of many cancers in the past decade, and finally this is happening also for gynecologic cancers.”
Discussing the rationale for immunotherapy, Dr. Colombo noted that in cervical cancer, human papillomavirus and the tumor microenvironment are enriched for programmed cell death protein 1–positive and CD8-positive T cells, and programmed cell death ligand 1 (PD-L1) is significantly upregulated. In endometrial cancer, there is a reason to combine immunotherapy with an inhibitor of vascular endothelial growth factor (VEGF), since VEGF inhibits T-cell function, stimulates immunosuppressive regulatory T cells, and inhibits dendritic cell function. Synergistic effects have been observed with lenvatinib plus pembrolizumab, she said.
‘The Good, the Bad, and the Ugly’
Dr. Colombo framed her take-home message as “the good, the bad, and the ugly.” For the combination of nivolumab and ipilimumab in CheckMate 358, the “good” is the confirmation of strong activity, the high response rate and prolonged survival, the benefit observed regardless of PD-L1 expression, and the chemotherapy-sparing nature of this regimen, she said. The “bad,” in her opinion, is the fact that toxicity was “not trivial,” though it was somewhat less with nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg. And the “ugly” is the lack of a control arm. Questions remain as to how to study this combination next, and whether to move a chemotherapy-sparing regimen into the front line, she added.
Since for endometrial cancer there is no second-line standard of care, an evaluation of pembrolizumab/lenvatinib in the 75% of patients whose tumors are not microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) was important, Dr. Colombo continued. The study delivered, leading to accelerated approval of the combination. At the latest data cutoff, the response rate was 43.5% by independent review; 38.9% by investigator review; and 37.2% by investigator review in the non–MSI-H/dMMR population. “But nothing comes without a price,” she added. Grade 3 or 4 adverse events occurred in 69% of patients, and the study drug was discontinued in 20%, interrupted in 72%, and dose-reduced in 65%.
“The ‘good’: the combination of pembrolizumab and lenvatinib led to unprecedented results in patients with advanced or recurrent previously treated endometrial cancer that is microsatellite-stable, and for the first time, a chemotherapy-free regimen demonstrated a high rate of deep and durable responses in this clinical setting with a high unmet need,” Dr. Colombo said. “The ‘bad’ is that toxicity was as remarkable as activity, and the ‘ugly,’ again, was the lack of a control arm.”
In closing, she emphasized, “Both regimens need confirmation in a prospective clinical trial.”
DISCLOSURE: Dr. Colombo has received honoraria from or served as a consultant or advisor for Genentech, AstraZeneca, PharmaMar, Amgen, Clovis Oncology, Pfizer, MSD, and Tesaro.
