The combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) showed anti-tumor activity in patients with recurrent advanced endometrial carcinoma -- regardless of microsatellite instability or programmed- death ligand 1 (PD-L1) expression status -- researchers reported in an interim analysis of an open-label phase II study.
Vicky Makker, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues said that at week 24, the investigators found an objective tumor response in 21 of 53 patients, while independent reviewers observed an objective response in 24 patients.
Writing online in Lancet Oncology, the team pointed to an unmet therapeutic need for patients with recurrent microsatellite-stable endometrial cancer: "Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population," the researchers stated.
Lenvatinib is a multikinase inhibitor of vascular endothelial growth factors (VEGFR1, VEGFR2, and VEGFR3), and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has shown some activity in biomarker-unselected endometrial cancer.
From September 10, 2015 to July 24, 2017, 11 U.S. centers enrolled 54 patients, 53 of whom were included in the analysis. Their mean age was 64, and 83% were white. Of these, 23 had received one systemic therapy, 23 had two systemic therapies, and seven had three or more.
A total of 52 patients had previously undergone platinum-based doublet therapy, and 43% each had received either two previous systemic therapies. Previous radiotherapy was reported by 57% of patients.
Although patients were not selected for microsatellite and PD-L1 biomarkers, 21% were PD-L1-negative and 25% were PD-L1-positive; 85% were microsatellite-stable, while just 8% had high microsatellite instability.
Only 20-30% of endometrial cancers have microsatellite instability, and PD-1 inhibition is much less efficacious in patients with microsatellite-stable disease, the researchers noted.
In 2018, the Food and Drug Administration granted breakthrough therapy designation to this new combination for the treatment of patients with advanced microsatellite-stable endometrial cancer previously treated with at least one systemic therapy.
All patients received 20 mg oral lenvatinib daily and 200 mg intravenous pembrolizumab every 3 weeks, a dose chosen on the basis of results from a dose-finding phase Ib study, Makker and co-authors noted.
Tumors were assessed by the investigators as well as external reviewers according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).
As of December 15, 2017, at a median follow-up of 13·3 months (IQR 6·7–20·1), the analysis yielded the following results, the researchers reported:
- A total of 21 patients (39.6%) had an objective antitumor response at week 24 (95% CI 26.5-54.0)
- One patient had a complete response
- 20 patients had a partial response
- 25 patients had stable disease
- Four patients had progressive disease
While it was not possible to estimate the median duration of response, some patients showed ongoing response at week 24, the team reported.
Serious treatment-related adverse events occurred in 16 patients (30%), and there was one treatment-related death, from intracranial hemorrhage. The most frequently reported treatment-related adverse events of any grade were as follows:
- Hypertension in 31 patients (58%)
- Fatigue in 29 patients (55%)
- Diarrhea in 27 patients (51%)
- Hypothyroidism in 25 patients (47%)
The most common grade 3 treatment-related adverse events were hypertension (18/34%) and diarrhea (four/8%); no grade 4 events were reported. Five (9%) patients withdrew owing to treatment-related adverse events.
The combination regimen is currently being investigated in the randomized KEYNOTE-775 trial, noted the author of an accompanying commentary: "The phase III study that is underway should help to clarify whether the promising results noted in this interim phase II analysis will translate to meaningful improvements in outcomes with an acceptable safety profile when compared with the standard chemotherapy available for patients with advanced microsatellite-stable endometrial cancer," wrote Gottfried E. Konecny, MD, of the University of California, Los Angeles.
He explained that the incidence of endometrial cancer has increased across several countries, especially areas in "rapid socioeconomic transition." The U.S. has one of the world's highest rates, at 19 cases per 100,000 among white women in 2006-2007.
Konecny noted that long-term outcomes for patients with advanced disease are poor, with chemotherapy and hormonal therapy having low activity in these patients. He said that considering that relatively few endometrial cancers show microsatellite instability, "modulation of a VEGF-mediated immune suppressive state in the tumor microenvironment through inhibition of angiogenesis could be an effective strategy to improve the clinical activity of PD-1 inhibition in endometrial cancer, irrespective of the tumor's microsatellite status."
He added that the combination regimen might also be a potential option for treating other cancers with low tumor mutational burden or microsatellite stability, against which single agents have shown poor activity. "However, further clinical validation is required to establish whether use of a multikinase inhibitor such as lenvatinib truly affects the tumour environment, resulting in increased sensitivity to immune checkpoint inhibitors," Konecny wrote.
The study was funded by Eisai and supported by Merck; one co-author received a Memorial Sloan Kettering Cancer Center support grant.
Makker reported financial relationships with AstraZeneca, Eisai, Merck, Karyopharm, Lilly, Takeda, and Genentech; other co-authors also reported various ties to industry.
Konecny reported financial relationships with AstraZeneca, Clovis, Tesaro, Pfizer, Merck, and Lilly.
( lenvatinib ) and keytruda ( pembrolizumab ) - Eisai Newsroom
The investigators looked specifically at self-reported answers to how to create a period-friendly workplace questions about vigorous exercise that makes you sweat or breathe hard. For signs or symptoms of SJS or TEN, withhold keytruda and refer the patient for specialized care for assessment and treatment. Control blood pressure prior to initiation. Keytruda, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (nsclc) whose tumors have high PD-L1 expression Tumor Proportion Score (TPS) 50 as determined by an FDA-approved test, with no egfr or ALK genomic tumor aberrations. Monitor blood pressure after 1 week, then another MS Drug Wins FDA Approval every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Treatment for...
Withhold keytruda for Grade 2 or 3; permanently discontinue keytruda for Grade 4 colitis. The trial is testing an immune checkpoint inhibitor called pembrolizumab (Keytruda) in combination with a targeted drug called lenvatinib (Lenvima). The most common adverse reactions (1) resulting what really happens in the brain during a hallucination? in discontinuation of lenvima were fatigue (1 hepatic encephalopathy (2 hyperbilirubinemia (1 and hepatic failure (1). The most common serious adverse reactions (2) were pneumonia (4 hypertension (3 and dehydration (3). The most common serious adverse reactions (2) were hepatic encephalopathy (5 hepatic failure (3 ascites (3 and decreased appetite (2). Resume after surgery based on clinical judgment of adequate wound healing.