FDA Grants Pembrolizumab/Lenvatinib Breakthrough Designation for RCC

The FDA has granted the combination of the PD-1 inhibitor pembrolizumab and the VEGF/FGF inhibitor lenvatinib a breakthrough therapy designation for the treatment of patients with advanced and/or metastatic renal cell carcinoma.

Roy Baynes, MD, PhD

The FDA has granted the combination of the PD-1 inhibitor pembrolizumab (Keytruda) and the VEGF/FGF inhibitor lenvatinib (Lenvima) a breakthrough therapy designation for the treatment of patients with advanced and/or metastatic renal cell carcinoma (RCC).

The designation is based on the RCC cohort of the multicenter, open-label phase Ib/II Study 111, in which patients treated with the combination had an objective response rate (ORR) of 63.3% (95% CI, 43-80). The breakthrough designation, which will help expedite the development of the combination in this setting, was announced by Merck (MSD) and Eisai, the manufacturers of pembrolizumab and lenvatinib, respectively.

"The FDA’s breakthrough therapy designation for the Lenvima and Keytruda combination in advanced and/or metastatic renal cell carcinoma provides us with the opportunity to accelerate our effort to bring an important potential treatment option to these patients," Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a statement.

The phase Ib portion of Study 111 enrolled 13 patients with metastatic solid tumors, 8 of whom had RCC that progressed after treatment with approved therapies and who had an ECOG performance status ≤1.

Patients began treatment with 24 mg daily lenvatinib but the dosage was reduced to 20 mg per day based on toxicity. This dosage of lenvatinib advanced to the phase 2 portion, which included 22 RCC patients with measurable disease who had undergone up to 2 prior lines of systemic therapy.

Patients in phase II who experienced intolerable toxicities to lenvatinib could have their lenvatinib dose interrupted, with successive dose reductions to 14 mg, 10 mg, 8 mg, and 4 mg, if necessary. Dose re-escalation was not allowed. Toxicities related to pembrolizumab were managed with dose interruptions. Pembrolizumab was administered at 200 mg every 3 weeks in both phases.

The combined phase Ib and phase II results (N = 30) had a data cutoff of March 1, 2017. Tumor assessments were performed using irRECIST criteria every 6 weeks until week 24, and then every 9 weeks.

Investigators assessed PD-L1 status in 26 patients. Using a 1% staining cutoff for positivity, 12 patients (40%) were PD-L1-positive.

Twelve patients (40%) were treatment-naïve and therefore treated in the first-line setting. Ten patients (33%) had one prior systemic therapy, 3 (10%) had 2 prior systemic therapies, and 5 (17%) had ≥3. Sixteen (53%) patients had at least 1 prior VEGF-targeted therapy, with the most common agents being sunitinib (n = 9), pazopanib (Votrient; n = 8), and axitinib (Inlyta; n = 6). Five patients were previously treated with an mTOR-targeted agent and 4 patients were previously treated with other agents.

ORR at 24 weeks was 83% (95% CI, 52-98) in the treatment-naïve cohort, and 50% in those patients who received previous treatment. All responses were partial responses. Two patients in the treatment-naïve group and 8 in the previously-treated population had stable disease. One patient in each cohort had primary progressive disease.

The median duration of response was not yet reached for the total cohort and the treatment-naïve cohort. The median duration of response was 8.5 months in the pretreated cohort.

When stratified by PD-L1 staining status, “objective responses could be seen in both the PD-L1—positive and PD-L1–negative populations, and appear to be similar, with 58% of the PD-L1-positive patients and 71% of PD-L1-negative patients achieving objective responses,” lead author Chung-Han Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, said when reporting the results at the 2017 ESMO Congress.

At the time of data cutoff, the median progression-free survival (PFS) had not yet been reached (95% CI, 9.9 months-not evaluable). Tumor responses assessed by a modified RECIST v1.1 were the same as with irRECIST. The median PFS by RECIST v1.1 was also not yet evaluable.

Ten of 12 patients in the treatment-naïve cohort remain on treatment.

“An extended duration of response could be seen in both PD-L1—positive and PD-L1–negative patients,” Lee said. “In the treatment-naïve cohort, prolonged stable disease could also be seen in PD-L1–positive patients who remained still on therapy at 12 months. In the previously treated patients, 6 of 18 patients remain on treatment, with 1 patient having a duration of response >8 months.”

Twenty-eight of 30 patients experienced tumor shrinkage, and Lee said there was a tendency for greater tumor shrinkage in the treatment-naïve patients. Tumor shrinkage was observed in both PD-L1—positive and PD-L1–negative patients, with no clear association between changes in tumor size and PD-L1 staining status.

Treatment-emergent adverse events (TRAEs) led to lenvatinib dose reductions in 18 patients. Five patients (17%) discontinued at least 1 study drug.

The most common TRAEs of any grade were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (60%), hypertension (57%), and nausea (57%). No new safety signals were found. The 2 grade-5 TRAEs were related to disease progression and not considered related to the study drugs.

Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma. Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 847O.


The median duration of therapy was 9.5 months. The mean dosage of lenvatinib received was 15.8 mg/day, with patients receiving 78.3% of the intended starting dose. The mean dosage of pembrolizumab administered was 191.9 mg per cycle, with patients receiving 95.9% of the intended doses.

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