FDA Grants Breakthrough Therapy Designation for Kidney Cancer Drug Combination

A new combination — Keytruda (pembrolizumab) plus Lenvima (lenvatinib) – was granted a breakthrough therapy designation to treat patients with advanced and/or metastatic renal cell carcinoma (RCC).

The designation is based on the RCC cohort of the multicenter, open-label phase 1b/2 Study 111, in which patients treated with the combination had an objective response rate (ORR) of 63.3 percent. 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 Keytruda and Lenvima, 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, M.D., Ph.D., senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a statement.

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

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

Patients in phase 2 who experienced intolerable toxicities to Lenvima could have their Lenvima 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 Keytruda were managed with dose interruptions. Keytruda was administered at 200 mg every three weeks in both phases.

The combined phase Ib and phase 2 results (30 patients) had a data cutoff of March 1, 2017. Tumor assessments were performed using irRECIST criteria every six weeks until week 24, and then every nine weeks.

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

Twelve patients (40 percent) were treatment-naïve and therefore treated in the first-line setting. Ten patients (33 percent) had one prior systemic therapy, 3 (10 percent) had two prior systemic therapies and five (17 percent) had three or more. Sixteen (53 percent) patients had at least one prior VEGF-targeted therapy, with the most common agents being Sutent (sunitinib) (nine patients), Votrient (pazopanib) (eight patients), and Inlyta (axitinib) (six patients). Five patients were previously treated with an mTOR-targeted agent and four patients were previously treated with other agents.

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

ORR at 24 weeks was 83 percent in the treatment-naïve cohort, and 50 percent in those patients who received previous treatment. All responses were partial responses. Two patients in the treatment-naïve group and eight 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 percent of the PD-L1-positive patients and 71 percent 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. 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, six of 18 patients remain on treatment, with one patient having a duration of response longer than eight 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 Lenvima dose reductions in 18 patients. Five patients (17 percent) discontinued at least one study drug.

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