Crizotinib Active in Orphan Kidney Malignancy


Get Permission

Crizotinib (Xalkori) achieved overall and durable responses in advanced inoperable papillary renal cell carcinoma type 1 characterized by somatic MET mutations, according to an investigator-initiated trial conducted by the European Organization for Research and Treatment of Cancer (EORTC).1


To my knowledge, this is the first prospective trial to focus exclusively on papillary renal cell carcinoma type 1, a rare malignancy that occurs in about 2% of all renal cell cancers…
— Patrick Schöffski, MD, MPH

“To my knowledge, this is the first prospective trial to focus exclusively on papillary renal cell carcinoma type 1, an ultra-rare malignancy that occurs in about 2% of all renal cell cancers and has been systematically excluded from many clinical trials. This study shows that EORTC is able to perform molecularly driven–screening phase II trials in rare cancers, with mandatory collection of tissue blocks, real-time reference pathology, and genetic profiling,” stated lead author Patrick Schöffski, MD, MPH, of the University Hospitals, Leuven, Belgium.

“Papillary renal cell carcinoma type 1 is often misdiagnosed, and there is no established standard of care for advanced metastatic disease,” he added.

Papillary renal cell carcinoma type 1 is associated with somatic or germline mutations of the MET gene. In the EORTC trial, the investigators found MET mutations in about 15% of patients and MET amplification in about 8%. Crizotinib targets MET, ALK, and ROS 1 and is approved for the treatment of ALK-positive non–small cell lung cancer (NSCLC).

Study Details

The EORTC study was conducted at 13 sites in 8 European countries over 3 years and recruited 41 patients with a local diagnosis of papillary renal cell carcinoma type 1, which was centrally confirmed in 27 patients (66%).

All patients consented to tumor tissue sampling. Mutational testing was conducted at a single center in Leuven by Sanger Sequencing. Investigators also assessed MET amplification. Patients were stratified by MET-positive and MET-negative status.

“The study focused on MET-positive patients, and MET-negative patients served as a nonrandomized control group,” he said.

Oral treatment with crizotinib at a starting dose of 250 mg twice daily (standard dose) for 3-week cycles was initiated in 23 patients with confirmed papillary renal cell carcinoma type 1. Of these patients, 4 had MET-positive disease, 16 had MET-negative disease, and 3 had an unconfirmed MET status due to technical failure of the ­sequencing.

Response Rates and Duration

Impressive treatment duration was seen among the 4 MET-positive patients, with a mean of 17.3 cycles vs 8 for MET-negative patients. The mean duration of treatment was 11.9 months vs 5.3 months, respectively.

Of the four MET-positive patients, three are still on treatment after 9 months. Early, confirmed partial responses were achieved in two patients (50%) with somatic mutations, and responses have been durable. No MET-negative patient achieved partial ­response.

Crizotinib Warrants Further Study in Orphan Kidney Cancer

  • Crizotinib appears to be highly active in an orphan kidney disease—papillary renal cell carcinoma type 1 with MET mutations.
  • There is no standard treatment for this disease, and this cancer has typically not been included in clinical trials.
  • Further study is needed to confirm these findings.

“The study met the definition of success,” Dr. Schöffski told listeners.

Among the 13 MET-negative patients, 2 had MET-amplified disease. Adding MET-positive and MET-amplified patients together, all had tumor shrinkage.

Survival and Safety

At 24 months, progression-free survival was seen in 75% of MET-positive patients (approximately 80% if the 2 MET-amplified patients are included) and only 34% of MET-negative patients.

The overall survival curves tell a similar story. A vast majority of MET-positive, crizotinib-treated patients are alive at 2 years, reported Dr. Schöffski.

The safety profile of crizotinib is similar in papillary renal cell carcinoma type 1 as it is in NSCLC, with a low incidence of grades 3 and 4 adverse events and hematologic grades 3 and 4 adverse events.

A larger study is needed to obtain approval for crizotinib in this orphan malignancy, Dr. Schöffski said, but he highlighted the difficulties of performing prospective trials in such a rare type of cancer. ■

Disclosure: Dr. Schöffski reported no potential conflicts of interest.

Reference

1. Schöffski P, Wozniak A, Escudier B, et al: Crizotinib achieves objective responses and long-lasting disease control in patients with metastatic papillary renal cell carcinoma type 1 (pRCC1) with somatic MET mutations. EORTC phase II trial 90101 ‘CREATE.’ 2016 AACR Annual Meeting. Abstract CT006. Presented April 17, 2016.


Related Articles

Expert Point of View: Mayer Fishman, MD, PhD


It is reasonable to move forward and use crizotinib in this group of patients (MET-positive patients with papillary renal cell carcinoma type 1).
— Mayer Fishman, MD, PhD

“This was a difficult study to conduct. It required 13 centers in 8 countries over 3 years to recruit these...


Advertisement

Advertisement



Advertisement