FGFR Inhibitors of Interest in Bladder and Lung Cancer


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Rodrigo Dienstmann, MD

Lecia Sequist, MD

FGFR Inhibitors in Cancer Therapy

Fibroblast growth factor receptor (FGFR) inhibitors are an emerging area of interest in cancer therapeutics. Studies presented at the 2014 American Association for Cancer Research (AACR) Annual Meeting in San Diego provided early encouraging data for two investigational pan-FGFR inhibitors for the treatment of advanced solid tumors driven by FGFR alterations—notably, bladder and lung cancer. Both drugs are oral agents that inhibit FGFR1, FGFR2, FGFR3, and FGFR4, and both are moving into further development for several types of cancer.

JNJ-42756493

The first study showed that the FGFR inhibitor JNJ-42756493 had excellent activity in patients with advanced solid tumors. This phase I trial enrolled 41 patients with various tumor types that had progressed despite previous therapies.

All patients enrolled in the trial had normal phosphate levels at baseline. Increased phosphate levels are an on-target effect of FGFR inhibition. As expected, hyperphosphatemia was the most frequent adverse event, occurring in 58% of patients. Other commonly reported adverse events were asthenia (20%), fatigue (60%), and gastrointestinal effects (20%). No cardiotoxicity was observed in these patients.

The dose-finding phase of the trial identified 9 mg as the recommended dose for phase II trials. At the 9-mg dose level, 7 of 8 patients developed hyperphosphatemia, said lead author Rodrigo Dienstmann, MD, Vall d’Hebron Hospital, Barcelona, Spain. Dr. Dienstmann and colleagues instituted a detailed management approach for hyperphosphatemia that included dose reductions. This approach seemed to reduce the occurrence of hyperphosphatemia.

Maximal RECIST responses were seen in patients treated at 6 mg or higher. Responses were observed in patients with FGFR amplification and translocation.

Ongoing studies of JNJ-42756493 include efforts to optimize dose and schedule and to analyze biomarkers. Expansion cohorts are currently enrolling patients with FGFR-aberrant tumors, including lung and breast cancer.

BGJ398

The second study evaluated a pan-FGFR inhibitor called BGJ398 in patients with solid tumors that expressed FGFR abnormalities. Study results suggested that bladder cancer and lung cancer are particularly susceptible to FGFR inhibition.

“About 15% of bladder cancer patients have FGFR mutations, and an additional 6% have an FGFR translocation. About 21% of non–small cell lung cancer patients have FGFR abnormalities,” explained lead author Lecia Sequist, MD, of Massachusetts General Hospital Cancer Center, Boston.

“We specifically enrolled only patients with FGFR genetic alterations in their tumors because we predicted that these patients would have the greatest chance of benefiting from the drug,” she said.

Dr. Sequist commented that the results in patients with bladder cancer were “exciting” because these patients have few treatment options.

The phase I study she reported included dose-escalation and dose-expansion phases. In the dose-escalation phase, patients were treated with oral BGJ398 once or twice a day in a 28-day cycle. The maximum tolerated dose was defined as 125 mg. Ongoing dose-expansion cohorts include squamous cell NSCLC and bladder cancer. Of 95 bladder cancer patients screened, 7 (7%) had an FGFR3 mutation; of 147 lung cancer patients screened, 14 (9%) had FGFR1 amplification.

The results Dr. Sequist presented were based on 107 patients with a mean age of 59 years. Thirty-eight percent had breast cancer, 34% had lung cancer, and 9% had bladder cancer. Eight patients remain on treatment at the time of the AACR meeting. Most withdrawals were due to disease progression.

At the maximum tolerated dose, 87% of patients developed hyperphosphatemia, 43% had stomatitis, 34% had decreased appetite, 23% had fatigue, 30% had alopecia, and 15% had nausea. These adverse events were mainly mild to moderate.

“Hyperphosphatemia is an on-target expected effect that is manageable with dietary restriction, phosphate-lowering therapy, and dose interruptions. We found that an intermittent dosing schedule reduced hyperphosphatemia, so going forward, 3 weeks on and 1 week off will be our preferred dosing schema,” Dr. Sequist said.

A waterfall plot showed tumor shrinkage by RECIST criteria in patients treated at doses > 100 mg/d, with the most notable responses seen in bladder and lung cancer. In her presentation at AACR, Dr. Sequist focused on the bladder cancer patients. She said the lung cancer data will be presented at this year’s ASCO Annual Meeting.

Of six patients with bladder cancer, five with a driver mutation of FGFR3 did very well. Overall response rate was 40%, and disease control rate was 100% in these five patients. The sixth patient had FGFR1 amplification and very aggressive disease.

“The key feature [of effective therapy] seems to be selection of patients based on FGFR abnormalities,” she said. ■

Disclosure: Drs. Sequist and Dienstmann reported no potential conflicts of interest.

References

1. Dienstmann R, Bahleda R, Adamo B, et al: First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. 2014 AACR Annual Meeting. Abstract CT325. Presented April 8, 2014.

2. Sequist LV, Cassier P, Varga A, et al: Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. 2014 AACR Annual Meeting. Abstract CT326. Presented April 8, 2014.

An earlier version of this article incorrectly identified Dr. Sequist's affiliation. This error has been corrected.


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FGFR abnormalities have been reported in many cancers, including breast, lung, and bladder cancers. While the types of events that occur in these cancers are different, preclinical evidence supports a role for oncogenesis in each of these types,” said formal discussant of the FGFR inhibitor studies ...


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