Studies Highlight Erdafitinib as an Encouraging Bladder Cancer Treatment Option

It has been an especially exciting time for our Genitourinary (GU) Oncology Program. Our team’s bladder (urothelial) cancer research recently made its way into two prestigious medical journals, with both studies highlighting erdafitinib – an oral inhibitor of fibroblast growth factor receptor (FGFR) – as an encouraging therapeutic option for the disease.

FGFR gene alterations are common in urothelial carcinoma and may be associated with low sensitivity to immunotherapy.

In a phase II study of 99 adults with locally advanced or metastatic urothelial carcinoma harboring FGFR gene alterations, Dr. Scott Tagawa and colleagues found erdafitinib to demonstrate impressive tumor control and tolerability. Forty percent of patients responded to the drug, and among the 22 patients who had previously received immunotherapy without success, the response rate jumped to 59 percent.

Weill Cornell Medicine“While not yet confirmed by randomized trial results, the fact that these patients with the unique molecular tumor selection were responsive to erdafitinib and resistant to prior lines of standard therapy makes this a pivotal study,” said Dr. Tagawa. “It’s wonderful to now have this option available for our patients early while awaiting results of the confirmatory randomized trial. It highlights the importance of genomic tumor testing.”

The research group’s findings were published in the New England Journal of Medicine and led to accelerated approval of erdafitinib as the first targeted drug for urothelial carcinoma from the United States Food and Drug Administration (FDA).

In addition to the use of next-generation sequencing of tumors to more precisely select those most likely to respond, the standard erdafitinib regimen also utilizes individualized dosing. Erdafitinib, partly depending on the dose used, is shown to induce increased phosphorus levels in the blood. As blood phosphorus levels are related to targeting of the key pathway (FGFR), the dose of erdafitinib is increased if phosphorus levels do not significantly increase in the absence of any significant side effect. In a retrospective analysis presented at the 2019 European Society of Medical Oncology (ESMO) annual meeting, erdafitinib-treated patients with increased blood phosphorus levels had improved outcomes.

Under the leadership of Dr. Bishoy Faltas, an in-depth analysis of the nuanced molecular characteristics of upper-tract urothelial carcinoma (UTUC) – an aggressive cancer occurring in the lining of the ureter and kidney – supports that erdafitinib has potential to improve the effectiveness of immunotherapy in this patient population.

Whole-exome and RNA sequencing of UTUC patient tumors yielded a number of insights into the biology of the disease – chiefly that it has low immune cells (T cells) and high expression of FGFR3. The research team found that inhibiting FGFR3 with erdafitinib increased the activity of BST2, a gene associated with immune system activation. Thus, combining FGFR3 inhibitors such as erdafitinib with a class of immunotherapy drugs called PD-1/PD-L1 inhibitors can serve as a viable treatment strategy for UTUC in the future.

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“By inhibiting FGFR3, we are able to stimulate genes that are associated with activation of the anti-tumor immune response,” said Dr. Faltas. “In the future, we could potentially use this strategy to reverse the T-cell depletion in these tumors.”

Findings from Dr. Faltas et al. were published in Nature Communications.

Erdafitinib is under further investigation and development in an ongoing clinical trial at Weill Cornell Medicine and NewYork-Presbyterian.

A Phase 1b-2 Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Erdafitinib Plus JNJ-63723283, an Anti-PD-1 Monoclonal Antibody, in Subjects with Metastatic or Surgically Unresectable Urothelial Cancer with Selected FGFR Gene

We are proud to draw upon our longstanding expertise in the bladder cancer field to lead advancements in the understanding and care of this disease, and we hope that sharing our findings will prompt additional discoveries.

 

New Team Member: Dr. Cora Sternberg

We are very excited to welcome Cora Sternberg, MD, to the Genitourinary (GU) Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian Hospital.Sternberg Welcome_Facebook

Dr. Sternberg is a leading international researcher and world expert in the field of medical oncology, genitourinary (GU) cancers, and drug development. She is known for her influential work in developing novel therapies and targeted agents for the treatment of prostate, renal and bladder cancers.

In her new role, Dr. Sternberg will facilitate the continued growth and development of clinical and translational research programs in genitourinary (GU) malignancies. She will also serve as Clinical Director of the Englander Institute for Precision Medicine (EIPM), developing strategies to incorporate genomic sequencing and precision medicine throughout the Weill Cornell Medicine and NewYork-Presbyterian healthcare network, including Lower Manhattan, Brooklyn and Queens.

Visit Dr. Sternberg’s profile to learn more about her medical experience and accomplishments.

 

ESMO 2017: Day 2 Recap

IMG_3948The second day of ESMO included the oral genitourinary (GU) oncology session that focused on renal cell (kidney) and urothelial (bladder) carcinoma.

Several years ago, the SWITCH study evaluated the sequence of sunitinib and sorafenib showing similar overall progression free survival and overall survival regardless of the order by which each drug was utilized. At ESMO 2017, results of the SWITCH-II trial were presented. This study tested the sequence of pazopanib and sorafenib in patients with advanced RCC of any histology (i.e. clear cell or non-clear cell).  The study sought to enroll 544 patients, but stopped after 377 patients due to slow accrual. Only half of the patients remained on study and switched to their assigned drug after tumor growth on drug #1. Overall, while the study didn’t complete planned accrual, there was a trend for improved progression-free and overall survival for the pazopanib → sorafenib sequence.

Historically when most patients were treated with cytokines (IL-2 and interferon), two randomized trials by U.S. and European cooperative groups showed that in the setting of metastatic kidney disease, patients live longer by first removing the kidney mass and then treating with interferon rather than treating with interferon without removal of the kidney. Since the introduction of new therapies in late 2005 which have higher rates of tumor shrinkage and longer lifespans for patients, it is unknown if patients should still have their kidney tumor removed prior to drug therapy.

IMG_3954In the EORTC 30073 SURTIME trial, European investigators decided to try to assess whether tumors remained under control longer and patients lived longer if surgery was performed first or if patients initiated sunitinib for 3 cycles prior to cytoreductive nephrectomy. Because enrollment was slow, the study design was changed to assess the percent of patients that were free of tumor progression at 28 weeks. Ninety-nine patients were randomized to immediate versus delayed surgery, most with large kidney tumors and intermediate-risk cancer. Overall there was no difference in the percent with cancer progression at 28 weeks with either approach.  With the caveat of a small study, there were trends for longer survival and less surgical complications in those with delayed surgery. While the amended study is not able to prove that delayed surgery is the better approach, it gives comfort for those physicians/patients that the choice to initiate medical therapy and then re-evaluate for surgery is acceptable. We await the results of the larger CARMENA study that is testing surgery followed by drug versus drug alone (with no surgery) to see if removal of the primary kidney tumor is necessary.

Additionally, two early-phase studies of novel drug combinations of immunotherapy + targeted therapy were presented. In a phase I study led by the NCI, the safety of the combinations of cabozantinib/nivolumab and cabozantinib/nivolumab/ipilimumab were tested in patients with a number of different treatment-refractory tumor types, especially urothelial and other types of bladder cancers. Overall, both combinations were deemed to be safe and are moving forward in a phase III trial. However, many toxicities did occur and most patients needed to reduce the dose of at least one drug so these combinations should only be used in a clinical trial setting.

IMG_3958The phase II portion of a phase I/II study testing the combination of lenvatinib + pembrolizumab. The initial (phase 1) portion of the study presented at ESMO 2016 determined the safe dose in patients with different types of tumors (mostly RCC). This year, new results were presented with 22 additional patients added to the 8 previously treated on the phase I portion. Overall, there was an impressive tumor response rate of 63%, with 83% significant tumor shrinkage in those patients treated in the 1st line setting. This combination is also being tested in a phase III study for patients with advanced RCC which will soon be opening at Weill Cornell Medicine and NewYork-Presbyterian.

Missed our Day 1 Recap of ESMO 2017? Check it out here.