2022 - Systemic Therapy for Bladder Cancer: Implications for the Urologist

Question 1

What types of systemic therapy are now included in the treatment of urothelial carcinoma?

Answer 1

In addition to standard chemotherapy, systemic therapy now includes immune checkpoint inhibition, FGFR tyrosine kinase inhibition, and antibody-drug conjugates (ADCs).

Question 2

How many CPIs are FDA approved for urothelial cancer, and what are their names?

Answer 2

There are 4 CPIs FDA approved for urothelial cancer: Atezolizumab, Avelumab, Nivolumab, and Pembrolizumab.

Question 3

What happened to Durvalumab’s approval for urothelial cancer?

Answer 3

Durvalumab was previously approved in the second-line (2L) setting, but approval was withdrawn when a phase III trial failed to meet the primary endpoint.

Question 4

What was the change in approval for Atezolizumab in urothelial cancer treatment?

Answer 4

The FDA withdrew Atezolizumab’s second-line (2L) indication after failing to meet superiority over chemotherapy, but it remains approved in the first-line (1L) setting for chemotherapy-ineligible patients.

Question 5

What is the standard first-line (1L) chemotherapy for metastatic or unresectable urothelial cancers?

Answer 5

Platinum-based chemotherapy, combined with gemcitabine and cisplatin or carboplatin. Accelerated methotrexate, vincristine, adriamycin, cisplatin is also a 1L choice.

Question 6

What is the role of pembrolizumab in BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC)?

Answer 6

Pembrolizumab, a PD-1 inhibitor, is FDA-approved for patients with BCG-unresponsive CIS-containing NMIBC, with complete response observed in 40% of patients.

Question 7

What are ADCs, and how might they be relevant to BCG-unresponsive bladder cancer in the future?

Answer 7

ADCs (Antibody-Drug Conjugates) target specific cancer cells, and studies suggest they may become a viable systemic option for patients with BCG-unresponsive bladder cancer.

Question 8

What is the main concern for patients with residual muscle invasive and/or lymph node-positive urothelial cancer after surgery?

Answer 8

The main concern is the high risk of recurrence, leading to the evaluation of adjuvant immunotherapy.

Question 9

What are the results of using nivolumab as adjuvant therapy, and is there a biomarker requirement?

Answer 9

Nivolumab has been FDA approved for a disease-free survival (DFS) rate of 22.9 months, compared to 13.7 months with placebo. There is no biomarker requirement, but a more profound effect was seen in patients with PD-L1+ tumors.

Question 10

What findings were discovered regarding atezolizumab in the postoperative setting?

Answer 10

Atezolizumab failed to meet its primary DFS endpoint but demonstrated significant improvement in overall survival in patients with detectable circulating tumor DNA (+ctDNA), leading to a follow-up trial.

Question 11

What is Avelumab, and how is it used in the context of urothelial cancer treatment?

Answer 11

Avelumab is a CPI tested and approved for maintenance therapy after achieving a clinical benefit following 1L platinum-based therapy. It’s administered IV every 2 weeks and has improved median overall survival.

Question 12

What were the results of the Javelin 100 trial for Avelumab in comparison to observation?

Answer 12

The Javelin 100 trial found that Avelumab maintenance led to improved median overall survival of 21.4 versus 14.3 months for observation.

Question 13

What precautions are needed when administering Avelumab, and why?

Answer 13

Avelumab carries an increased risk of infusion-related anaphylaxis. Patients are initially premedicated with Benadryl® and acetaminophen, and if no infusion-related events occur, subsequent treatments may be without premedication.

Question 14

What options are available for patients with disease progression on or after 1L chemotherapy or those who defer avelumab maintenance?

Answer 14

For patients with disease progression, CPI therapy, including pembrolizumab, nivolumab, and avelumab, is approved in the 2L (second-line) and beyond setting.

Question 15

How does pembrolizumab stand out among the CPI therapies for use in the 2L and beyond setting?

Answer 15

Pembrolizumab was associated with improved overall survival, better tolerance, and quality of life compared to chemotherapy. It carries level 1 evidence, indicating strong support for its effectiveness.

Question 16

What is next-generation sequencing, and what is it used for in the context of urothelial cancer?

Answer 16

Next-generation sequencing is a process where DNA is extracted from tissue samples to identify specific patterns like FGFR alterations. It helps in finding therapeutic options for patients with advanced urothelial cancer.

Question 17

How does the presence of FGFR alterations expand therapeutic options in urothelial cancer?

Answer 17

FGFR alterations are biomarker targets identified through sequencing. Their presence determines the candidacy for specific treatments like erdafitinib, an FDA-approved therapy for urothelial cancer.

Question 18

What is erdafitinib, and how is it used in treating urothelial cancer with FGFR3 alterations?

Answer 18

Erdafitinib is an oral FGFR1-4 tyrosine kinase inhibitor used to treat metastatic urothelial cancer with FGFR3 mutations or fusions. It received accelerated FDA approval in 2019 for patients who had undergone prior chemotherapy.

Question 19

: What were the results of the BLC2001 phase II clinical trial involving erdafitinib, and what are some unique toxicities of this class?

Answer 19

The BLC2001 trial showed a 40% objective response rate and 13.8-month median overall survival with erdafitinib. Toxicities include hyponatremia, stomatitis, weakness, hyperphosphatemia, and ocular toxicity.

Question 20

How does hyperphosphatemia relate to FGFR inhibition in urothelial cancer?

Answer 20

Hyperphosphatemia is a unique toxicity of FGFR inhibitors like erdafitinib. In the case of infigratinib, another FGFR inhibitor, hyperphosphatemia correlated with clinical benefit, possibly serving as a biomarker of response.

Question 21

What are ADCs, and how do they work in targeting cancer cells?

Answer 21

ADCs are Antibody-Drug Conjugates that include an antibody (targeting part), a cytotoxic moiety (destructive part), and a linker sequence. They bind to specific antigens on cancer cells, get inside the cells, and release a toxic substance to destroy them.

Question 22

What are the two FDA-approved ADCs for metastatic bladder cancer, and what do they target?

Answer 22

The two FDA-approved ADCs are Enfortumab Vedotin (targets Nectin-4) and Sacituzumab Govitecan (targets Trop-2). Both have shown positive results in clinical trials.

Question 23

What are some common side effects of ADCs like Enfortumab Vedotin and Sacituzumab Govitecan?

Answer 23

Common side effects include rash, fatigue, decreased neutrophil count or neutropenia for Enfortumab Vedotin, and neutropenia, leukopenia, anemia, and diarrhea for Sacituzumab Govitecan.

Question 24

What is the THOR trial, and what is its purpose?

Answer 24

The THOR trial is a study that aims to answer the sequence question in patients with FGFR3 alterations. It’s randomizing patients to different treatments to find the best order for using certain drugs like erdafinitib or pembrolizumab in the treatment of urothelial carcinoma.