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Bladder Cancer: Strategies to Address Checkpoint Inhibitor Failure


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CHECKPOINT INHIBITORS have rapidly become the standard of care as second-line treatment, and in some patients first-line treatment, of advanced bladder cancer. However, the majority of patients do not respond and eventually experience disease progression; these patients will need subsequent therapy, and there are few data to guide the selection of therapy after checkpoint inhibitor failure.

Arjun V. Balar, MD

Arjun V. Balar, MD

Arjun V. Balar, MD, of the Genitourinary Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health, New York, discussed the emerging evidence on promising new drugs and novel combinations after failure of checkpoint inhibitors. He focused on agents with the most supportive evidence: antibody-drug conjugates (ie, enfortumab vedotin [ASG-22ME] and sacituzumab govitecan [IMMU-132]), molecularly targeted FGFR3 inhibitors erdafitinib and rogaratinib, and a novel immunotherapy combination with sitravatinib plus nivolumab (Opdivo).1

“Programmed cell death protein 1 (PD-1) pathway inhibitors have revolutionized bladder cancer management. A minority of patients respond, and options after disease progression on PD-1 inhibitors are a significant unmet need,” Dr. Balar told the audience at the 2018 Annual Chemotherapy Foundation Symposium.

“Cytotoxics still have a role in the treatment of metastatic urothelial cancer,” he reminded listeners.

Platinum-based combinations are the standard of care in the first-line treatment of metastatic urothelial cancer. Immunotherapy with pembrolizumab (Keytruda) or atezolizumab (Tecentriq) is also used in the first-line setting for programmed cell death ligand 1 (PD-L1)– positive patients and platinum-ineligible patients. Second-line immunotherapy with any of the five approved agents (pembrolizumab, atezolizumab, nivolumab, avelumab [Bavencio], or durvalumab [Imfinzi]) is the standard of care for metastatic urothelial cancer after disease progression on platinum-based chemotherapy.

“There is no standard of care for third-line treatment,” he said. “This population was created ‘overnight’ due to the rapid uptake of immunotherapy.”

Antibody-Drug Conjugates

TWO ANTIBODY-DRUG conjugates are being studied in the setting after checkpoint inhibitor failure: enfortumab vedotin and sacituzumab govitecan. Enfortumab vedotin consists of a humanized monoclonal antibody targeted to nectin-4, which is expressed in 93% of metastatic urothelial cancers, linked to the microtubule-disrupting agent monomethyl auristatin E, noted Dr. Balar.

“PD-1 pathway inhibitors have revolutionized bladder cancer management. A minority of patients respond, and options after disease progression on PD-1 inhibitors are a significant unmet need.”
— Arjun V. Balar, MD

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The EV-101 phase I dose-escalation trial, which included 112 patients with metastatic urothelial cancer, dosed with enfortumab vedotin at 1.25 mg/kg intravenously, the recommended phase II dose identified for further study.2

In the overall study population, the confirmed response rate was 40%, and the disease control rate was 71%. Confirmed response rates were similar in patients treated with or without prior checkpoint inhibitor: 40% and 43%, respectively, and 39% in patients with liver metastases. Disease control rates were 74%, 61%, and 61%, respectively. Among 46 responders, the median duration of response was 5.75 months.

“Responses were durable in some patients,” Dr. Balar reported. “Patients can remain on this ‘targeted’ cytotoxic therapy for many months.”

Adverse events to be aware of include cumulative neuropathy and rash. “Patients can develop peripheral neuropathy or even motor neuropathy over time,” he noted.

Based on these phase I data, enfortumab vedotin was granted Breakthrough Therapy status by the U.S. Food and Drug Administration for patients with metastatic urothelial cancer previously treated with a checkpoint inhibitor. Three additional studies are planned: EV-103 (phase I of enfortumab vedotin plus a checkpoint inhibitor); EV-201 (pivotal phase II in locally advanced or metastatic disease previously treated with a checkpoint inhibitor); and EV-301 (phase III of enfortumab vedotin vs chemotherapy in metastatic urothelial cancer previously treated with platinum-containing chemotherapy and a checkpoint inhibitor).

Sacituzumub govitecan targets Trop2 on cancer cells, which is highly expressed in metastatic urothelial cancer and metastatic triple-negative breast cancer, as well as other malignancies. This antibody-drug conjugate has SN-38 (the active metabolite of irinotecan) as the payload, requires premedication plus growth factor support for administration, and is associated with adverse events typical for irinotecan, such as gastrointestinal effects and myelosuppression.

A phase I study of sacituzumub govitecan showed response rates of 15% to 30% across solid tumors, including metastatic urothelial cancer, and the antibody-drug conjugate is furthest along in triple-negative breast cancer.3 Among 41 patients with metastatic urothelial cancer who had a median of 3 prior therapies, the response rate was 34%. Grade 3 diarrhea was reported in 7%, grade 3 neutropenia was reported in 25%, and grade 3 febrile neutropenia was reported in 5%.

Sacituzumub govitecan was granted Breakthrough Therapy status in 2016 for triple-negative breast cancer and is being studied in metastatic urothelial cancer. A phase II trial will open soon, with planned enrollment of 140 patients; cohort 1 will include third-line treatment of metastatic urothelial cancer; cohort 2 will include second-line treatment of patients who are ineligible for cisplatin and after checkpoint inhibitor therapy.

POTENTIAL AGENTS AFTER IMMUNOTHERAPY FAILURE IN BLADDER CANCER

  • Antibody-drug conjugates: enfortumab vedotin, sacituzumab govitecan
  • FGFR inhibitors: erdafitinib, rogaratinib
  • Small-molecule tyrosine kinase inhibitor plus checkpoint inhibitor: sitravatinib + nivolumab

FGFR3 Inhibitors

A PHASE II trial of erdafitinib is currently under way in FGFR3-mutated metastatic urothelial cancer. Among 99 patients treated so far, the response rate was 44% (majority were partial responses), with a median duration of response of 5.6 months.4 A phase III trial of erdafitinib is ongoing.

A phase I trial of rogaratinib is also underway in 51 patients with FGFR-overexpressing metastatic urothelial cancer. In evaluable patients, the objective response rate was 21% (7 of 12 patients without FGFR mutations). A phase III trial plans to enroll patients with and without FGFR mutations.

Combination Therapy With Small-Molecule and Checkpoint Inhibitors

A SMALL-MOLECULE inhibitor plus a checkpoint inhibitor is another promising approach, although the optimal combination has not been identified yet.

“The overriding concept is that small-molecule inhibitors will target immunosuppressive populations in the tumor microenvironment. Sitravatinib inhibits a number of targets and has promising activity in combination with checkpoint inhibitors in non–small cell lung cancer [NSCLC],” Dr. Balar explained. “Other small-molecule tyrosine kinase inhibitors may have similar properties and may be good partners for checkpoint inhibition,” he added.

On the heels of a promising phase II study in NSCLC, a phase II study is now recruiting patients with checkpoint inhibitor–refractory metastatic urothelial cancer for treatment with sitravatinib plus nivolumab.

“In theory, the combination addresses mechanisms of immune resistance. The biology has to be studied further,” Dr. Balar stated.

DISCLOSURE: Dr. Balar has received honoraria from Merck, AstraZeneca, Incyte, and Genentech/Roche; is a consultant/advisor to Pfizer/EMD Serono, Cerulean Pharma, AstraZeneca/MedImmune, Genentech/Roche, Incyte, and Merck; and has received institutional research funding from Seattle Genetics, AstraZeneca/MedImmune, Genentech/Roche, and Merck.

REFERENCES

1. Balar AV: What to do after checkpoint inhibitor failure: Emerging agents and combinations. 2018 Annual Chemotherapy Foundation Symposium. Presented November 7, 2018.

2. Rosenberg JE, Sridhar SS, Zhang J, et al: Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer. 2018 ASCO Annual Meeting. Abstract 4504. Presented June 3, 2018.

3. Tagawa ST, Faltas B, Lam E, et al: Sacituzumab govitecan (IMMU-132) for patients with pretreated metastatic urothelial cancer: Interim results. 2017 ESMO Congress. Abstract 858P. Presented September 10, 2017.

4. Siefker-Radtke AO, Necchi A, Park SH, et al: First results from the primary analysis of the phase 2 study of erdafitinib in patients with metastatic or unresectable urothelial carcinoma and FGFR alterations. 2018 ASCO Annual Meeting. Abstract 4503. Presented June 3, 2018.


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